New CD38 inhibitors

Abstract

The present disclosure provides compounds of Formula I, acceptable salts thereof, compositions comprising the same, and methods of using the same, including the use in treating diseases, disorders, and / or conditions mediated by the CD38 enzyme.

Description

Attorney Docket No.15768.0041-00304 NEW CD38 INHIBITORS

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 641,780, filed May 2, 2024; the contents of which are herein incorporated by reference in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to biochemistry, and medicine. More specifically, this disclosure relates to novel compounds, processes for their preparation, compositions thereof, and methods of treating diseases, disorders, and / or conditions by modulating the level of cellular NAD+ and related metabolites thereof through the inhibition of the CD38 enzyme. BACKGROUND

[0003] Nicotinamide Adenine Dinucleotide (NAD+) is a biochemical that is found in all cells performing its critical role in oxidoreductase reactions. NAD+ and its related pyridine nucleotides NADH, nicotinamide adenine dinucleotide phosphate (NADP+), and NADPH are recognized as major redox carriers in all organisms. These pyridine dinucleotides regulate the cytosolic and mitochondrial redox state and are key participants monitoring the metabolic status of the cell (Houtkooper et al. (2010) Endo. Rev.31(2):194-223); Koch-Nolte et al. (2009) Sci. Signal. 2(57); Houtkooper et al. (2012) J. Cell Biol.) 199(2):205-209).

[0004] In addition to its role as a cofactor for oxidoreductases, NAD+ is also a substrate for various enzymes, where it is consumed in the process of donating its adenosine diphosphate (ADP) ribose to acceptor molecules or in the process of hydrolysis or cyclization. The enzymes that are the major consumers of NAD+ are the ADP ribosyl transferases (i.e., poly(ADP-ribose) polymerase (PARP) and ADP-ribosyltransferase (ART) family of enzymes), the sirtuins (Sirt1- 7), and the ADP ribosyl cyclases / hydrolases (CD38 / CD157). These enzymes are involved in pathways that regulate Ca2+signaling, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. Thus, NAD+ and its phosphorylated relatives NADP and nicotine acid adenine dinucleotide phosphate (NAADP), both of which are derived from NAD+, also act as signaling molecules. NAD+ is also a component of the circadian cycle with daily oscillations that tie cellular metabolism to chromatin remodeling and gene transcription. It is known that exercise and caloric restriction elevate NAD+ levels while aging and obesity decrease cellular NAD+ levels.

[0005] Cellular NAD+ is produced by either the de novo synthesis pathway from tryptophan or - 1 -Attorney Docket No.15768.0041-00304 by the Preiss-Handler and / or the salvage synthesis pathways from precursors such as nicotinic acid (niacin), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononuscleotide (NMN), which are imported into the cells. The modulation of cellular NAD+ levels can be achieved by blocking the consumption of NAD+ by inhibiting enzymes that consume NAD+. CD38 is one of such NAD+ consuming enzymes and is reported to be the main cellular NAD+ consumer. Also known as ADP ribosyl cyclase, CD38 is a type II membrane- anchored enzyme. It efficiently catalyzes the breakdown of NAD+ to nicotinamide (NAM) and ADP ribose (ADPR) and hydrolyzes NAADP to ADPR phosphate (ADPRP). CD38 acts as a cyclase converting NAD+ to cyclic ADPR (cADPR). Finally, ADPR is also a breakdown product of cADPR hydrolysis mediated by CD38.

[0006] ADP ribose (ADPR) and cyclic ADPR (cADPR) are metabolites of NAD+ generated by CD38-mediated hydrolysis or cyclization and they play a key role as intracellular Ca2+mobilizing second messengers. cADPR is mainly involved stimulating Ca2+release from the endoplasmic reticulum via ryanodine receptors, whereas ADPR activates the plasma membrane cation channel TRPM2 (Transient receptor potential melastatin 2) facilitating calcium entry into the cells. Aberrant TRPM2 activation has been shown to induce abnormal intracellular Ca2+accumulation and cell death in a variety of cell types, including neurons, and is implicated in several neurological disorders. In particular, the activation of TRPM2 has been linked to diseases such as ischemia-reperfusion injury, bipolar disorder, Alzheimer’s disease, neuropathic pain, and Parkinson's disease.

[0007] Nicotinamide (NAM) is a precursor for NAD+ and is a key molecule involved in energy metabolism. NAM is converted into nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). Alternatively, NAM can be irreversibly methylated by Nicotinamide N-methyltransferase (NNMT) enzyme and excreted from the body. The methylated form of NAM (i.e., N1-methylnicotinamide (MNAM)) has been shown to be associated with coronary artery disease (CAD), obesity, type-2 diabetes, hepatotoxicity, Parkinson’s disease, and cancers.

[0008] Although NAM supplementation has shown positive effects, high levels of NAM can exert negative effects through multiple routes, including inhibition of PARPs and sirtuins and alteration of methyl metabolism. NAM supplementation has been shown to cause a significant decrease of insulin sensitivity in human subjects, neurotoxicity and hepatotoxicity.

[0009] Accordingly, there is still a need for novel inhibitors of CD38 and treatments of diseases, disorders, and / or conditions that benefit from the modulation of the level of cellular NAD+ and related metabolites thereof and / or wherein CD38 is upregulated. - 2 -Attorney Docket No.15768.0041-00304 SUMMARY

[0010] In an aspect, the present disclosure provides compounds, processes for their preparation, compositions thereof, and methods of treating diseases, disorders, and / or conditions by, for example, modulating the level of cellular NAD+ and related metabolites thereof through the inhibition of the CD38 enzyme.

[0010] An aspect of the disclosure pertains to a compound of Formula I: I), an acceptable salt of the omer of the compound of FormulaI, or an acceptable salt of the tautomer of the compound of Formula I, wherein: n is 0 or 1; RNis selected from H and C1-C6 alkyl; Ring A is selected from C6-C10aryl, C3-C10cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic, wherein 0 to 4 atoms of the 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10fused bicyclic are independently O, S, N, or NRA, and wherein the C6-C10 aryl, C3-C10 cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10fused bicyclic are each optionally substituted with one or more RA; each RAis independently selected from H, -CN, halo, optionally substituted C1-C6alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -SRA1, -S(O)2NRA2RA3, -S(O)2RA1, -S(O)RA1, -NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, and optionally substituted 5-6 membered heteroaryl; wherein the optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, and optionally substituted 5-6 membered heteroaryl are each independently optionally substituted with one to three substituents selected from C1-C6 alkyl, oxo, and halogen; wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6 fluoroalkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 - 3 -Attorney Docket No.15768.0041-00304 alkoxy, optionally substituted 5-9 membered heterocycloalkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; each RA2and RA3is independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; Ring B is selected from nd each RBis independent alkyl.

[0011] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of , ,- 4 -Attorney Docket No.15768.0041-00304 , ,, tautomers thereof, and acceptable salts of any of the foregoing.nts, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I are selected from any one of the compounds shown in Table 1, tautomers thereof, and acceptable salts of these compounds and tautomers.

[0013] In some embodiments, the present disclosure provides compositions comprising a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, and an acceptable carrier. In some embodiments, the compositions may comprise a compound, tautomer, or acceptable salt selected from any one of the compounds shown in Table 1, tautomers thereof, and acceptable salts of these compounds and tautomers. These compositions may further comprise an additional active pharmaceutical agent.

[0014] Another aspect of the present disclosure provides methods of treating a disease, a disorder, or a condition mediated by the modulation of the CD38 protein in a subject, comprising administering an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, or a composition comprising any of the foregoing. In some embodiments, the methods of treatment comprise administering to a subject an effective amount, e.g., a therapeutically effective amount of a compound, tautomer, or acceptable salt selected any one of the compounds shown in Table 1, tautomers thereof, and acceptable salts of any of the foregoing, or a composition comprising any of the foregoing. - 5 -Attorney Docket No.15768.0041-00304

[0015] In some embodiments disclosed herein, methods of treatment comprise administration of an additional active pharmaceutical agent to the subject in need thereof, either in the same composition as a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, or a composition comprising any of the foregoing, or in a separate composition. In some embodiments disclosed herein, methods of treatment comprise administering a compound, tautomer, or acceptable salt selected from any one of the compounds shown in Table 1, tautomers thereof, and acceptable salts of any of the foregoing with one or more additional active pharmaceutical agent(s) either in the same composition or in a separate composition.

[0016] Also disclosed herein are methods of modulating CD38 protein activity comprising administering to a subject an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, or a composition comprising any of the foregoing. In some embodiments disclosed herein, the methods of modulating a CD38 protein comprise administering to a subject a compound selected from any one of the compounds shown in Table 1, tautomers thereof and acceptable salts of any of the foregoing, or a composition comprising any of the foregoing.

[0017] The disclosure also provides a composition comprising an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, including any compound recited herein, and an acceptable carrier. In some embodiments, the formulation comprises an effective amount, e.g., a therapeutically effective amount of at least one additional medicinal or pharmaceutical agent. In some embodiments, this additional agent is a therapeutically effect amount of an anti-aging agent. In some embodiments, this additional agent is a therapeutically effect amount of an anti-rheumatoid arthritis agent.

[0018] In some embodiments, the disclosure provides a method of treating a disease, disorder, condition, or medical disorder in a subject suffering therefrom and which benefits from modulation of level(s) of NAD+ and / or related metabolites thereof comprising administering to the subject a formulation in an amount effective to modulate the level(s) of NAD+ and / or related metabolites thereof, the formulation comprising an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, including any compound recited herein, and an acceptable carrier, and optionally comprising - 6 -Attorney Docket No.15768.0041-00304 administering another agent which modulates the level(s) of NAD+ and / or related metabolites thereof.

[0019] In some embodiments, the disease, disorder, or disorder is or is related to nonalcoholic steatohepatitis, aging, aging chronical condition, senescence, immunometabolism, sepsis, inflammation, infection, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, lupus, lupus erythematosus, Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, fibrosis, hepatic fibrosis, renal fibrosis, pulmonary fibrosis, cardiac fibrosis, cancer, multiple myeloma, cardiovascular disorder, neurological disorder, infertility, loss of ovarian follicles, decreased oocyte quality and quantity, ovarian senescence, transient receptor potential melastatin 2 (TRPM2) regulation, calcium flux regulation, ischemia-reperfusion-injury, bipolar disorder, Alzheimer’s disease, neuropathic pain, Parkinson’s disease, coronary arteries, obesity, type-2 diabetes, hepatotoxicity, pulmonary disorder, metabolic disorder, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, a liver disorder, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, diseases of the skin, damage caused by exposure to radiation, periodontal disease, Leber’s hereditary amaurosis, a sleep disorder, exercise intolerance, chronic disease associated with cell death, neurodegeneration, peripheral neuropathy associated with chemotherapy, or the like. In some embodiments, the disease, disorder, or condition is or is related to nonalcoholic steatohepatitis or the like. In some embodiments, the disease, disorder, or condition is or is related to an age-related disease, disorder, condition, or the like. In some embodiments, the disease, disorder, or condition is or is related to a fibrotic disease of the digestive system, lung, heart, kidney, liver, lung, or the like. In some embodiments, the fibrotic disease is a fibrotic disease of the liver, such as diabetic nephropathy or chronic kidney disease. In some embodiments, the disease, disorder, or condition is or is related to multiple myeloma or the like, and the method further comprises administering an immuno-oncology drug to the subject in need thereof.

[0020] In some embodiments, the disclosure provides the use of a formulation comprising a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, including any compound recited herein, to treat a disease, disorder, or condition in a subject that benefits from modulation of the level(s) of NAD+ and / or related metabolites thereof. In some embodiments, the formulation comprising a compound of Formula I, a tautomer of a compound of Formula I, - 7 -Attorney Docket No.15768.0041-00304 an acceptable salt of a compound of Formula I, and / or an acceptable salt of the tautomer of Formula I, including any compound recited herein, is used to treat a disease, disorder, or condition in a subject that benefits from the subject benefiting from inhibition of CD38. In some embodiments, the disease, disorder, or condition is or is related to aging or the like.

[0021] In some embodiments, a formulation is used to treat a disease, disorder, or condition selected from small lung cell carcinoma, renal clear cell carcinoma, chronic lymphocytic leukemia, multiple myeloma, hypertension, hypoxic pulmonary vasoconstriction, cardiac hypertrophy, congestive heart failure, stroke, Alzheimer's disease, bipolar disorder, schizophrenia, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, optic neuropathy, epilepsy, idiopathic pulmonary fibrosis, viral-induced fibrosis of the lung, infection-induced fibrosis of the lung, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity, sarcopenic obesity, sarcopenia, dyslipidemia, diabetes (such as type I diabetes), diabetic neuropathy, insulin resistance, pancreatitis, acute lung injury (ALI) acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, steatosis, non- alcoholic steatohepatitis (NASH), postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin hyperpigmentation, UV skin damage, psoriasis, X-ray-induced DNA damage, periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, neurodegeneration, a peripheral neuropathy associated with chemotherapy, a mitochondrial myopathy, and a disease, disorder, or conditionmodulated by TNF- and / or IL-6.

[0022] In some embodiments, the formulation is used to treat a disease, disorder, or condition selected from aging, age-related chronic disease, inflammation, cancer, cardiovascular disorder, neurological disorder, pulmonary disorder, fibrotic diseases, SARS, COVID-19, metabolic disorder, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, a liver disorder, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, diseases of the skin, damage caused by exposure to radiation, periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, and a chronic disease associated with cell death.

[0023] In some embodiments, the use for treatment is for multiple myeloma, and the treatment further comprises treatment of the subject with an immuno-oncology drug. In some - 8 -Attorney Docket No.15768.0041-00304 embodiments, the use is treatment of nonalcoholic steatohepatitis (NASH), and in an embodiment, the treatment of NASH is with the use of 2-(1H-imidazol-1-yl)-6-methoxy-N-(2- (trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] For the purpose of illustrating the present disclosure, the appended drawings illustrate some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown.

[0025] FIG. 1 and FIG.2 depict in vivo efficacy of acute oral administration of I-7 (15 mg / kg) against CD38 in mice as measured by liver NAD+ (FIG.1A), NAM (FIG.1B), ADPR (FIG.1C) levels and by spleen NAD+ (FIG. 2A), NAM (FIG.2B), ADPR (FIG.2C) levels. The time- response plot represents the average (+ / -) standard deviation for the measurement of I-7 plasma free concentration (black circle) and NAD+ metabolites (white bars for vehicle and black bars for treated group) where n = 3 over 1 experiment. *, p 0.05; **, p 0.01; ***, p 0.001; ****, p < 0.0001 compared with Vehicle sample, one-way ANOVA.

[0026] FIG. 1A depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver NAD+ levels.

[0027] FIG. 1B depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver NAM levels.

[0028] FIG. 1C depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver ADPR levels.

[0029] FIG. 2A depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen NAD+ levels.

[0030] FIG. 2B depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen NAM levels.

[0031] FIG. 2C depicts in vivo efficacy of acute oral administration of 15 mg / kg of Compound I- 7 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen ADPR levels.

[0032] FIG. 3 and FIG.4 depict in vivo efficacy of acute oral administration of Compound I-16 - 9 -Attorney Docket No.15768.0041-00304 (30 mg / kg) against CD38 in mice as measured by liver NAD+ (FIG.3A), NAM (FIG. 3B), ADPR (FIG.3C) levels and by spleen NAD+ (FIG.4A), NAM (FIG.4B), ADPR (FIG.4C) levels. The time-response plot represents the average (+ / -) standard deviation for the measurement of I-16 plasma free concentration (black circle) and NAD+ metabolites (white bars for vehicle and black bars for treated group) where n = 3 over 1 experiment. *, p 0.05; **, p 0.01; ***, p 0.001; ****, p < 0.0001 compared with Vehicle sample, one-way ANOVA.

[0033] FIG. 3A depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver NAD+ levels.

[0034] FIG. 3B depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver NAM levels.

[0035] FIG. 3C depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and liver ADPR levels.

[0036] FIG. 4A depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen NAD+ levels.

[0037] FIG. 4B depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen NAM levels.

[0038] FIG. 4C depicts in vivo efficacy of acute oral administration of 30 mg / kg of Compound I- 16 of the present disclosure against CD38 in mice as measured by unbound plasma exposure and spleen ADPR levels. DETAILED DESCRIPTION Definitions

[0039] The disclosures of patents, patent applications, and publications referred to herein are hereby incorporated by reference in their entireties into this application. The instant disclosure will govern in the instance that there is any inconsistency between the patents, patent applications, and publications and this disclosure.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The initial definition provided for a group or term herein applies to that group or term - 10 -Attorney Docket No.15768.0041-00304 throughout the present specification individually or as part of another group, unless otherwise indicated.

[0041] As used herein, the singular forms "a," "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compound.

[0042] As used herein, the term "optional" or "optionally" means that the subsequently described event, circumstance, or substituent may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0043] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0044] As used herein, the term "about" or "approximately" when used in reference to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass art-accepted variations of and from the specified value, such as variations of + / -10% or less, + / -5% or less, + / -1% or less, + / -0.5% or less, and + / -0.1% or less of and from the specified value, insofar as such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" or "approximately" refers is itself also specifically, and preferably, disclosed.

[0045] As used herein, the term "alkyl" means saturated aliphatic hydrocarbons, including linear chains and branched chains. For example, as used herein, the term "C1-C6alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., (C1-C6)alkoxy), means linear or branched radicals of 1, 2, 3, 4, 5, or 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, secondary-butyl, tertiary-butyl), optionally substituted by 1, 2, 3, 4, or 5 suitable substituents.

[0046] As used herein, the terms “cycloalkyl” and “cyclic alkyl” mean saturated or unsaturated (non-aromatic) monocyclic or bicyclic hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl); optionally substituted by 1, 2, 3, 4, and 5 suitable substituents, such as, but not limited to, H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3. The cycloalkyl group may have 3 to 10 carbon atoms in the ring(s), such as 3 to 9 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3, 4, 6, 7, 8, 9, or 10 carbon atoms. For example, a monocyclic cycloalkyl group may have 3 to 6 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms in the ring, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl. In some embodiments, the cycloalkyl may optionally contain one, two or more non- cumulative non-aromatic double or triple bonds. - 11 -Attorney Docket No.15768.0041-00304

[0047] The term “carbocyclyl” means the term “cycloalkyl” and refers to a monocyclic C3-C10hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C7-C10 hydrocarbon that is completely saturated, or is partially saturated as it contains one or more units of unsaturation but is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 9 members. In some embodiments, the fused bicyclic ring system has 4 to 9 members. Bicyclic carbocyclyls include combinations of a monocyclic carbocyclic ring fused to, for example, a phenyl. In some embodiments, carbocyclyl groups are substituted. In some embodiments, carbocyclyl groups are unsubstituted. In some embodiments, the carbocyclyl is a C3to C10carbocyclyl. In some embodiments, the carbocyclyl is a C3 to C9 carbocyclyl. In some embodiments, the carbocyclyl is a C3to C8carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc.

[0048] As used herein, the term “alkylene” means a divalent alkyl radical. Representative examples of C1-C10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n- heptylene, n-octylene, n-nonylene and n-decylene.

[0049] The term “alkenyl” as used herein, means a linear, branched, or cyclic, substituted or unsubstituted hydrocarbon chain containing one or more double bonds.

[0050] The term “alkynyl” as used herein, means a linear, branched, or cyclic, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon triple bonds. The point of attachment can be on a saturated carbon or unsaturated carbon. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1- butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0051] As used herein, the term “heterocycloalkyl” means a monocyclic, bridged, polycyclic or fused polycyclic saturated or unsaturated non-aromatic 3- to 14- membered ring including 1 or more heteroatoms selected from O, S, N, and NR, such as a 3 to 10 membered ring, or a 3 to 6 membered ring, or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered ring. Examples of such heterocycloalkyl rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Further nonlimiting examples of heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, - 12 -Attorney Docket No.15768.0041-00304 imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl, and the like. The heterocycloalkyl ring is optionally substituted by 1 to 5 suitable substituents such as, but not limited to, H, halo, -CN, -(C1-C3)alkyl, -NH2, (C1-C3)alkyl- (NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3, and -OCF3. In some embodiments, R, as used herein, means a substituent such as, but not limited to, H, C1-C6linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6 linear, branched, or cyclic alkyl).

[0052] As used herein, the term "aryl" means all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. In some embodiments, an aryl group has 6 to 14, 6 to 10, or 6, 8, 9, 10, 11, 12, 13, or 14 carbon atoms in the ring(s). One nonlimiting, exemplary aryl group is a 6-carbon atom phenyl ring. In some embodiments, an aryl group is optionally substituted by 1 to 5 suitable substituents, such as 1 to 3 substituents, such as, but not limited to, H, halo, -CN, (C1-C3)alkyl, - NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3.

[0053] As used herein, the term “heteroaryl” means a monocyclic or fused-ring polycyclic aromatic heterocyclic group with one or more heteroatoms selected from O, S, and N in the ring. In some embodiments, a heteroaryl group has 5- to 14- ring atoms including one to 4 heteroatoms selected from O, S, N, and NR, such as 5- to 14-ring atoms, 5- to 8-ring atoms, or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-ring atoms. For example, as used herein, the term heteroaryl encompasses aromatic radicals containing at least one ring heteroatom selected from O, S and N and from 1 to 13 carbon atoms, such as from 2 to 9 carbon atoms, from 3 to 8 carbon atoms, or from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms, such as, but not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3- oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like. In some embodiments, a heteroaryl group is optionally substituted by 1 to 5 suitable substituents, such as, but not limited to, H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3. In some embodiments, R, as used herein, means a substituent such as, but not limited to, H, C1-C6 linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6 linear, branched, or cyclic alkyl).

[0054] The term “unsaturated”, as used herein, means that a moiety has one or more units or - 13 -Attorney Docket No.15768.0041-00304 degrees of unsaturation. Unsaturation is the state in which not all of the available valence bonds in a compound are satisfied by substituents and thus the compound contains double or triple bonds.

[0055] The term “alkoxy” as used herein, refers to an -O-alkyl group, wherein alkyl is as defined above. As used herein, the term “alkoxy” encompasses, but is not limited to, -O-(C1-C5 alkyl), and -O-(C2alkyl). In some embodiments, an alkoxy group is optionally substituted by one or more alkoxy groups. Examples of an alkoxy group that is substituted by one or more alkoxy groups include, but are not limited to, -O-(C1-C3alkyl)-O-CH3and -O-(C1-C2alkyl)-O-(C1-C2alkyl).

[0056] An "alkylaminoalkyl" group means an -alkyl-NR-alkyl group. In some embodiments, R, as used herein, means a substituent such as, but not limited to, H, C1-C6 linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6linear, branched, or cyclic alkyl).

[0057] An "amino" group means an -NH2 or an NRR'group-. In some embodiments, R and R’, as used herein, independently mean a substituent such as, but not limited to, H, C1-C6linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6 linear, branched, or cyclic alkyl).

[0058] An "aminoalkyl" group means an –alkyl-NRR' group. In some embodiments, R and R’, as used herein, independently mean a substituent such as, but not limited to, H, a C1-C6 linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and a SO2(C1-C6linear, branched, or cyclic alkyl).

[0059] An “aminocarbonyl” means a –C(O)NRR’ group. In some embodiments, R and R’, as used herein, independently mean a substituent such as, but not limited to, a C1-C6 linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and a SO2(C1-C6linear, branched, or cyclic alkyl).

[0060] An "arylalkyl" group means -alkylaryl, where alkyl and aryl are defined herein.

[0061] An "aryloxy" group means both an –O-aryl and an –O-heteroaryl group, as defined herein.

[0062] A "carbonyl" group means a –(C=O) group.

[0063] A "carboxylic acid" group means a –(C=O)OH group.

[0064] A "cyano" group means a -CN group. As used herein, a “cyano” or “nitrile” group referto -C N.

[0065] The term "halo" or “halogen” means F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0066] As used herein, the term “haloalkyl group” means an alkyl group substituted with one or - 14 -Attorney Docket No.15768.0041-00304 more halogen atoms.

[0067] A "dialkylamino" group means an –N(alkyl)2 or NR2 group. In some embodiments, R, as used herein, means a substituent such as, but not limited to, H, C1-C6linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6 linear, branched, or cyclic alkyl).

[0068] A "hydroxy" group means an –OH group.

[0069] As used herein, the term "hydroxyalkyl" means an alkyl group, as previously defined, wherein one or more of the hydrogen atoms have been replaced by a hydroxy (-OH) group.

[0070] As used herein, the term "thioalkyl" means an alkyl group, as previously defined, wherein at least one carbon of the alkyl group is replaced by a sulfur atom, provided that the sulfur atom is linked between two carbon atoms.

[0071] As used herein, the term "alkylthiol" means an alkyl group, as previously defined, wherein one or more of the hydrogen atoms have been replaced by a thiol (-SH) group.

[0072] An "N-amido" group means a –R'(C=O)NR group. In some embodiments, R, as used herein, means a substituent se such as, but not limited to, H, C1-C6linear, branched, or cyclic alkyl wherein 0-2 atoms are independently O, and SO2(C1-C6 linear, branched, or cyclic alkyl).

[0073] A "fluoroalkyl group" means an alkyl group, as previously defined, wherein one or more of the hydrogen atoms have been replaced with fluorine atoms.

[0074] A "fluoroalkoxy group" means an fluoroalkyl group, as previously defined, wherein one or more of the carbon atoms have been replaced with oxygen atoms.

[0075] As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”

[0076] In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described herein in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0077] As used herein, a substituent that is depicted as being attached to a ring without denoting a specific attachment point (i.e., an atom within that ring) may replace any hydrogen of that ring. - 15 -Attorney Docket No.15768.0041-00304 For instance, in the chemical formul , the RBsubstituent may replace any of thehydrogens on the imidazolyl group, leading to any of the following structur ,. urated," as used herein, means that a moiety has one or more units ofunsaturation but is not aromatic.

[0079] The term “adjacent” as used herein refers to positions on the ring wherein the two ring atoms are bonded to each other. Two ring atoms with an intervening ring atom are not considered adjacent even when that intervening atom does not allow substitution due to valency.

[0080] The phrase "up to," as used herein, refers to zero or any integer number that is equal or less than the number following the phrase. For example, "up to 3" means any one of 0, 1, 2, and 3. 0081] The term “tautomer,” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom, e.g., a hydrogen atom, a proton, or group within the molecule. As the term “tautomer” refers to a subgroup of compounds, all definitions of a “compound” provided herein are, in principal, also applicable to tautomers.

[0082] As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0083] As used herein, the term "composition" refers to a product comprising a particular ingredient in a particular amount and any product directly or indirectly brought about by the combination of particular ingredients in particular amounts. In some embodiments, a composition comprises an active ingredient and an inactive ingredient. In some embodiments, the composition - 16 -Attorney Docket No.15768.0041-00304 is a formulation. In some embodiments, the formulation is a composition that is suitable for administration to and / or consumption by a subject, such as a human. A composition may be a pharmaceutical composition, and a formulation may be a pharmaceutical formulation.

[0084] In some embodiments, the pharmaceutical composition or pharmaceutical formulation comprises a combination of an active agent with an acceptable carrier, diluent, excipient, solubilizing agent, or vehicle, inert or active.

[0085] In some embodiments, a formulation of the disclosure is in the form of a beverage or a food product. In some embodiments, the beverage or food product is formulated for general consumption, such as by being food grade. In some embodiments, the beverage or food product is formulated as a dietary supplement or other nutritional composition. In some embodiments, the beverage or food product is pharmaceutical grade. For the avoidance of doubt, it is to be understood that, in some embodiments, a formulation of the disclosure may be suitable for consumption by a subject, such as a human, but not necessarily be of pharmaceutical grade (for example, by being of food grade or nutritional supplement grade, but not necessarily pharmaceutical grade).

[0086] In some embodiments, the formulation may contain one or more of a solubilizing agent, an emulsifier, a stabilizer, a dispersal agent, an anti-foaming agent, or a diluent. The formulation may additionally contain one or more antioxidant compounds. It is anticipated that any antioxidants suitable for oral administration, such as vitamin A, vitamin E, vitamin C, retinal, tocopherol, L-ascorbyl palmitate, riboflavin and carotenoids, including lutein, beta-carotene, zeaxanthin, and lycopene, and combinations thereof, may be formulated into an embodiment described herein. In some embodiments, the composition is naturally unreactive to oxidation and does not require the addition of antioxidant compounds.

[0087] Disclosed herein are acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0088] As used herein, the term "acceptable" as applied to a salt, carrier, diluent, excipient, solubilizing agent, or vehicle means that the salt, carrier, diluent, excipient, solubilizing agent, or vehicle is compatible with the compounds of the disclosure and with other components of a composition and is non-toxic to a subject. Thus, an “acceptable salt” is a non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp.1-19. In some embodiments, the “acceptable” salt, carrier, diluent, excipient, solubilizing agent, or vehicle is a “pharmaceutically acceptable” - 17 -Attorney Docket No.15768.0041-00304 salt, carrier, diluent, excipient, solubilizing agent, or vehicle.

[0089] As used herein, the term “pharmaceutically acceptable” means that a salt, carrier, diluent, excipient, solubilizing agent, or vehicle is appropriate for administration to and / or consumption by a subject, such as a human, and is approved by the U.S. Food and Drug Administration and / or the European Medicines Agency for such administration and / or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. As used herein, the term “pharmaceutical composition” refers to a pharmaceutically acceptable composition, which is, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0090] Acids commonly employed to form acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, - hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0091] Acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-C4alkyl)4salts. The present disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, - 18 -Attorney Docket No.15768.0041-00304 carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of acceptable salts include besylate and glucosamine salts.

[0092] The term “excipient” means any ingredient other than the compound(s) according to the disclosure. The choice of excipient depends to a large extent depend on factors such as, but not limited to, the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0093] The term “subject” means an animal, including but not limited to, a human.

[0094] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. In some embodiments, “effective amount” means “therapeutically effective amount.”

[0095] The term “therapeutically effective amount” means that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in symptoms of diseases, disorders, and / or conditions mediated by the modulation of CD38, lessening the severity of diseases, disorders, and / or conditions mediated by the modulation of CD38 and / or of one or more symptoms thereof, and / or reducing progression of diseases, disorders, and conditions mediated by the modulation of CD38 and / or one or more symptoms thereof). The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0096] As used herein, the term “treatment” and its cognates refer to slowing or stopping progression of a disease, disorder, or condition. “Treatment” and its cognates as used herein include but are not limited to the following: complete or partial remission, lower risk of diseases, disorders, and conditions mediated by the modulation of CD38, and related complications. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0097] As used herein, the term “in combination with” when referring to two or more compounds or agents means that the order of administration includes the compounds or agents being administered to a subject or a patient prior to, concurrent with, or subsequent to each other.

[0098] The compounds of Formula I, may have asymmetric carbon atoms and may exist as two or more stereoisomers. The carbon-carbon bonds of the compounds of the present disclosure maybe depicted herein using a solid line ( ), a solid wedge ( ), or a dotted wedge ( ). Theuse of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all - 19 -Attorney Docket No.15768.0041-00304 possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of Formula I may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

[0099] Stereoisomers of Formula I include cis- and trans- isomers, optical isomers such as (R)- and (S)- enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of Formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Compounds and Compositions

[0100] This disclosure pertains to a compound of Formula I: I), an acceptable salt of theomer of the compound of Formula I, or an acceptable salt of the tautomer of the compound of Formula I, wherein: n is 0 or 1; RNis selected from H and C1-C6alkyl; Ring A is selected from C6-C10 aryl, C3-C10 cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic, wherein 0 to 4 atoms of the 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic are independently O, S, N, or NRA, and wherein the C6-C10aryl, C3-C10cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic are each optionally substituted with one or more RA; - 20 -Attorney Docket No.15768.0041-00304 each RAis independently selected from H, -CN, halo, optionally substituted C1-C6alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -SRA1, -S(O)2NRA2RA3, -S(O)2RA1, -S(O)RA1, -NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, and optionally substituted 5-6 membered heteroaryl; wherein the optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 5-6 membered heteroaryl are each independently optionally substituted with one to three substituents selected from C1-C6alkyl, oxo, and halogen; wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6 fluoroalkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted 5-9 membered heterocycloalkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; each RA2and RA3is independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6 alkoxy; Ring B is selected from nd each RBis independentalkyl.

[0101] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not selected from: ,- 21 -Attorney Docket No.15768.0041-00304 ,

[0102] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-i: i), an acceptable salt of the co, a tautomer of the compound of Formula E-i, or an acceptable salt of the tautomer of the compound of Formula E-i, wherein: - 22 -Attorney Docket No.15768.0041-00304 , C1-C6alkyl)2N-, HOC(O)-, (C1-C3 alkyl)(O)(C=O)-, (C1-C3 alkyl)-O-(C1-C3 alkyl)-NH-, HO-(C1-C3 alkyl)-N(C1-C3alkyl)-, (C1-C3alkyl)O(C1-C3alkyl)-N(C1-C3alkyl)-, (C1-C3alkyl)-(C=O)-NH-, (C1-C3alkyl)-(C=O)-N(C1-C3alkyl)-, H2N-(C=O)-, and (C1-C3alkyl)2N-(C=O)-; B1 is selected from ndR1bis selected fro

[0103] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-ii: (E-ii), an acceptable salt of tha tautomer of the compound of Formula E-ii, or an acceptable salt of the tautomer of the compound of Formula E-ii, wherein: Ring A2is selected from 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, C6cycloalkyl, and C7-C10cycloalkyl, wherein the 4-8 membered heterocycloalkyl, C3-C5cycloalkyl, and C7-C10 cycloalkyl are each optionally substituted with R2aor wherein the C6cycloalkyl is substituted with R2a; each R2ais independently selected from -CN, halo, optionally substituted C1-C6 alkyl, C1- C6haloalkyl, C1-C6cyanoalkyl, -OR21a, -SR21a, -S(O)2NR22aR23a, -S(O)2R21a, -S(O)R21a, -NR21aR23a, -C(O)R21a, -C(O)OR21a, -C(O)NR22aR23a, and 5-8 membered heterocycloalkyl; wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or 5-6 membered heteroaryl; each R21ais independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy; and - 23 -Attorney Docket No.15768.0041-00304 each R22aand R23ais independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy.

[0104] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-II’: ’), an acceptable salt of th automer of the compound ofFormula E-ii’, or an acceptable salt of the tautomer of the compound of Formula E-ii’, wherein: Ring A2is selected from 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, C6cycloalkyl, and C7-C10cycloalkyl, each of which is independently substituted with at least one group selected from -S(O)2R2A1, -S(O)R2A1, and -S(O)2NR2A1R2A2; wherein the 4-8 membered heterocycloalkyl, C3-C5cycloalkyl, C6cycloalkyl, and C7-C10 cycloalkyl are each optionally substituted with one or more R2a; R2ais independently selected from halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, -OR2A1, -SR2A1, -S(O)2NR2A1R2A2, -S(O)2R2A1, -S(O)R2A1, -NR2A1R2A2, -C(O)R2A1, - C(O)OR2A1, -C(O)NR2A1R2A2, and 4-8 membered heterocycloalkyl; each R2A1and R2A2is independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; Ring B2is selected from nd each R3bis independentalkyl.

[0105] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-iii: (E-iii), an acceptable salt, utomer of the compound of Formula E-iii, or an acceptable salt of the tautomer of the compound of Formula E-iii, wherein: - 24 -Attorney Docket No.15768.0041-00304 L is selected from a bond and CH2; R31ais independently selected from H and methyl; R32ais independently selected from H and C1-C4alkyl; R31aand R32atogether with the nitrogen atom to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may optionally be substituted with fluoro; nd alkyl.

[0106] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-iv: v), an acceptable salt of thetautomer of the compound of Formula E-iv, or an acceptable salt of the tautomer of the compound of Formula E-iv, wherein: Ring A4is selected from C4-C9cycloalkyl, phenyl, pyridinyl, and 4-9 membered heterocycloalkyl; wherein the C4-C9cycloalkyl is optionally substituted with -OH, halo, C1-C6alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy optionally substituted with C1-C6alkoxy, C(O)OC1-C6alkyl, and pyridinyl; wherein the phenyl is optionally substituted with one or more halo; wherein the 4-9 membered heterocycloalkyl is optionally substituted with halo, C1-C6 alkyl, C(O)OC1-C6 alkyl, and C(O)C1-C6 alkyl; and wherein the pyridinyl is optionally substituted with halo or C1-C6 alkyl; nd6 alkyl.

[0107] In some embodiments, a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a compound of Formula I, and an acceptable salt of the tautomer of Formula I is not a compound of Formula E-v: - 25 -Attorney Docket No.15768.0041-00304 v), an acceptable salt o mer of the compound of Formula E-v, or an acceptable salt of the tautomer of the compound of Formula E-v, wherein: Ring A5is selected C3-C7 cycloalkyl, wherein the C3-C7 cycloalkyl is optionally substituted with one or two groups selected from halo, C1-C4alkyl, C1-C4haloalkyl, -NHSO2C1- C4 alkyl, and -SO2C1-C4 alkyl; R5ais independently selected from H and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with C1-C4 alkoxy; n is 0 or 1; Ring B5is selected from nd each R5bis independent alkyl.

[0108] In some embodiments, n is 1. In some embodiments, n is 0.

[0109] In some embodiments, RNis selected from H and methyl. In some embodiments, RNis H. In some embodiments, RNis methyl.

[0110] In some embodiments, Ring A is selected from cyclohexyl, quinuclidinyl, phenyl, pyridinyl, pyrimidinyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidinyl, wherein each of the foregoing is optionally substituted with RA. , ,- 26 -Attorney Docket No.15768.0041-00304 and

[0113] In some embodiments, Ring A is selected fro ,nd

[0114] In some embodiments, Ring A i . In some embodiments, Ring A ise embodiments, Ring A i ise embodiments, Rin isn . In some embodiments, Ring A isn some embodiments, Ring A i . In some embodiments, Ring A is- 27 -Attorney Docket No.15768.0041-00304 . In some embodiments, Ring A i A is. In some embodiments, Ring A i . In some embodiments, Ring A is. In some embodiments, Ring A A is., ,- 28 -Attorney Docket No.15768.0041-00304 , , ,- 29 -Attorney Docket No.15768.0041-00304

[0117] In some embodiments, Ring A i . In some embodiments, Ring AIn some embodiments,meembodiments, Ring In some embodiments, Ring A isA is is ing. In some embodiments,Ring A is . In some embodiments, Ring A meembodiments, Ring . In- 30 -Attorney Docket No.15768.0041-00304 some embodiments, Rin In some embodiments, Ring A isIn some embodiments,Ring In someembodiments, Ring A i . Insome embodiments, Ring A i . In some embodiments, Ring A isIn some embodiments,Ring n some embodiments, Rin In someembodiments, Ring In some embodiments, Ri Insome embodiments, Rin In some embodiments, Ri . Insome embodiments, Ring A i . In some embodiments, Ring A . In- 31 -Attorney Docket No.15768.0041-00304 some embodiments, Ring A i . In some embodiments, Ring A isnts,nts,meembodiments, Ring .In some embodiments, Rin In some embodiments, Ring A isIn some embodiments,nts, s,- 32 -Attorney Docket No.15768.0041-00304 Ring n some embodiments, Ring A is . In someembodiments, Ring A is . In some embodiments, Rin . Ing Aembodiments, Ring A is . In some embodiments, Ring A is a .

[0118] In some embodiRAis independently selected from H, -lo, optionally substituted C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, -ORA1, -S(O)2NRA2RA3, - S(O)2RA1, -NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, tetrazolyl, 4,5-dihydro- 1H-imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl, wherein the cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, tetrazolyl, 4,5-dihydro- 1H-imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl are each independently optionally substituted with one to three substituents selected from C1-C6 alkyl, oxo, and halogen; wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6 fluoroalkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted 5-9 membered heterocycloalkyl, wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6 alkoxy; - 33 -Attorney Docket No.15768.0041-00304 each RA2and RA3is independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy.

[0119] In some embodiments, each RAis independently selected from H, F, -CN, -OH, Me, Et, n-Pr, i-butyl, -CHF2, -CF3, -CH2CHF2, -CH2CN, -C(O)OH, -C(O)OMe, -C(O)CH2OMe, - C(O)NHMe, -S(O)2NHMe, -S(O)2NMe2, -S(O)2Me, -S(O)2Et, NH2, -NHMe, -NMe2, - , is -CN. In some embodiments, RAis -OH. In some embodiments, RAis Me. In some embodiments, RAis Et. In some embodiments, RAis n-Pr. In some embodiments, RAis i-butyl. In some embodiments, RAis -CHF2. In some embodiments, RAis -CF3. In some embodiments, RAis - CH2CHF2. In some embodiments, RAis -CH2CN. In some embodiments, RAis -C(O)OH. In some embodiments, RAis -C(O)OMe. In some embodiments, RAis -C(O)CH2OMe. In some embodiments, RAis -C(O)NHMe. In some embodiments, RAis -S(O)2NHMe. In some embodiments, RAis -S(O)2NMe2. In some embodiments, RAis -S(O)2Me. In some embodiments, RAis -S(O)2Et, NH2. In some embodiments, RAis -NHMe. In some embodiments, RAis -NMe2. In some embodiments, RAis -NHS(O)2Me. In some embodiments, RAis . Insome embodiments, RAis . In some embodiments, RAis . In someembodiments, RAis . In some embodiments, RAi . In some embodiments, RA. Insome embodiments, RAi . In some embodiments, RAis . In some- 34 -Attorney Docket No.15768.0041-00304 embodiments, RAis . In some embodiments, RAi . In some embodiments,AA. In some embodiments, RA.In some embodiments, RAi . In some embodiments, RAmeembodiments, RAis . In some embodiments, RAis -C(O)NH2. In some embodiments,RAis -Oi-Pr. In some embodiments, RAis -S(O)2CF3. In some embodiments, RA. In some embodiments, RAis-NHS(O)2Et. In some embodiments, RAis -NHS(O)2n-Pr. In some embodiments, RAis -NHS(O)2n-Bu. In some embodiments, RAi . In soments,t, n-Pr, i-butyl, -CHF2, -CF3, -CH2CHF2, -CH2CN, -C(O)OH, -C(O)OMe, -C(O)CH2OMe, - C(O)NH2, -C(O)NHMe, -Oi-Pr, -S(O)2NHMe, -S(O)2NMe2, -S(O)2Me, -S(O)2Et, -S(O)2CF3, Bu, ,- 35 -Attorney Docket No.15768.0041-00304 embodiments, each RAis independently selected from -CN, -OH, -CHF2, -CF3, -CH2CHF2, - CH2CN, NH2, -NHMe, -NMe2, -NHS(O)2Me, , , , , 3, -, - ,embodiments, Ring B i . In some embodiments, Ring B .

[0123] In some embodiments, Ring B is selected fro meembodiments, Ring .

[0124] In some emo e s, he compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the compound of Formula I, or the acceptable salt of the tautomer of the compound of Formula I is selected from a compound of Table 1, a tautomer - 36 -Attorney Docket No.15768.0041-00304 thereof, and an acceptable salt of any of the foregoing. Table 1- 37 -Attorney Docket No.15768.0041-00304- 38 -Attorney Docket No.15768.0041-00304- 39 -Attorney Docket No.15768.0041-00304- 40 -Attorney Docket No.15768.0041-00304- 41 -Attorney Docket No.15768.0041-00304- 42 -Attorney Docket No.15768.0041-00304- 43 -Attorney Docket No.15768.0041-00304

[0125] The compounds and tautomers of the present disclosure that are basic in nature can form - 44 -Attorney Docket No.15768.0041-00304 a wide variety of salts with various inorganic and organic acids. The acid addition salts of the base compounds of this disclosure can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as, but not limited to, methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

[0126] Those compounds of Formula I and tautomers of compounds of Formula I that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the acceptable base salts of this disclosure are those which form non-toxic base salts with the acidic compounds of Formula I. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as, but not limited to, an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. These salts may also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, for example, under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents can be employed in order to ensure completeness of reaction and maximum yields of the desired final product.

[0127] If the compound of Formula I or tautomer of the compound of Formula I is a base, the desired acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as, but not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as, but not limited to, glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as, but not limited to, citric acid or tartaric acid, an amino acid, such as, but not limited to, aspartic acid or glutamic acid, an aromatic acid, such as, but not limited to, benzoic acid or cinnamic acid, a sulfonic acid, such as, but not limited to, p-toluenesulfonic acid or ethanesulfonic acid, or the like. - 45 -Attorney Docket No.15768.0041-00304

[0128] Acceptable salts of compounds of Formula I or of tautomers of compounds of Formula I may be prepared, e.g., by: reacting the compounds of the present disclosure with the desired acid or base; removing an acid- or base-labile protecting group from a suitable precursor of the compound of the present disclosure or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or converting one salt of the compound of the present disclosure to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. These reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0129] Certain compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of compounds of Formula I, and / or acceptable salts of tautomers of compounds of Formula I according to the disclosure may exist in more than one crystal form ("polymorphs"). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various modes of cooling, ranging from very fast to very slow cooling during crystallization.

[0130] Polymorphs may also be obtained by heating or melting the compound according to the disclosure followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X- ray diffraction or such other techniques. Polymorphs may be prepared according to techniques well-known to those skilled in the art.

[0131] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0132] 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).

[0133] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I or tautomer of the compound of Formula I contains an acidic or basic moiety, a base or acid such as, but not limited to, 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means - 46 -Attorney Docket No.15768.0041-00304 well known to a skilled person.

[0134] Chiral compounds according to the disclosure (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from about 0 to about 50% by volume of isopropanol, from about 2% to about 20%, and from about 0 to about 5% by volume of an alkylamine, or about 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0135] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0136] The compounds of the formulae of the present disclosure are assessed for their biopharmaceutical properties, such as, but not limited to, solubility and solution stability (across pH), permeability, etc., in order to select the appropriate dosage form and route of administration for treatment of the proposed indication.

[0137] The compounds of the formulae of the present disclosure are useful for modulating NAD+ hydrolase activity of CD38 protein. Accordingly, these compounds are useful for the prevention and / or treatment of disease states associated with NAD+ modulation and NAD+ related metabolites dis-regulations such as, but not limited to, aging, obesity, diabetes, cancer, heart disease, asthma, and inflammation.

[0138] The disclosure is also directed to compositions comprising a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I, and an acceptable carrier.

[0139] Compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, according to the disclosure intended for pharmaceutical use may be comprised in formulations. They may be incorporated into these formulations in the form of crystalline or amorphous products. The compounds, tautomers, and acceptable salts may be, for example, formulated as solid plugs, powders, or films obtained by methods such as, but not limited to, precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0140] These compounds, tautomers, and acceptable salts may be administered alone, in combination, and / or in coformulation with one or more other compounds according to the - 47 -Attorney Docket No.15768.0041-00304 disclosure, or in combination and / or coformulation with one or more other drugs (or as any combination or co-formulation thereof). Generally, they are administered as a combination, formulation, or coformulation in association with one or more acceptable excipients. For example, and without any limitation, the compounds disclosed herein can be co-formulated with one or more supplements and / or inhibitors, such as an NAD supplement and / or a JAK inhibitor.

[0141] For example, in such formulations, compounds according to the disclosure may be combined with soluble macromolecular entities, such as, but not limited to, cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0142] Drug-cyclodextrin complexes, for example, may be useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. For example, commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148 (specifically page 3, line 25 to page 6, line 8 inclusive). The entire contents of WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148 (and specifically the cyclodextrins of page 3, line 25 to page 6, line 8 inclusive) are fully incorporated herein by reference.

[0143] Compositions suitable for the delivery of compounds of the present disclosure and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), the entire contents of which (and specifically the passages relating to pharmaceutical compositions and their methods of preparation) is fully incorporated herein by reference.

[0144] The formulation according to the disclosure may be administered orally. Oral administration may involve swallowing, so that the compound in the formulation enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0145] Formulations suitable for oral administration include solid, semi-solid and liquid systems such as, but not limited to, tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal / mucoadhesive patches.

[0146] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations - 48 -Attorney Docket No.15768.0041-00304 may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0147] The compounds according to the disclosure may also be used in fast-dissolving, fast- disintegrating dosage forms such as, but not limited to, those described in Liang et al. (2001) Expert Opinion in Therapeutic Patents, 11 (6): 981-986, the entire contents of which (and specifically the passages relating to fast-dissolving, fast-disintegrating dosage forms) is fully incorporated herein by reference.

[0148] For tablet dosage forms, depending on dose, the compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the tautomer of the compound of Formula I, and / or the acceptable salt of the compound of Formula I may make up from about 1 weight % to about 99 weight % of the dosage form. In some embodiments, the tablet dosage forms, the compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the tautomer of the compound of Formula I, and / or the acceptable salt of the compound of Formula I may make up from about 1 weight % to about 80 weight % of the dosage form. In addition to the compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the tautomer of the compound of Formula I, and / or the acceptable salt of the compound of Formula I tablets may one or more disintegrant(s), binder(s), lubricant(s) and / or film-coating(s). Nonlimiting examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. In some embodiments, the disintegrant may comprises from about 1 weight % to about 25 weight %, or from about 5 weight % to about 20 weight % of the dosage form.

[0149] Binders may be used to impart cohesive qualities to a tablet formulation. Suitable binders include, but not are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as, but not limited to, lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0150] Tablets may also optionally comprise surface active agents, such as, but not limited to, - 49 -Attorney Docket No.15768.0041-00304 sodium lauryl sulfate and polysorbate 80, and glidants such as, but not limited to, silicon dioxide and talc. When present, surface active agents may comprise from about 0.2 weight % to about 5 weight % of the tablet, and glidants may comprise from about 0.2 weight % to about 1 weight% of the tablet.

[0151] Tablets may also contain lubricants such as, but not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from about 0.25 weight % to about 10 weight %, or from about 0.5 weight % to about 3 weight % of the tablet.

[0152] Other useful ingredients include, but are not limited to, antioxidants, colorants, flavoring agents, preservatives, taste-masking agents, flavorings and flavor enhancers, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, and surfactants.

[0153] Exemplary tablets may contain anywhere from >0 to >99% of a compound of the present disclosure, wherein the remainder may comprise binders, diluent, disintegrant, and lubricants. In some embodiments, the tablet contains up to 80% of a compound of the present disclosure, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

[0154] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may be encapsulated.

[0155] The formulation of tablets is discussed in Lieberman et al. (1980) Pharmaceutical Dosage Forms: Tablets, Vol.1, (Marcel Dekker, New York,), the entire contents of which (and specifically the passages relating to the formulation of tablets) is fully incorporated herein by reference.

[0156] Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of the present disclosure, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

[0157] The compound of the present disclosure may be water-soluble or insoluble. A water- soluble compound comprises from about 1 weight % to about 99 weight %, or from 1 weight % to about 80 weight %, or from about 20 weight % to about 50 weight %, of the solutes. Less - 50 -Attorney Docket No.15768.0041-00304 soluble compounds may comprise a greater proportion of the composition, typically up to about 88 weight % of the solutes. Alternatively, the compound of the present disclosure may be in the form of multiparticulate beads.

[0158] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range of about 30 weight % to about 80 weight %.

[0159] Films in accordance with the disclosure may be prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, for example, by a combined coater dryer, or by freeze-drying or vacuuming.

[0160] Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0161] Suitable modified release formulations for the purposes according to the disclosure are described in US Patent No.6,106,864, the entire contents of which (and specifically the modified release formulations from column 2, line 34 to column 4, line 26, in which references to “darifenacin” should be read as referring to the compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the tautomer of the compound of Formula I, and / or the acceptable salt of the compound of Formula I of the disclosure) is fully incorporated herein by reference. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al. (2001) Pharm. Technol. On-line, 25(2):1-14, the entire contents of which (and specifically the passages relating to suitable release technologies including high energy dispersions and osmotic and coated particles) is fully incorporated herein by reference. The use of chewing gum to achieve controlled release is described in International Patent Publication WO 00 / 35298, the entire contents of which is fully incorporated herein by reference.

[0162] The formulations including a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I, according to the disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ. Exemplary suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0163] Parenteral formulations are typically aqueous solutions which may contain excipients - 51 -Attorney Docket No.15768.0041-00304 such as, but not limited to, salts, carbohydrates and buffering agents (e.g., to a pH of from about 3 to about 9), but, for some applications, they may be formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as, but not limited to, sterile, pyrogen-free water.

[0164] The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0165] The solubility of compounds, tautomers, and acceptable salts of the present disclosure used in the preparation of parenteral formulations may be increased by the use of appropriate formulation techniques, such as, but not limited to, the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus, compounds according to the disclosure may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Nonlimiting examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug- loaded poly(dl-lactic-coglycolic) acid (PGLA) microspheres.

[0166] The formulations according to the disclosure may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include, but are not limited to, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include, but are not limited to, alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated (see, Finnin et al. (1999) J. Pharm. Sci.88 (10):955-958), the entire contents of which (and specifically the passages relating to penetration enhancers) is fully incorporated herein by reference.

[0167] Other nonlimiting means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., Powderject™, Bioject™, etc.) injection.

[0168] Formulations for topical administration may be formulated to be immediate and / or modified release. Exemplary modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0169] The formulations including a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable - 52 -Attorney Docket No.15768.0041-00304 salt of a compound of Formula I, according to the disclosure may also be administered intranasally or by inhalation, e.g., in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as, but not limited to, phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (or an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as, but not limited to, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent such as, but not limited to, chitosan or cyclodextrin.

[0170] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound according to the disclosure comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant such as, but not limited to, sorbitan trioleate, oleic acid, or an oligolactic acid.

[0171] Prior to use in a dry powder or suspension formulation, the formulation is micronized to a size suitable for delivery by inhalation (e.g., less than about 5 microns). This may be achieved by any appropriate comminuting method, such as, but not limited to, spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0172] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound according to the disclosure, a suitable powder base such as, but not limited to, lactose or starch and a performance modifier such as, but not limited to, l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other exemplary excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0173] An exemplary formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 g to about 20 mg of the compound according to the disclosure per actuation, and the actuation volume may vary from about 1 L to about 100 L. An exemplary formulation comprises a compound of Formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative exemplary solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0174] Suitable flavors, such as, but not limited to, menthol and levomenthol, or sweeteners, such as, but not limited to, saccharin or saccharin sodium, may be added to those formulations - 53 -Attorney Docket No.15768.0041-00304 according to the disclosure intended for inhaled / intranasal administration.

[0175] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, poly(glycolide-co-L-lactide (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0176] In the case of dry powder inhalers and aerosols, the dosage unit may be determined by means of a valve which delivers a metered amount. Units in accordance with the disclosure are provided, e.g., in a metered dose containing from about 0.01 µg to about 100 mg of the compound of the present disclosure, such as from about 0.01 µg to about 25 mg, from about 0.01 µg to about 10 mg, or from about 0.01 µg to about 5 mg. The overall daily dose may be in the range of about 1 µg to about 200 mg, which may be administered in a single dose or, as divided doses throughout the day and possibly during multiple days.

[0177] The compositions according to the present disclosure may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0178] The compositions according to the disclosure may also be administered directly to the eye or ear, for example, in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as, but not limited to, niosomes or liposomes. A polymer such as, but not limited to, crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as, but not limited to, benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Compositions for ocular / aural administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

[0179] Since the present disclosure includes one or more aspects that relates to the treatment of the diseases or conditions described herein with a combination of active ingredients which may be administered separately, the disclosure also relates to combining separate compositions in kit - 54 -Attorney Docket No.15768.0041-00304 form. Such a kit comprises two separate compositions: a compound, tautomer, or acceptable salt of the present disclosure, and a second compound as described above. The kit comprises means for containing the separate compositions such as, but not limited to, a container, a divided bottle, or a divided foil packet. The kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0180] A non-limiting example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. The strength of the sheet may be such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0181] A memory aid may be provided on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday” etc. “Second Week, Monday, Tuesday” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a compound of Formula I, a tautomer of the compound of Formula I, an acceptable salt of the tautomer of the compound of Formula I, and / or an acceptable salt of the compound of Formula I can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid can reflect this.

[0182] In some embodiments, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. The dispenser may be equipped with a memory-aid, so as to further facilitate compliance with the regimen. A nonlimiting example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been - 55 -Attorney Docket No.15768.0041-00304 dispensed. Another nonlimiting example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken.

[0183] The disclosure includes a method for treating, retarding, or preventing a disease, disorder, or condition in a subject, e.g., a mammal such as, but not limited to, a human, comprising administering to a subject in need thereof an effective amount, e.g., a therapeutically effective amount of a compound of the present disclosure, or an acceptable salt thereof.

[0184] The compounds of the present disclosure are also useful for modulating or inhibiting NAD hydrolase activity of CD38 protein. Accordingly, the present disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention, retardation, and / or treatment of diseases, disorders, and / or conditions associated with NAD+ depletion or NAD+ metabolites dysregulation, such as aging, age-related chronic diseases, disorders, and / or conditions), cancer, cardiovascular disorders, neurological disorders, pulmonary disorders, fibrotic diseases, metabolic disorders, inflammation, liver disorders, or diseases, disorders, and / or conditions of the skin, as well as its identification as a cell-surface marker in hematologic cancers such as multiple myeloma (see, Chin et al. (2018) Trends Pharmacol. Sci. 39(4):424-436). The methods comprise administering to a subject in need thereof an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, or an acceptable salt thereof.

[0185] Additionally, the disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of cancer, such as small lung cell carcinoma, renal clear cell carcinoma, chronic lymphocytic leukemia, or multiple myeloma.

[0186] The role of CD38 dysfunction in cancers has been demonstrated such as in small lung cell carcinoma (see, e.g., Blanco et al. (2010) Can. Res. 70(10):3896-3904) and in renal clear cell carcinoma (see, Sartini et al. (2006) J. Urol.176(5):2248-2254). The role of CD38 in chronic lymphocytic leukemia has been described (see, Deaglio et al. (2010) Can. Biol.20(6):416-423). The role of CD38 in PD-1 / PD-L1 resistant cancers has been described (see, Verma et al. (2019) Nature Immunology 20: 1231–1243; Chen et al. (2018) Cancer Discov.8(9):1156-1175).

[0187] The disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of - 56 -Attorney Docket No.15768.0041-00304 compounds of Formula I, for the prevention and / or treatment of cardiovascular disorders, such as hypertension, hypoxic pulmonary vasoconstriction, cardiac hypertrophy, congestive heart failure, or stroke.

[0188] The role of CD38 inhibition in cardiovascular disorders has been documented, such as for hypertension (see, e.g., Thai et al. (2009) Am. J. Renal Physiol. 297(1):F169-76. Hypoxic pulmonary vasoconstriction has been described in Wilson et al. (2001) J. Biol. Chem.276(14): 11180-8). Cardiac hypertrophy / CHF has been described in Pillai. et al. (2010) J. Biolog. Chem. 285(5): 3133-3144. The role in stroke is described Choe et al. PLoS One (2011), 6(5):e19046.

[0189] The disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of neurological disorders, such as Alzheimer's disease, bipolar disorder, schizophrenia, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, optic neuropathy, or epilepsy. Thus, the compounds described herein may be used as neuroprotective agents. The compounds, tautomers, and acceptable salts of the present disclosure may also be administered in the tissue or organ likely to encounter cell death.

[0190] Neurological disorders have also been demonstrated to be mediated by CD38 dysfunction. The role of CD38 in Alzheimer's disease has been described in Gong Bing, et al. (2013) Neurobiol. Aging 34(6):1581-8. The role of CD38 in neurocognitive disorders has been described in, e.g., Banerjee et al. (2008) J. Neuroim. Pharmacol.3(3):154-64. The role of CD38 in bipolar disorder and schizophrenia is described in, e.g., Christoforou (2007) Mol. Psych.12(11);1011-1025. The role of CD38 in Huntington's disease has been described inWeydt (2009) Mol. Neurodeg.4:3. The role of CD38 has been described for amyotrophic lateral sclerosis in Lawton et al. (2012) Amyotrophic Lateral Sclerosis 13(1):110-118, and for Parkinson's disease (see, e.g., Aoyama et al. (2001) Neurosci. Lett. 298(1):78-80. The role of CD38 in multiple sclerosis has been described in Penberthy et al. (2009) Curr. Pharm. Design15(1):64-99. The role of CD38 in optic neuropathy has been described in Kitaoka et al. (2009) J. Neuropathol. Exp. Neurol.68(8):915-927. The role of CD38 in epilepsy has been described, for example, Kinton Lucy et al. (2002) Ann. Neurol.51(6);740-9.

[0191] The present disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of pulmonary disorders, such as idiopathic pulmonary fibrosis, cystic fibrosis, COVD-19, SARS, asthma, or chronic obstructive pulmonary disease (COPD). - 57 -Attorney Docket No.15768.0041-00304

[0192] The disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of fibrotic diseases, such as diabetic nephropathy, chronic kidney disease, idiopathic pulmonary fibrosis or cystic fibrosis.

[0193] The role of CD38 dysfunction in pulmonary disorders has been described, for example, in idiopathic pulmonary fibrosis, O'Neill et al. (1994) Expt. Lung Res. 20(1):41-56. The role of CD38 in cystic fibrosis has been described in Wetmoreet et al. (2010) J. Biolog. Chem. 285(40):30516-30522. The role of CD38 in asthma is described in Kang et al. (2006) Curr. Res. Med. Rev. 2(2):143-156. The role of CD38 in COPD is described in Hageman et al. (2003) Free Radical Biol. Med.35(2):140-148.

[0194] The present disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of metabolic disorders, such as metabolic syndrome, obesity, sarcopenic obesity, sarcopenia, dyslipidemia, diabetes (such as type I diabetes), diabetic neuropathy, insulin resistance, infection-induced and viral-induced lung fibrosis, or pancreatitis.

[0195] The use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of obesity may encompass the use wherein the subject has or is likely to develop obesity (e.g., mammals having an elevated risk of developing diet-induced obesity). A mammal may be identified as having or being likely to develop obesity using standard clinical techniques. For example, analysis of a human's family history or eating habits may be used to determine whether the human is likely to develop an obesity condition. As described herein, a mammal identified as having or being susceptible to developing an obesity condition may be treated by administering a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I.

[0196] The role of CD38 dysfunction in metabolic disorders have been described, for example, as in metabolic syndrome, in Escande Carlos et al. (2013) Diabetes 62(4):1084-93. The role of CD38 in obesity and sarcopenic obesity have been described in Maria et al. (2007) FASEB J. 21(13):3629-39. The role of CD38 in dyslipidemia is described in Surakka Ida et al. (2011) PLoS Gen.7(10):e1002333. The role of CD38 in Diabetes has been described in Arya et al. (2004) Am. J. Hum. Gen.74(2):272-282. The role of CD38 in in diabetic neuropathy has been described in Geeta et al. (2010) Neuropharmacol.58(3):585-92. The role of CD38 in insulin resistance is - 58 -Attorney Docket No.15768.0041-00304 described in Yoshino et al. (2011) Cell Metab.14(4):528-536. The role of CD38 in Type I diabetes is described in Elliott. et al. (1993) Annals NY Acad. Sci.696: 333-41. The role of CD38 in pancreatitis has been described in Chan et al. (2011) Antiox. Redox Sig.15(10):2743- 2755. CD38 inhibition has been reported to counteract CAR (chimeric antigen receptor) T cell exhaustion and increase the efficacy of CAR-T cells against hematological malignancies (see, Huang et al. (2024) Cell Reports Medicine, 101400).

[0197] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The role of CD38 in acute lung injury and ARDS has been described, e.g., Su et al. (2007) Eur. Res. J.30(2):199-204.

[0198] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of hyperphosphatemia. The role of CD38 in hyperphosphatemia has been described inTakahashi et al. (2004) Kidney Int.65(3):1099-1104.

[0199] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of alcohol intolerance. The role of CD38 in alcohol intolerance has been described in, e.g., Larson et al. (2005) J. Biol. Chem.280(34):30550-30556.

[0200] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of lupus. For the role of CD38 in lupus has been described in, e.g., Gonzalez-Escribano et al. (2004) Hum. Immunol (2004) 65(6):660-4; Pavon et al. (2013) Cytokine 62(2):232-243.

[0201] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of arthritis, such as rheumatoid arthritis. The role of CD38 in rheumatoid arthritis has been described in Jorge Postigo et al. (2012) PLoS One 7(3):e33534.

[0202] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of ataxia- - 59 -Attorney Docket No.15768.0041-00304 telangiectasia. The role of CD38 in ataxia-telangiectasia has been described in Stern et al. (2012) J. Biol. Chem.277(1):602-608.

[0203] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of irritable bowel syndrome (IBS) and colitis. The role of CD38 in IBS and colitis has been described, for example, in Durnin et al. (2012) J. Physiol. (Oxford, UK) 590(8):1921-1941.

[0204] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of gout. See, Nik Cummings et al. (2010) European Journal of Human Genetics, 18(11), 1243-7.

[0205] The present disclosure encompasses the use of compounds of Formula I for the prevention and / or treatment of end stage renal disease. The role of CD38 in end stage renal disease has been described in Freedman et al. (2005) Nephrol. Dialysis, Transpl.20(4):712-718.

[0206] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of hearing loss. The role of CD38 in hearing loss has been described in Someya et al. (2010) Cell 43(5):802-812.

[0207] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of liver disorders, such as steatosis and non-alcoholic steatohepatitis (NASH). The role of CD38 in liver disorders such as steatosis and NASH has been described, for example, in Choi et al. (2013) Aging Cell 2(6):1062-72.

[0208] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of postmenopausal osteoporosis. Postmenopausal osteoporosis disease progression is described in Drummond et al. (2006) J. Bone Mineral Met. 24(1):28-35.

[0209] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of fertility disorders or diseases. Restoration of oocyte quality and enhancement of ovulation rate and fertility is described in Bertoldo et al. (2020) Cell Rep 30(6): 1670–1681. - 60 -Attorney Docket No.15768.0041-00304

[0210] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of Hartnup disease. The role of CD38 in Hartnup disease has been described in Jepson et al. (1960) Met. Basis Inherited Dis.1338-64. Hansen's disease is described in Dhople et al. (1985) Microbio. Letts. 28(109):17-20.

[0211] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of tuberculosis. The role of CD38 in tuberculosis has been described in Vilcheze et al. (2010) Mol. Microbiol. 76(2):365-377.

[0212] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of leishmaniasis. The role of CD38 in leishmaniasis has been described in Michels et al. (2011) Mol. Microbiol. 82(1):4-8.

[0213] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of muscular dystrophy. The role of CD38 in muscular dystrophy has been described in Goody et al. (2012) PLoS Biology 10(10):e1001409.

[0214] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of organ reperfusion injury. Organ reperfusion injury mediated through CD38 is described in Yan Ge et al. (2010) Biochem. Biophys. Res. Comm. 399(2):167-172.

[0215] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of pellagra. The role of CD38 in pellagra has been described, for example, in Williams et a. (2007) Med. Hypoth.69(3):618-628.

[0216] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of diseases, - 61 -Attorney Docket No.15768.0041-00304 disorders, and / or conditions of the skin, such as skin hyperpigmentation, UV skin damage and psoriasis.

[0217] Diseases of the skin are linked to NAD and CD38 dysfunction. Skin hyperpigmentation, for example, has been reported (Van Woert (1967) Life Sci.6(24):2605-12). UV skin damage has been reported (see Benavente et al. (2009) Curr. Pharm. Design 15(1);29-38. Likewise, NAD dysfunction is involved in psoriasis (see, Wozniacka et al. (2007) Skin Pharmacol. Physiol. 20(1):37-42).

[0218] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of damage caused by exposure to radiation, such as X-ray-induced DNA damage, e.g. by promoting NAD+ modulated DNA repair and / or cell survival. The disclosure includes a method of promoting DNA repair in cells. Cells exposed to conditions that may trigger DNA damage, e.g., radiation, may be protected by contacting them before, during and / or after exposure to the DNA damaging agent, with a compound of the present disclosure.

[0219] Protection from exposure to radiation has been described, for example, in Caibin et al. (2012) Internat. J. Physiol. Pathophysiol. Pharmacol. 4(1):1-9.

[0220] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of periodontal disease. The role of CD38 in periodontal disease has also been reported in, e.g., Fujita et al. (2005) J. Periodontol.76(11):1960-5.

[0221] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of Leber's hereditary amaurosis. Leber's hereditary amaurosis has also been reported. See, for example, Koenekoop et al. (2012) Nat. Gen.44(9):1035-1039.

[0222] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of sleep disorders. NAD+ involvement in sleep disorders has been described (see Robinson et al. (1977) Biol. Psych. 12(1):139-43).

[0223] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or - 62 -Attorney Docket No.15768.0041-00304 acceptable salts of compounds of Formula I, for the prevention and / or treatment of exercise intolerance. Exercise intolerance has also been reported (see, e.g., Glick (1966) Am. J. Physiol. 210(6):1215-21.

[0224] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of diseases, disorders, and / or conditions benefiting from a modulation of IL-6 (see, for example, Zhang et al. (2022) Clin. Exp. Rheumatol. 41(7):1384–1395; Choy et al. (2020) Nat. Rev. Rheumatol. 16:335–345; Kang et al. (2015) Int. Immunol.27(1):21–29,).

[0225] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of diseases,disorders, and / or conditions benefiting from a modulation of TNF- (see, for example, Gerriets etal. (2018) StatPearls Publishing, Treasure Island (FL); 2023).

[0226] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of mitochondrial myopathies (see, for example, Li et al. (2023) J. Med. Chem. 66(18):12762–12775).

[0227] The present disclosure encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of diseases, disorders, and / or conditions benefiting from a modulation of ADP-Ribosyl Cyclase Activity (see, for example, Deshpande et al. (2004) Am. J. Physiol. Lung. Cell. Mol. Physiol.288(5):L773– L788; Malavasi et al. (2008) Physiol. Rev.88(3):841–886).

[0228] The present disclosure encompasses the use of compounds of the present disclosure to extend the life span of cells and protect them from stress. Accordingly, the disclosure includes the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, for the prevention and / or treatment of diseases, disorders, and / or conditions, e.g., chronic diseases, associated with cell death, such as, but not limited to, e.g., diseases associated with neural cell death or muscular cell death. In addition, the methods may be used to prevent or alleviate neurodegeneration and peripheral neuropathies associated with chemotherapy, such as, but not limited to, cancer chemotherapy (e.g., taxol or cisplatin treatment).

[0229] The compounds, tautomers, and / or acceptable salts of the present disclosure may be - 63 -Attorney Docket No.15768.0041-00304 administered to subjects in which caloric restriction, or the effects thereof, is beneficial. Subjects may be subjects suffering from an aging disease, e.g., stroke, heart disease, arthritis, high blood pressure. They may also be administered for treating a metabolic disease, such as, but not limited to, insulin -resistance or other precursor symptom of type II diabetes, type II diabetes or complications thereof. Methods may increase insulin sensitivity or decrease insulin levels in a subject. For example, a method may comprise administering to a subject, such as a subject in need thereof, an effective amount of an agent that increases the activity or protein level of a protein involved in the NAD+ salvage pathway, i.e., in the synthesis of NAD+ and the degradation of nicotinamide. A subject in need of such a treatment may be a subject who has insulin resistance or other precursor symptom of type II diabetes, who has type II diabetes, or who is likely to develop any of these conditions. For example, the subject may be a subject having insulin resistance, e.g., having high circulating levels of insulin and / or associated conditions, such as impaired glucose tolerance, high blood glucose sugar level and hypertension.

[0230] The compounds, tautomers, and / or acceptable salts of the present disclosure may also be used for stimulating fat mobilization, e.g., for treating obesity and any condition resulting therefrom or for reducing weight gain.

[0231] The disclosure provides a method for treating any of the conditions recited above in a mammal comprising administering an effective amount, e.g., a therapeutically effective amount of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I, or an acceptable salt thereof to the mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human animal, such as a domestic animal, a working animal, or a farm animal. Domestic animals include, but are not limited to, rabbits, birds, cats, dogs, fishes, rats, tortoises, and reptiles. Working animals include, but are not limited to, cattle, yaks, and horses. Farm animals include, but are not limited to sheep, pigs, cows, chickens, goats, geese, ducks, and llamas.

[0232] Administration of the compounds of the present disclosure may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, transdermal, subcutaneous, intramuscular, intravascular or infusion), intra-articular administration, intravitreal administration, topical, ocular, vaginal rectal administration, and the like.

[0233] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic - 64 -Attorney Docket No.15768.0041-00304 situation. It is advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier.

[0234] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as may the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0235] Dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. For any subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses dose-escalation or dose-reduction as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the active agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0236] The amount of a compound of the present disclosure that is administered to a subject is dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. An effective dosage may be in the range of about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day, or about 1 mg / kg body weight / day to about 35 mg / kg body weight / day in single or divided doses. For a 70 kg human, this amounts to about 0.05 g / day to about 7 g / day or about 0.1 g / day to about 2.5 g / day. In some embodiments, an effective dosage may be in the range of about 0.1 g / day to about 2.5 g / day, such as about 1 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate depending on, e.g., the severity of the disorder treated, and the age and weight of the subject being treated, - 65 -Attorney Docket No.15768.0041-00304 while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0237] The present disclosure includes the use of a combination of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I, and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present disclosure also includes compositions comprising an amount of: (a) a first agent comprising a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I; (b) a second pharmaceutically active agent; and (c) an acceptable carrier, vehicle or diluent. In some embodiments, the administration of a compound of Formula I, a tautomer of a compound of Formula I, an acceptable salt of a tautomer of a compound of Formula I, and / or an acceptable salt of a compound of Formula I, in combination with one or more additional pharmaceutically active agent(s) results in a synergistic therapeutic effect, which refers to a therapeutic effect that is greater than merely the therapeutic effect of the compound added to the therapeutic effect of the one or more additional pharmaceutically active agent(s).

[0238] Various pharmaceutically active agents may be selected for use in conjunction with compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the present disclosure include, without limitation, the following combination therapies.

[0239] For treating non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD), combination therapy includes combinations with agents including, but not limited to, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, an inhibitor of CCR2and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid 17- dehydrogenase (HSD17B13) inhibitor,a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor or an MPO inhibitor; orlistat, a TZD, or another insulin- sensitizing agent, an FGF21 analog, metformin, an omega-3-acid ethyl ester (e.g. Lovaza), a fibrates, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 - 66 -Attorney Docket No.15768.0041-00304 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, a carnitine, N- acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin), phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist (such as tirzepatide), an angiotensin-receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, or an MPO inhibitor.

[0240] For the treatment of other diseases, disorders, or conditions, combination therapy alsoincludes combinations with, for example, anti-obesity agents including an 11 -hydroxy steroiddehydrogenase-1 (11 .-HSD type 1) inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, aMCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (such as, but not limited to, sibutramine), a sympathomimetic agent, a -3 adrenergic agonist, a dopamine agonist (such as, but not limited to, bromocriptine), a melanocyte-stimulating hormone analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor (such as, but not limited to, tetrahydrolipstatin, i.e., orlistat), an anorectic agents (such as, but not limited to, a bombesin agonist), a neuropeptide-Y antagonists (e.g., an NPY Y5 antagonist), PYY3-36 (including an analog thereof), a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor (such as, but not limited to, Axokine®, available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company, Cincinnati, Ohio), a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor (e.g., a gut-selective MTP inhibitor, such as, but not limited to, dirlotapide), an opioid antagonist, an orexin antagonist, the combination of naltrexone with buproprion, or the like.

[0241] The present disclosure also encompasses the use of the compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, alone, for the treatment of cancers, such as, but not limited to, multiple myeloma. The present disclosure also encompasses the use of the compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, in combination - 67 -Attorney Docket No.15768.0041-00304 therapies for the treatment of cancers, such as, but not limited to, multiple myeloma. Such treatments include, but are not limited to, combinations of a compound of the present disclosure with one or more immuno-oncology drugs including, but not limited to, Ipilimumab (Yervoy), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi), and PD-1 / PD-L1 agonist antibodies.

[0242] The present disclosure also encompasses the use of the compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, alone, for the treatment of neurodegenerative disorders. The present disclosure also encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, in combination therapies for the treatment of neurodegenerative disorders. Such treatments include, but are not limited to, combinations of a compound of Formula I, and / or an acceptable salt thereof, with one or more neurodegenerative disorder therapeutics including, e.g., an acetylcholinesterase inhibitors, such as, but not limited to, donepezil hydrochloride, physostigmine salicylate, physostigmine sulfate, metrifonate, neostigmine, ganstigmine, pyridostigmine, ambenonium, demarcarium, rivastigmine, ladostigil, galantamine hydrobromide, tacrine, tolserine, velnacrine maleate, memoquin, huperzine A, phenserine, and edrophonium; amyloid-ß or fragments thereof, such as, but not limited to, Aß1-15 conjugated to pan HLA DR-binding epitope; an antibody to amyloid-ß, such as, but not limited to, bapineuzumab; an amyloid-lowering or -inhibiting agent (including those that reduce amyloid production, accumulation and fibrillization) such as, but not limited to, colostrinin, bisnorcymserine, pioglitazone, clioquinol, flurbiprofen, tarenflurbil, nitroflurbiprofen, fenoprofen, ibuprofen, meclofenamic acid, meclofenamate sodium, indomethacin, diclofenac, sulindac, diflunisal, naproxen, gingko biloba extract, tramiprosate, eprodisate, and neprilysin; a dopamine receptor agonist, such as, but not limited to, apomorphine, bromocriptine, cabergoline, dihydrexidine, dihydroergocryptine, fenoldopam, lisuride, pergolide, piribedil, pramipexole, quinpirole, ropinirole, rotigotine, and sarizotan; levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa, benserazide, - methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m- hydroxybenzylhydrazine; a monoamine oxidase (MAO) inhibitor, such as, but not limited to, selegiline, dimethylselegilene, brofaromine, phenelzine, tranylcypromine, moclobemide, befloxatone, safinamide, isocarboxazid, nialamide, rasagiline, iproniazide, iproclozide, toloxatone, bifemelane, desoxypeganine, harmine, harmaline, linezolid, and pargyline; and a muscarinic receptor (particularly M1 subtype) agonist, such as, but not limited to, bethanechol - 68 -Attorney Docket No.15768.0041-00304 chloride, itameline, pilocarpine, arecoline, furtrethonium iodide, oxotremorine, sabcomeline, or carbachol.

[0243] Combination therapy also includes combinations with cardiovascular agents including, but not limited to, a beta-adrenergic receptor blocking agent (beta blocker), such as, but not limited to, carteolol, esmolol, labetalol, oxprenolol, pindolol, propanolol, sotalol, timolol, acebutolol, nadolol, metoprolol tartrate, metoprolol succinate, atenolol and butoxamine; calcium channel blockers such as, but not limited to, nilvadipine, diperdipine, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, lifarizine, diltiazem, verapamil, or enecadin.

[0244] In addition, combination therapy includes combinations with a catechol O- methyltransferase (COMT) inhibitor, such as, but not limited to, tolcapone (TASMAR), entacapone (COMTAN), or tropolone.

[0245] Combination therapy also includes combinations with an immunomodulator such as, but not limited to, glatiramer acetate, dimethyl fumarate, fingolimod, roquinimex, laquinimod, rituximab, alemtuzumab, daclizumab, or natalizumab.

[0246] In addition, combination therapy includes combinations with an interferon, including, but not limited to, interferon beta-1a or interferon beta-1b.

[0247] Combination therapy also includes combinations with a neuroprotective drug such as, but not limited to, 2,3,4,9-tetrahydro-1H-carbazol-3-one oxime, desmoteplase, anatibant, astaxanthin,neuropeptide NAP, neurostrol, perampenel, ispronicline, bis(4- -D-glucopyranosyloxybenzyl)-2--D-glucopyranosyl-2-isobutyltartrate (also known as dactylorhin B or DHB), formobactin, xaliproden, lactacystin, dimeboline hydrochloride, disufenton, arundic acid, citicoline, edaravone, granulocyte-colony stimulating factor, ancrod, 17-ß-hydroxyepiandrosterone, oligotropin, pyridoxal 5'-phosphate, microplasmin, piclozotan, tacrolimus, L-seryl-L-methionyl- L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine, stilbazulenyl nitrone, or zonampanel.

[0248] Combination therapy also includes combinations with a trophic factor, such as, but not limited to, a nerve growth factor (NGF), a basic fibroblast growth factor (bFGF), neurotrophin-3, cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial- derived neurotrophic factor (GDNF), or an agent that stimulate production of trophic factors, such as, but not limited to, propentofylline and idebenone.

[0249] The present disclosure also encompasses the use of the compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, alone, for the treatment of aging-related diseases, disorders, and / or conditions. The present disclosure also encompasses the use of - 69 -Attorney Docket No.15768.0041-00304 compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, in combination therapies for the treatment of aging-related diseases, disorders, and / or conditions. Such treatments include, but are not limited to, combinations of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I with a nutraceutical product, i.e., a substance which has physiological benefit or provides protection against chronic disease, including a vitamin, e.g., Prenatal Vitamins, Vitamin D3, or Vitamin B12, Garcinia Cambogia, raspberry ketones, a green tea supplements, echinacea, a probiotics, an omega-3 fatty acids, alpha-lipoic acid, or an NAD+ or NAD+ precursor, e.g., NMN, NR, and NA.

[0250] The present disclosure also encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, in combination therapies for the treatment of diseases, disorders, and / or conditions modulated by IL-6. Such treatments include, but are not limited to, combinations of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I with an anti-IL-6 antibody, such as, but not limited to, sarilumab or tocilizumab.

[0251] The present disclosure also encompasses the use of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compounds of Formula I, in combination therapies for the treatment ofdiseases, disorders, and / or conditions modulated by TNF- . Such treatments include, but are notlimited to, combinations of compounds of Formula I, tautomers of compounds of Formula I, acceptable salts of tautomers of compounds of Formula I, and / or acceptable salts of compoundsof Formula I, with an anti-TNF- antibody, such as, but not limited to, etanercept, adalimumab,or infliximab.

[0252] As used herein, the term “another active agent” refers to any therapeutic agent, other than the compound of Formula I, the tautomer of the compound of Formula I, the acceptable salt of the compound of Formula I, and / or the acceptable salt of the tautomer of the compound of Formula I, that is useful for the treatment of a subject suffering from a disease, disorder, or condition. Active agents include for example, without limitation, anti-rheumatic arthritis drugs such as NSAIDs, acetaminophen / paracetamol, disease-modifying antirheumatic drugs (DMARDs), steroids, methotrexate, anti-IL-1, JAK inhibitors, and the like.

[0253] Reference will now be made to specific examples illustrating the disclosure. It is to be understood that the examples are provided to illustrate exemplary embodiments and that no - 70 -Attorney Docket No.15768.0041-00304 limitation to the scope of the disclosure is intended thereby. NUMBERED EMBODIMENTS

[0254] The compounds of the present disclosure may be of any one of the following embodiments. Embodiment 1. A compound of Formula I: I), an acceptable salt of the omer of the compound of FormulaI, or an acceptable salt of the tautomer of the compound of Formula I, wherein: n is 0 or 1; RNis selected from H and C1-C6 alkyl; Ring A is selected from C6-C10aryl, C3-C10cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic, wherein 0 to 4 atoms of the 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10fused bicyclic are independently O, S, N, or NRA, and wherein the C6-C10 aryl, C3-C10 cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic are each optionally substituted with one or more RA; each RAis independently selected from H, -CN, halo, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -SRA1, -S(O)2NRA2RA3, -S(O)2RA1, -S(O)RA1, -NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6aryl, and optionally substituted 5-6 membered heteroaryl; wherein the optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, and optionally substituted 5-6 membered heteroaryl are each independently optionally substituted with one to three substituents selected from C1-C6 alkyl, oxo, and halogen; wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6cycloalkyl, C1-C6- 71 -Attorney Docket No.15768.0041-00304 alkoxy, optionally substituted 5-9 membered heterocycloalkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; each RA2and RA3is independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; nd alkyl;provided that the compound, acceptable salt of the compound, tautomer, or acceptable , ,- 72 -Attorney Docket No.15768.0041-00304 , ,, tautomers thereof, and acceptable salts of any of the foregoing.compound, tautomer, or acceptable salt of embodiment 1, wherein the compound, tautomer, or acceptable salt is not a compound of Formula E-i: i), an acceptable salt of the coa tautomer of the compound of Formula E-i, or an acceptable salt of the tautomer of the compound of Formula E-i, wherein: ,, (C1-C6 alkyl)2N-, HOC(O)-, (C1-C3alkyl)(O)(C=O)-, (C1-C3alkyl)-O-(C1-C3alkyl)-NH-, HO-(C1-C3alkyl)-N(C1-C3 alkyl)-, (C1-C3 alkyl)O(C1-C3 alkyl)-N(C1-C3 alkyl)-, (C1-C3 alkyl)-(C=O)-NH-, (C1-C3alkyl)-(C=O)-N(C1-C3alkyl)-, H2N-(C=O)-, and (C1-C3alkyl)2N-(C=O)-; - 73 -Attorney Docket No.15768.0041-00304 B1 is selected from ndR1bis selected fro Embodiment 3. Thecompound, tautomer, or acceptable salt of embodiment 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-ii: i), an acceptable salt of th utomer of the compound ofFormula E-ii, or an acceptable salt of the tautomer of the compound of Formula E-ii, wherein: Ring A2is selected from 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, C6 cycloalkyl, and C7-C10 cycloalkyl, wherein the 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, and C7-C10 cycloalkyl are each optionally substituted with R2aor wherein the C6cycloalkyl is substituted with R2a; each R2ais independently selected from -CN, halo, optionally substituted C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 cyanoalkyl, -OR21a, -SR21a, -S(O)2NR22aR23a, -S(O)2R21a, -S(O)R21a, -NR21aR23a, -C(O)R21a, -C(O)OR21a, -C(O)NR22aR23a, and 5-8 membered heterocycloalkyl; wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or 5-6 membered heteroaryl; each R21ais independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy; and each R22aand R23ais independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy. Embodiment 4. The compound, tautomer, or acceptable salt of embodiment 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-iii: (E-iii),- 74 -Attorney Docket No.15768.0041-00304 an acceptable salt of the compound of Formula E-iii, a tautomer of the compound of Formula E-iii, or an acceptable salt of the tautomer of the compound of Formula E-iii, wherein: L is selected from a bond and CH2; R31ais independently selected from H and methyl; R32ais independently selected from H and C1-C4 alkyl; or R31aand R32atogether with the nitrogen atom to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may optionally be substituted with fluoro; Ring B3is selected from nd each R3bis independent alkyl.Embodiment 5. The compound, tautomer, or acceptable salt of embodiment 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-iv: v), an acceptable salt of thetautomer of the compound of Formula E-iv, or an acceptable salt of the tautomer of the compound of Formula E-iv, wherein: Ring A4is selected from C4-C9cycloalkyl, phenyl, pyridinyl, and 4-9 membered heterocycloalkyl; wherein the C4-C9cycloalkyl is optionally substituted with -OH, halo, C1-C6alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy optionally substituted with C1-C6alkoxy, C(O)OC1-C6alkyl, and pyridinyl; wherein the phenyl is optionally substituted with one or more halo; wherein the 4-9 membered heterocycloalkyl is optionally substituted with halo, C1-C6 alkyl, C(O)OC1-C6 alkyl, and C(O)C1-C6 alkyl; and wherein the pyridinyl is optionally substituted with halo or C1-C6alkyl; Ring B4is selected from and ; and each R4bis independently selected from H and C1-C6 alkyl. - 75 -Attorney Docket No.15768.0041-00304 Embodiment 6. The compound, tautomer, or acceptable salt of embodiment 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-v: v), an acceptable salt o mer of the compound ofFormula E-v, or an acceptable salt of the tautomer of the compound of Formula E-v, wherein: Ring A5is selected C3-C7cycloalkyl, wherein the C3-C7cycloalkyl is optionally substituted with one or two groups selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, -NHSO2C1- C4 alkyl, and -SO2C1-C4 alkyl; R5ais independently selected from H and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with C1-C4 alkoxy; n is 0 or 1; Ring B5is selected from nd each R5bis independentalkyl. Embodiment 7. The compound, tautomer, or acceptable salt of any one of embodiments 1- 6, wherein n is 1. Embodiment 8. The compound, tautomer, or acceptable salt of any one of embodiments 1- 6, wherein n is 0. Embodiment 9. The compound, tautomer, or acceptable salt of any one of embodiments 1- 8, wherein RNis selected from H and methyl. Embodiment 10. The compound, tautomer, or acceptable salt of any one of embodiments 1- 8, wherein RNis H. Embodiment 11. The compound, tautomer, or acceptable salt of any one of embodiments 1- 8, wherein RNis methyl. Embodiment 12. The compound, tautomer, or acceptable salt of any one of embodiments 1- 11, wherein Ring A is selected from cyclohexyl, quinuclidinyl, phenyl, pyridinyl, pyrimidinyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidinyl, wherein each of the foregoing is optionally substituted with RA. - 76 -Attorney Docket No.15768.0041-00304 Embodiment 13. The compound, tautomer, or acceptable salt of any one of embodiments 1- 11, wherein Ring A is selected fro ,, odiments 1-11, wherein Ring A is selected fro ,.one of embodiments 1- , .Embodiment 16. The compound, tautomer, or acceptable salt of any one of embodiments 1- ,- 77 -Attorney Docket No.15768.0041-00304 and ments 1-11, wherein Ring A is selected from, ,- 78 -Attorney Docket No.15768.0041-00304 , , ,1- 16, wherein each RAis independently selected from H, -CN, -OH, halo, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -S(O)2NRA2RA3, -S(O)2RA1, - NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, pyrrolidinyl, oxadiazolyl, tetrazolyl, 4,5-dihydro-1H- imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl, wherein the cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, pyrrolidinyl, oxadiazolyl, tetrazolyl, 4,5-dihydro- 1H-imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl are each independently optionally substituted with one to three substituents selected from C1-C6 alkyl, oxo, and halogen; wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or 5-6 membered heteroaryl; - 79 -Attorney Docket No.15768.0041-00304 each RA1is independently selected from H, optionally substituted C1-C6alkyl, and C1-C6alkoxy, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; and each RA2and RA3is independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy. Embodiment 19. The compound, tautomer, or acceptable salt of any one of embodiments 1- 16, wherein each RAis independently selected from H, F, -CN, -OH, Me, Et, n-Pr, i-butyl, - CHF2, -CF3, -CH2CHF2, -CH2CN, -C(O)OH, -C(O)OMe, -C(O)CH2OMe, -C(O)NH2, - , ,ts 1- 16, wherein each RAis independently selected from H, F, -CN, -OH, Me, Et, n-Pr, i-butyl, - , ,- 80 -Attorney Docket No.15768.0041-00304 Embodiment 21. The compound, tautomer, or acceptable salt of any one of embodiments 1- 16, wherein each RAis independently selected from -CN, -OH, -CHF2, -CF3, -CH2CHF2, - , - , , ents 1-21, wherein Ring B is selected from . Embodiment 23. The compounptable salt of any one of embodiments 1- 21, wherein Ring B is . Embodiment 24. The compound, tautomer, or acceptable salt of any one of embodiments 1-21, wherein Ring B is .Embodiment 25. A compound selected from:- 81 -Attorney Docket No.15768.0041-00304- 82 -Attorney Docket No.15768.0041-00304- 83 -Attorney Docket No.15768.0041-00304- 84 -Attorney Docket No.15768.0041-00304- 85 -Attorney Docket No.15768.0041-00304- 86 -Attorney Docket No.15768.0041-00304- 87 -Attorney Docket No.15768.0041-00304- 88 -Attorney Docket No.15768.0041-00304Embodiment 26. A composition comprising one or more compound(s), tautomer(s), and / or acceptable salt(s) of any one of embodiments 1 to 25 and an acceptable carrier. Embodiment 27. The composition of embodiment 26, further comprising one or more additional therapeutic agent(s). Embodiment 28. The composition of embodiment 27, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, - 89 -Attorney Docket No.15768.0041-00304 an ASK1 inhibitor, an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid17- dehydrogenase (HSD17B13) inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin-sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrates, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N- acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin-receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid- lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta- adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT) inhibitor, an immunomodulator, anti-IL-6 antibody, an anti-TNF-antibody, an NSAID, a disease-modifying antirheumatic drug (DMARD), a steroid,methotrexate, an anti-IL-1 agent, a JAK inhibitor, an interferon, an 11 -hydroxy steroiddehydrogenase-1 (11 .-HSD type 1) inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, anMCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte-stimulating hormone analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent. Embodiment 29. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, - 90 -Attorney Docket No.15768.0041-00304 or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject that benefits from modulation of the level of NAD+ and / or a related metabolite thereof and / or wherein CD38 is upregulated. Embodiment 30. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to small lung cell carcinoma, renal clear cell carcinoma, chronic lymphocytic leukemia, multiple myeloma, hypertension, hypoxic pulmonary vasoconstriction, cardiac hypertrophy, congestive heart failure, stroke, Alzheimer's disease, bipolar disorder, schizophrenia, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, optic neuropathy, epilepsy, idiopathic pulmonary fibrosis, viral-induced fibrosis of the lung, infection-induced fibrosis of the lung, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity, sarcopenic obesity, sarcopenia, dyslipidemia, diabetes, diabetic neuropathy, insulin resistance, pancreatitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, steatosis, non-alcoholic steatohepatitis (NASH), postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin hyperpigmentation, UV skin damage, psoriasis, hidradenitis suppurativa, X-ray-induced DNA damage, periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, neurodegeneration, peripheral neuropathies associated with chemotherapy, a mitochondrial myopathy, or a disease, disorder, orcondition mediated by TNF- or IL-6.Embodiment 31. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition related to aging. Embodiment 32. The compound, tautomer, acceptable salt, or composition of embodiment 31, wherein the disease, disorder, or condition related to aging is or is related to a chronic age- related disease, disorder, or condition. Embodiment 33. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to aging, a age-related chronic disease, - 91 -Attorney Docket No.15768.0041-00304 inflammation, cancer, a cardiovascular disorder, a neurological disorder, a pulmonary disorder, a fibrotic disease, SARS, COVID-19, a metabolic disorder, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, a liver disorder, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, a disease of the skin, damage caused by exposure to radiation, a periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, or a chronic disease associated with cell death. Embodiment 34. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to a fibrotic disease, disorder, or condition of the lung, heart, or kidney. Embodiment 35. The compound, tautomer, or acceptable salt, or composition of embodiment 34, wherein the fibrotic disease is diabetic nephropathy, chronic kidney disease, infection-induced fibrosis of the lung or a virus-induced infection of the lung. Embodiment 36. The compound, tautomer, or acceptable salt of any one of embodiments 1 to 25, or the composition of any one of embodiments 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to multiple myeloma. Embodiment 37. The compound, tautomer, acceptable salt, or composition of embodiment 36, wherein the treatment further comprises administering an immuno-oncology drug to the subject. Embodiment 38. The compound, tautomer, acceptable salt, or composition of embodiment 29, wherein the modulation is an increase in the level of NAD+ and / or a related metabolite thereof. Embodiment 39. The compound, tautomer, acceptable salt, or composition of embodiment 29, wherein the modulation is a decrease in the level of NAD+ and / or a related metabolite thereof. Embodiment 40. The compound, tautomer, acceptable salt, or composition of embodiment 29, wherein the NAD+ and / or related metabolite thereof is selected from the group consisting of NAD+, NMN, ADPR, cADPR, NAM, NAAD, NAADP, NR, and MNAM. Embodiment 41. A method of treating a disease, disorder, or condition in a subject that benefits from modulation of the level of NAD+ or a related metabolite thereof and / or wherein - 92 -Attorney Docket No.15768.0041-00304 CD38 is upregulated in a subject comprising administering to the subject an effective amount of the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28. Embodiment 42. The method of embodiment 41, further comprising administering to the subject one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28. Embodiment 43. The method of embodiment 42, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid17- dehydrogenase (HSD17B13) inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin-sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrates, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N- acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin-receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid- lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta- adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT) inhibitor, an immunomodulator, anti-IL-6 antibody, an anti-TNF-antibody, an NSAID, a disease-modifying antirheumatic drug (DMARD), a steroid,methotrexate, an anti-IL-1 agent, a JAK inhibitor, an interferon, an 11 -hydroxy steroiddehydrogenase-1 (11 .-HSD type 1) inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, anMCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte-stimulating hormone analog, a 5HT2c - 93 -Attorney Docket No.15768.0041-00304 agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent. Embodiment 44. The method of embodiment 42, wherein the one or more additional therapeutic agent(s) are selected from sarilumab, tocilizumab, etanercept, adalimumab, and infliximab. Embodiment 45. The method of embodiment 43 or 44, wherein the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28 is administered to the subject in one, two, or three daily dose(s). Embodiment 46. The method of any one of embodiments 42 to 45, wherein the subject is a mammal. Embodiment 47. The method of any one of embodiments 42 to 45, wherein the subject is a human. Embodiment 48. The method of any one of embodiments 42 to 45, wherein the subject is an animal. Embodiment 49. The method of any one of embodiments 42 to 45, wherein the subject is a domestic animal, wherein the domestic animal is selected from a rabbit, a bird, a cat, a dog, a fish, a rat, a tortoise, and a reptile. Embodiment 50. The method of any one of embodiments 42 to 45, wherein the subject is a working animal or a farm animal, wherein the working animal is selected from cattle, yaks, and horses; and wherein the farm animal is selected from sheep, pigs, cows, chickens, goats, geese, ducks, and llamas. Embodiment 51. A kit comprising the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28 and instructions for use thereof. Embodiment 52. The kit of embodiment 51, further comprising one or more additional therapeutic agent(s). Embodiment 53. The kit of embodiment 52, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) - 94 -Attorney Docket No.15768.0041-00304 inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, aninhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid 17- dehydrogenase(HSD17B13) inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin- sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrate, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin- receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid- lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta- adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT) inhibitor, an immunomodulator, anti-IL-6 antibody, an anti-TNF-antibody, an NSAID, a disease-modifying antirheumatic drug (DMARD), a steroid,methotrexate, an anti-IL-1 agent, a JAK inhibitor, an interferon, an 11 -hydroxy steroiddehydrogenase-1 (11 .-HSD type 1) inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, anMCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte-stimulating hormone analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent. - 95 -Attorney Docket No.15768.0041-00304 Embodiment 54. The kit of embodiment 52 or 53, wherein the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28 and the one or more additional therapeutic agent(s) are in separate containers. Embodiment 55. The kit of embodiment 52 or 53, wherein the compound, tautomer, or acceptable salt of any one of embodiments 1 to 25 or the composition of any one of embodiments 26 to 28 and the one or more additional therapeutic agent(s) are in the same container. Embodiment 56. The kit of embodiment 54 or 55, wherein the container is a bottle, vial, or blister pack, or a combination thereof. EXAMPLES

[0255] While several experimental Examples are contemplated, these Examples are merely exemplary and are non-limiting.

[0256] To fully understand the present disclosure, the following examples are disclosed. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any manner.

[0257] All the specific and generic compounds, and the intermediates disclosed for making those compounds, are considered to be part of the present disclosure.

[0258] The compounds of the present disclosure may be made according to standard chemical and biological practices or as disclosed herein. Throughout the following schemes and in the descriptions for preparing the compounds of this disclosure, the following abbreviations are used: aq. Aqueous Boc, BOC, boc N-tert-butoxycarbonyl d Doublet dd Doublet of doublet DCM Dichloromethane (CH2Cl2) DIPEA, IDEA Diisopropyl ethyl amine DMA N,N-dimethylacetamide DMF Dimethylformamide Eq Equivalents EtOH Ethanol EtOAc Ethyl acetate g Grams - 96 -Attorney Docket No.15768.0041-00304 h Hour(s) H2O WaterHATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HOAc Acetic acid HPLC High-performance liquid chromatography Hz Hertz IPA, iPrOH Isopropanol LCMS Liquid chromatography–mass spectrometry LiCl Lithium Chloride NaH Sodium hydride M Molar MeOH Methanol mg Milligrams MgSO4Magnesium sulphate MHz Megahertz min Minute or minutes mL Milliliters mmol Millimoles mM Millimolar MTBE Methyl t-butyl ether MS Mass spectrometry Na2SO4 Sodium sulphate nM Nanomolar nm Nanometer pM Picomolar ppm Parts per million q Quartet rt or RT Room temperature, ambient, about 25 °C s Singlet t Triplet - 97 -Attorney Docket No.15768.0041-00304 T3P® 2,4,6-Tripropyl-1,3,5,2 5,4 5,6 5-trioxatriphosphinane-2,4,6-trione TBAF Tetrabutylammonium fluoride TCFH N,N,N’,N’-Tetramethylchloroformamidinium hexafluorophosphate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran THP Tetrahydropyran TLC Thin Layer Chromatography TMA Trimethylaluminium L Microliter mol Micromoles °C Degrees Celsius I. Synthesis Routes

[0259] As will be appreciated by those skilled in the art, the compounds provided herein, including tautomers and acceptable salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthesis routes. The following general synthesis schemes are provided as examples of such synthesis routes and are not meant to limit the disclosure of the compounds herein in any way. - 98 -Attorney Docket No.15768.0041-00304

[0260] In Scheme 1, Ring B is connected to the pyrimidine ring through a C atom. ORXis OH or (ORX)2 is a pinacol ester.

[0261] Compound (IV) may be obtained by reaction of chloride (II) with alkyl stannane (III) under Stille cross-coupling reaction conditions. Typical conditions comprise, reaction of compound (III) with chloride (II) in the presence of a suitable palladium catalyst, optionally in the presence of a catalyst such as LiCl, in a suitable solvent at elevated temperature. Preferred conditions comprise, reaction of compounds (II) and (III) in the presence of Pd(dppf)Cl2 or Pd(PPh3)4, optionally in the presence of LiCl in dioxane or DMF at between 100 °C and 120 °C, optionally under microwave irradiation.

[0262] Compound (V) may be obtained by oxidation of compound (IV) using a suitable oxidizing agent, such as KMnO4 in conjunction with NaIO4, in aqueous dioxane at rt.

[0263] Compound (VIII) may be obtained through cross coupling of heterocycloalkyl stannane (VI) and chloride (V) under Stille-type reaction conditions, as described above. - 99 -Attorney Docket No.15768.0041-00304

[0264] Alternatively, compound (VIII) may be obtained by reaction of chloride (V) with boronate ester or acid (VII) under Suzuki-type cross coupling reaction conditions. Typical conditions comprise, reaction of compound (VII) with chloride (V) in the presence of a suitable palladium catalyst and base, in a suitable solvent at elevated temperature. Preferred conditions comprise, reaction of the compounds (V) and (VII) in the presence of Pd(dppf)Cl2 and K3PO4 in THF or dioxane at about 90 °C to 100 °C.

[0265] Compound (IX) may be obtained from ester (VIII) by hydrolysis in the presence of an appropriate alkali metal hydroxide, such as LiOH in aqueous polar solvents such as MeOH or THF at rt.

[0266] Compound (I) may be obtained by aminolysis of compound (VIII) with amine (X) in the presence of trimethyl aluminium in a suitable solvent, such as toluene at about 90 °C to 100 °C.

[0267] Alternatively, compound (I) may be obtained by reaction of amine (X) and acid salt (IX) under standard amide coupling conditions, typically using a suitable coupling agent such as HATU or T3P® and an organic base such as DIPEA or TCFH and 1-methylimidazole in a suitable solvent such as DMF, DCM, or MeCN at rt.

[0268] In Scheme 2, Ring B is linked to the pyrimidine ring through an N atom.

[0269] Compound (XII) may be obtained by an Ullmann-type copper catalyzed aminolysis of compound (V) with amine (XI) in the presence of a suitable copper catalyst such as CuI, a suitable inorganic base such as Cs2CO3 in a suitable solvent such as DMF at elevated temperature, such as 120 °C.

[0270] Compound (I) may be obtained by reaction of amine (X) and acid (XII) under standard amide coupling conditions, as previously described in Scheme 1. - 100 -Attorney Docket No.15768.0041-00304

[0271] In scheme 3, RAis NRA2RA3. Compound (XIV) may be obtained from the acid salt (IX) and amine (XIII) by an acid amine coupling reaction, as previously described in Scheme 1.

[0272] Compound (XV) may be obtained by hydrolysis of compound (XIV). Typical conditions comprise reaction of compound (XIV) in aqueous acetone, catalyzed by a mild acid such as p- TSA at elevated temperature, such as 90 °C.

[0273] Compound (I) may be obtained from an amine, HNRA2RA3, and ketone (XV) under reductive amination reaction conditions. Preferred conditions comprise reaction of the amine, HNRA2RA3, and ketone (XV) in a solvent such as MeOH in the presence of a reducing agent, such as NaBH3CN and AcOH at about 80 °C.

[0274] Compounds (I), (VIII), (XII), (XIV) and (XV) may undergo further reaction to provide alternative compounds (I), (VIII), (XII), (XIV) and (XV) by chemical transformations known to those skilled in the art. These transformations include, but are not limited to: alkylation of a primary or secondary amine, to provide a secondary or tertiary amine; reductive amination of a primary or secondary amine, to provide a secondary or tertiary amine; sulfonation of an amine to provide a sulfonamide; aminolysis of an ester to provide an amide; and hydrolysis of an ester to provide a carboxylic acid

[0275] Compounds (III), (VI), (VII), (X), (XI) and (XIII) may be commercially available or prepared by analogy with the methods described in the Examples and Intermediates section below. - 101 -Attorney Docket No.15768.0041-00304

[0276] Compound (XVII) may be obtained by the condensation of amidine (XVI) with 1,1,1- trifluoropentane-2,4-dione at elevated temperature. Carboxylic acid (XVIII) may be obtained by the oxidation of compound (XVII) using a suitable oxidizing agent, such as KMnO4, in aqueous dioxane. Compound (I) may be obtained by reaction of acid (XVIII) with amine (X) as previously described in Scheme 1.

[0277] It will be appreciated by those skilled in the art that it may be necessary to utilize a suitable protecting group strategy for the preparation of compounds of Formula (I). Typical protecting groups may comprise a carbamate, preferably a Boc group or Fmoc, for the protection of primary or secondary aliphatic amines, C1-C4alkyl, preferably, tert-butyl, ethyl or methyl for the protection of carboxylic acids or acetals for the protection of ketones.

[0278] The need for a protection group and the selection of an appropriate protecting group can be readily assessed by one skilled in the art. Suitable protecting groups and protecting group strategies are described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., Wiley & Sons, Inc., New York (1999); and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006). - 102 -Attorney Docket No.15768.0041-00304 II. Synthesis of Compounds Intermediate 1: Synthesis of ethyl 2-chloro-6-(trifluoromethyl)pyrimidine-4-carboxylate Step 1:

[0279] To a stirred solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (10 g, 46.1 mmol) in dioxane (0.1 L) was added tributyl(1-ethoxyethenyl)stannane (16.6 g, 46.1 mmol) at rt under N2 atmosphere. The mixture was degassed with N2for 5 min, Pd(PPh3)4(5.33 g, 4.61 mmol) was added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by column chromatography (100-200 Mesh silica gel) eluting with 1-2% EtOAc in heptane to give the title compound as a yellow liquid (6 g, 52%).1H NMR (400 MHz, DMSO-d6): 7.96 (s, 1H), 5.70 (d, 1H), 4.90 (d, 1H), 4.02 (q, 2H), 1.36 (t, 3H). Step 2: Synthesis of ethyl 2-chloro-6-(trifluoromethyl)pyrimidine-4-carboxylate

[0280] To an ice-cold stirred solution of NaIO4(10.5 g, 47.6 mmol) in water (75 mL) were added 2-chloro-4-(1-ethoxyethenyl)-6-(trifluoromethyl)pyrimidine (6 g, 23.8 mmol) in dioxane (150 mL) and KMnO4 (1.87 g, 11.9 mmol) under N2 atmosphere. The reaction mixture was stirred at rt for 10 min, then diluted with water (100 mL) and EtOAc (200 mL). The biphasic mixture was filtered through Celite® and the layers separated. The organic layer was washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (100-200 Mesh silica gel) eluting with 2-3% EtOAc in heptane to give the title compound as white solid (3 g, 50%).1H NMR (400 MHz, DMSO-d6): 8.41 (s, 1H), 4.43 (q, 2H), 1.36 (t, 3H). Intermediate 2: Synthesis of ethyl 2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxylate Step 1: Synthesis ofhyl)pyrimidine-4- carboxylate

[0281] To a stirred solution of ethyl 2-chloro-6-(trifluoromethyl)pyrimidine-4-carboxylate - 103 -Attorney Docket No.15768.0041-00304 (Intermediate 1, 200 mg, 0.786 mmol) in THF (8 mL) was added 4,4,5,5-tetramethyl-2-(1- methyl-5-imidazolyl)-1,3,2-dioxaborolane (196 mg, 0.942 mmol) at rt under N2. K3PO4 (334 mg, 1.57 mmol) dissolved in water (0.8 mL) was added to the reaction and the mixture was degassed with N2 for 5 min. Pd(dppf)Cl2 (57 mg, 0.078 mmol) was added, and the reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by column chromatography (230-400 Mesh silica gel) eluting with 25-30% EtOAc in heptane to give the title compound as white solid (80 mg, 34%). LCMS m / z = 301 [M+H]+. Intermediate 3: Synthesis of lithium 2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxylate

[0282] To a stirred s(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2, 250 mg, 0.833 mmol) in THF (5 mL) was added LiOH·H2O (70 mg, 1.66 mmol) dissolved in water (2.5 mL) under N2 and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, the crude was triturated with Et2O, filtered, and the solid was dried in vacuo to give the title compound as an off white solid (200 mg, crude). LCMS m / z = 273 [M+H]+. Intermediate 4: Synthesis of (Z)-2-amino-2-(1-methyl-1H-imidazol-5-yl)ethen-1-ol [02azole-5-carbonitrile (50 g, 467 mmol) and NaHCO3 (98 g, 1.167 mol) were charged to a reactor, with stirring. NH2OH.HCl (36.5 g, 525 mmol) was then added and the reaction mixture was warmed to 35±5oC and stirred for 5 h. The solid in the reactor was removed by filtration and the cake washed with EtOH (250 mL). The filtrate was concentrated under vacuum, below 40oC, until the volume <100 mL. Heptane (250 mL) was added and the mixture further concentrated under vacuum. The mixture was cooled and stirred for 1h at 15±5oC. The solid was isolated by filtration, washed with heptane (50 mL) and dried in a stream of dry N2 to give the title compound as a white solid (56.54 g, 87% yield).1H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), (d, J = 4.5 Hz, 1H), 7.28 (d, J = 0.9 Hz, 1H), 5.76 (s, 2H). - 104 -Attorney Docket No.15768.0041-00304 Intermediate 5: Synthesis of 1-methyl-1H-imidazole-5-carboximidamide [02 l-1H-imidazol-5-yl)ethen-1-ol (Intermediate 4, 500g, 3.59 mol) and EtOH (10 L) was purged with N2. Pt / V / C (75 g, 15%wt) was charged to the solution in a reactor and the reaction mixture was stirred and heated under H2 (10 bar) for 21 h at50±5 . The mixture was cooled to 20±5 and the catalyst removed by filtration throughCelite®. The filtrate was concentrated under vacuum below 50oC until the volume was <2.5 L. Heptane was added (2 x 5 L) and distillation continued to remove EtOH until the volume <2.5 L. This was then repeated by addition of a further volume of heptane (100 mL) and then distillation down to <50 mL in order to remove the EtOH. The mixture was cooled to 0±5oC and stirred for 1 h at 0±5oC. The product was filtered off and dried in a stream of dry N2 to give the title compound as a yellow solid (374.4 g, 84% yield).1H NMR (300 MHz, DMSO-d6,): 7.65 (s, 1 H), 7.37 (d, J = 1.2 Hz, 1H), 6.36 (br, 3H), 3.84 (s, 3H). Intermediate 6: Synthesis of 4-methyl-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine [02ide (Intermediate 5, 648 g, 5.22 mol) and toluene (6.5 L) were charged to a reactor under N2atmosphere.1,1,1-Trifluoropentane-2,4-dione (1.6 kg, 10.4 mol) was added slowly to the reactor. The mixture was heated to 70±5oC and then stirred for 1 h. The mixture was cooled to 25±5oC and water (6.5 L) was added. The organic layer was separated and the aqueous phase was extracted with MtBE, (3.24 L x 2). The combined organic phases were washed with water (3.24 L). The organic phase was concentrated, under vacuum, below 50oC until the volume was <3.2L. The toluene was exchanged for heptane by distillation (heptane 3.2 L x 3) and added after each distillation down to <3.2L). The mixture was cooled to 0±5oC and stirred for 1 h at 0±5oC. The solid product was filtered off and drie in a stream of dry N2 to give the title compound as a yellow solid (1.21 Kg, 96% yield).1H NMR (300 MHz DMSO-d6): 7.90 (q, JF-H= 0.6 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 4.02 (s, 3H), 2.63 (s, 3H). - 105 -Attorney Docket No.15768.0041-00304 Intermediate 7: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4- carboxylic acid [02 79 g, 10.3 mol) were charged to a reactor. 4-Methyl-2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine (Intermediate 6, 500 g, 2.06 mol) was then charged to the reactor with stirring. The mixture was cooled to 5±5oC and KMnO4 (1.3 kg, 4.0 eq.) was added in several portions, keeping the temperature at 5±5oC. The mixture was stirred for 13.5 h at 5±5oC. Na2SO3 (1.3 kg) in H2O (5 L) was added and the mixture was stirred for 18 h at 15±5oC. The mixture was filtered and the filtrate was extracted with MTBE (2.5 L). The aqueous phase was collected and the pH adjusted to 5-6 by addition of 6M HCl (7.5eq.) at 5±5oC. The resulting suspension was stirred for 1h at 5±5oC and then filtered. The solid cake was washed with cold water (1 L). THF (2.5L) was charged to the reactor and the solid product was added. The suspension was stirred for 1 h at 15±5oC, MTBE (3 L) was added and stirring continued for a 1 h. The solid was filtered off and the cake washed with THF / MTBE (1:1, 1 L). The isolated product was dried under vacuum at 50oC to afford the title compound as white solid (67% yield). LCMS m / z = 273 [M+H]+ Example 1: N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-1)

[0287] T(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2, 80 mg, 0.266 mmol) and 2-(2- methoxyethoxy)pyrimidin-5-amine (68 mg, 0.4 mmol) in toluene (3 mL) was added TMA (0.66 mL, 2 M, 1.33 mmol) dropwise under N2 and the reaction mixture stirred at 100 °C for 3 h. The reaction mixture was quenched with aq. NH4Cl (20 mL) and extracted with 25% IPA in CHCl3(2 x 20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was triturated with Et2O (20 mL) and dried under reduced pressure to give the desired compound as an off-white solid (58 mg, 50%).1H NMR (400 MHz, DMSO-d6): 10.89 (s, 1H), 8.99 (s, 2H), 8.32 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 4.44 (t, 2H), 4.07 (s, 3H), 3.68 (t, 2H), 3.31 (s, 3H). LCMS m / z = 424 [M+H]+. - 106 -Attorney Docket No.15768.0041-00304 Example 2: 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-morpholinocyclohexyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-2)

[0288] To a(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2, 150 mg, 0.5 mmol) and 4- morpholinocyclohexylamine hydrochloride (128 mg, 0.5 mmol) in toluene (5 mL) was added drop wise TMA (1.25 mL, 2.5 mmol) at 0 °C under N2. The reaction mixture was stirred at 100 °C for 16 h, then quenched with NH4Cl (20 mL) and extracted with 25% IPA in CHCl3 (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (neutral alumina gel, 4 g SNAP) eluting with 4-6% MeOH in DCM to give the desired product as an off white solid (58 mg, 26%).1H NMR (400 MHz, DMSO-d6): 8.71 (d, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 4.03 (s, 3H), 3.80-3.78 (m, 1H), 3.56-3.54 (m, 4H), 2.50 (m, 4H), 2.20-2.00 (m, 1H), 1.89-1.87 (m, 4H), 1.55-1.52 (m, 2H), 1.32-1.30 (m, 2H). LCMS m / z = 439 [M+H]+. Example 3: 2-(1-methyl-1H-imidazol-5-yl)-N-(quinuclidin-4-ylmethyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-32)

[0289] The titlthyl 2-(1-methyl- 1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2) and quinuclidin- 4-ylmethanamine, following the procedure described in Example 1.1H NMR (400 MHz, DMSO-d6): 8.86 (t, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.05 (s, 3H), 3.15 (d, 2H), 2.72 (t, 6H) and 1.35 (t, 6H). LCMS m / z = 395 [M+H]+. Examples 4 to 7

[0290] The compounds in the following table were obtained from ethyl 2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2) and the appropriate amine, following a similar procedure to that described in Example 2 (I-2). The crude products were isolated by flash column chromatography (100-200 Mesh silica gel) eluting with 5-10% MeOH in DCM, unless stated otherwise. - 107 -Attorney Docket No.15768.0041-00304 Cmpd No Name, Structure Amine, Data I-3 N-(1-(1-methyl-1H-imidazol-2- 1-(1-methyl-2-imidazolyl)-4- s, - s, e s, s, , e s,- 108 -Attorney Docket No.15768.0041-00304 1.81 (m, 2H), 1.73-1.63 (m, 6H). LCMS = 447 [M+H]+.(trifluoromethyl)pyrimidine-4-carboxamide (I-4) S

[0291] To an ice-cold stirred solution of tert-butyl (1-(5-fluoropyridin-2-yl)piperidin-4- yl)carbamate 220 mg, 0.75 mmol) in DCM (5 mL) was added TFA (1.5 mL) dropwise under N2 and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure, the crude was basified with aq. NaHCO3 (10 mL) and the mixture extracted with 25% IPA in CHCl3 (2 x 25 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale-yellow solid (120 mg, 71%). LCMS m / z = 196 [M+H]+. Step 2: Synthesis of N-(1-(5-fluoropyridin-2-yl)piperidin-4-yl)-2-(1-methyl-1H-imidazol-5-yl)- 6-(trifluoromethyl)pyrimidine-4-carboxamide

[0292] The title compound was obtained as a white solid, 58 mg, 39%, from ethyl 2-(1-methyl- 1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2) and 1-(5-fluoro- 2-pyridyl)-4-piperidylamine, following a similar method to that described in Examples 4 to 7, except the product was purified by silica gel chromatography, eluting with 40- 45% EtOAc in heptane.1H NMR (400 MHz, DMSO-d6): 8.83 (d, 1H), 8.22 (s, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.50 (dt, 1H), 6.93 (d, 1H), 4.28 (d, 2H), 4.19-4.11 (m, 1H), 4.02 (s, 3H), 2.96 (t, 2H), 1.83-1.81 (m, 2H), 1.73-1.67 (m, 2H). LCMS m / z = 450 [M+H]+. - 109 -Attorney Docket No.15768.0041-00304 Example 9: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(1-(pyridin-2-yl)piperidin-4-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-11)

[0293] To a s(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3), (100 mg, 0.36 mmol) and 1-(2- pyridyl)-4-piperidylamine (63.7 mg, 0.36 mmol) in DMF (2 mL) were added HATU (205 mg, 0.54 mmol) and DIPEA (0.3 mL, 1.8 mmol) under N2 and the reaction mixture stirred at rt for 3 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with chilled brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by RP-HPLC purification [X Bridge Shield RP18 (19*250) 10 m] using buffer 5 mM NH4CO3in water and MeCN to give the title compound as white solid (65 mg, 42%).1H NMR (400 MHz, DMSO-d6): 8.83 (d, 1H), 8.21 (d, 1H), 8.11 (dd, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.54-7.50 (m, 1H), 6.88 (d, 1H), 6.61-6.58 (m, 1H), 4.36 (m, 2H), 4.22-4.12 (m, 1H), 4.02 (s, 3H), 2.96 (m, 2H), 1.84-1.81 (m, 2H), 1.75-1.65 (m, 2H). LCMS m / z = 432 [M+H]+. Example 10: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(pyrrolidin-1- yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-14)

[0294] The tithium 2-(1-methyl- 1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and (1r,4r)-4-(1- pyrrolidinyl)cyclohexylamine hydrochloride, following a similar procedure to that described in Example 9 (I-11).1H NMR (400 MHz, DMSO): 8.71 (d, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.03 (s, 3H), 3.85-3.77 (m, 1H), 2.61-2.50 (m, 4H), 2.02-1.99 (m, 3H), 1.87-1.84 (m, 2H), 1.67 (m, 4H), 1.60-1.51 (m, 2H), 1.32-1.23 (m, 2H). LCMS m / z = 423 [M+H]+. - 110 -Attorney Docket No.15768.0041-00304 Example 11: 2-(1-methyl-1H-imidazol-5-yl)-N-(1-(N-methylsulfamoyl)piperidin-4-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-54)

[0295] T 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 1- (methylaminosulfonyl)-4-piperidinamine hydrochoride, following the procedure described in Example 9 (I-11).1H NMR (400 MHz, DMSO-d6): 8.87 (d, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.11 (q, 1H), 4.04 (s, 3H), 4.01-3.99 (m, 1H), 3.57-3.54 (m, 2H), 2.86-2.81 (m, 2H), 2.53 (q, 3H), 1.88-1.81 (m, 2H) and 1.79-1.72 (m, 2H). LCMS m / z = 448 [M+H]+. Example 12: Synthesis of N-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-13)

[0296] To a6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 60 mg, 0.216 mmol) in DMF (6 mL) was added 4-(1-methyl-1H-imidazol-2-yl)aniline (37 mg, 0.216 mmol) under N2. DIPEA (0.188 mL, 1.08 mmol) and HATU (123 mg, 0.324 mmol) were added, and the reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with ice-cold water (25 mL) and extracted with 25% IPA in CHCl3(2 x 25 mL). The combined organic layer was washed with chilled brine solution (2 x 25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (4 g SNAP, neutral alumina) eluting with 8-9% MeOH in DCM to give the title product as a yellow solid (39 mg, 41%).1H NMR (400 MHz, DMSO-d6): 10.79 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 8.02-8.00 (m, 3H), 7.76 (d, 2H), 7.26 (s, 1H), 6.98 (s, 1H), 4.09 (s, 3H), 3.78 (s, 3H). LCMS m / z = 428 [M+H]+. - 111 -Attorney Docket No.15768.0041-00304 Example 13: Synthesis of N-(4-(1H-imidazol-2-yl)phenyl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-17)

[0297] The titl ithium 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 4- (2-imidazolyl)aniline following a similar procedure to that described in Example 12 (I-13).1H NMR (400 MHz, DMSO-d6): 12.49 (s, 1H), 10.73 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.97 (s, 4H), 7.19-7.08 (m, 2H), 4.09 (s, 3H). LCMS m / z = 414 [M+H]+. Example 14: Synthesis of N-(6-hydroxypyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-20):

[0298] The tithium 2-(1-methyl- 1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 5-amino-2- pyridinol, following a similar procedure to that described in Example 12 (I-13). The crude waspurified by RP-HPLC purification using [X Bridge C18 (19*100) 10 m] in 5 mM NH4CO3 inwater and MeCN.1H NMR (400 MHz, DMSO): 11.28 (br s, 1H), 10.50 (s, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.80 (dd, 1H), 6.44 (d, 1H), 4.06 (s, 3H). LCMS m / z = 365 [M+H]+. Example 15: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4-ylmethyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-18)ne- 4-carboxamido)methyl)piperidine-1-carboxylate:

[0299] To an ice-cold stirred solution of lithium 2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) (70 mg, 0.252 mmol) and tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate (53.9 mg, 0.252 mmol) in DMF (1 mL) were added - 112 -Attorney Docket No.15768.0041-00304 HATU (239 mg,0.629 mmol) and DIPEA (0.13 mL, 0.755 mmol) under N2and the reaction stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with 25% IPA in CHCl3(50 mL). The organic layer was washed with chilled brine solution (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 Mesh silica gel) eluting with 3- 4% MeOH in DCM to give the title compound 10 (59 mg, 50%). LCMS m / z = 469 [M+H]+. Step 2: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4-ylmethyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide

[0300] To an ice-cold stirred solution of tert-butyl 4-((2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamido)methyl)piperidine-1-carboxylate (59 mg, 0.126 mmol) in DCM (4 mL) was added TFA (1 mL) under N2 and the reaction mixture stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure, the residue was basified with aq. NaHCO3 (20 mL) and extracted with 25% IPA in CHCl3 (2 x 20 mL). The combined organic layer was dried over Na2SO4,filtered, and concentrated under reduced pressure. The crude waspurified by RP-HPLC using X Bridge C18 (19*100) 10 m in 5 mM NH4CO3 in water andMeCN to give the title compound as white solid (9 mg, 20%).1H NMR (400 MHz, DMSO): 9.05 (br s, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 4.04 (s, 3H), 3.97 (m, 1H), 3.24-3.21 (m, 2H), 2.93-2.90 (m, 2H), 2.43-2.40 (m, 2H), 1.69-1.66 (m, 1H), 1.60-1.57 (m, 2H), 1.10-1.02 (m, 2H). LCMS m / z = 369 [M+H]+. Example 16: Synthesis of N-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-21): Step 1: Sy, oxylate:

[0301] To an ice-cold stirred solution of 4-(2-imidazolin-2-yl)aniline (0.1 g, 0.620 mmol) and Boc anhydride (203 mg, 0.930 mmol) in DMF (3 mL) was added TEA (0.258 mL, 1.86 mmol) under N2 and the reaction mixture stirred at rt for 2 h. The reaction mixture was diluted with ice - 113 -Attorney Docket No.15768.0041-00304 cold water (50 mL) and extracted with 25% IPA in CHCl3(2 x 50 mL). The combined organic layer was washed with chilled brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with 4-5% MeOH in DCM to give the title compound as brown solid (95 mg, 59%). LCMS m / z = 262 [M+H]+. Step 2: Synthesis of tert-butyl 2-(4-(2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamido)phenyl)-4,5-dihydro-1H-imidazole-1-carboxylate:

[0302] To an ice-cold stirred solution of lithium 2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 100 mg, 0.359 mmol) and tert-butyl 2-(4-aminophenyl)-4,5-dihydro-1H-imidazole-1-carboxylate (94 mg, 0.359 mmol) in DMF (3 mL) were added HATU (205 mg, 0.539 mmol) and DIPEA (0.18 mL, 1.07 mmol) under N2 and the reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (20 mL) and filtered through a sintered funnel. The solid material was washed with Et2O (20 mL) and dried under reduced pressure to give the title compound as a yellow solid (70 mg, 38%). LCMS m / z = 516 [M+H]+. Step 3: Synthesis of N-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide:

[0303] The title compound was obtained as a beige solid, 28 mg, 53%, from tert-butyl 2-(4-(2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamido)phenyl)-4,5-dihydro- 1H-imidazole-1-carboxylate, following the procedure described in Example 8, step 1 (I-4).1H NMR (400 MHz, DMSO): 10.77 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.87 (d, 2H), 7.13 (br s, 1H), 4.09 (s, 3H), 3.61 (br s, 4H). LCMS m / z = 416 [M+H]+.: Example 17: Synthesis of N-(1-cyclopentylpiperidin-4-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl) pyrimidine-4-carboxamide (I-30):

[0304] To(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 100 mg, 0.359 mmol) and 1- cyclopentylpiperidin-4-amine hydrochloride (104 mg, 0.431 mmol) in DMF (3 mL) were added DIPEA (0.3 mL, 1.79 mmol) and HATU (205 mg, 0.539 mmol) under N2 and the reaction mixture was stirred at rt for 5 h. Ice-cold water (10 mL) was added and the resulting mixture was filtered through a sinter funnel. The solid was dried under reduced pressure, then triturated with - 114 -Attorney Docket No.15768.0041-00304 Et2O and DCM to give the title compound as white solid (33 mg, 22%).1H NMR (400 MHz, DMSO-d6): 8.75 (d, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.04 (s, 3H), 3.89-3.78 (m, 1H), 2.99-2.91 (m, 3H), 2.06-1.95 (m, 2H), 1.86-1.68 (m, 6H), 1.60-1.49 (m, 4H) 1.35-1.31 (m, 2H). LCMS m / z = 423 [M+H]+. Example 18: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(4-(1-methyl-1H-tetrazol-5-yl) phenyl)-6-(trifluoromethyl) pyrimidine-4-carboxamide (I-33):

[0305] The t (1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 4-(1-methyl- 1H-tetrazol-5-yl)aniline, following the procedure described in Example 17 (I-30).1H NMR (400 MHz, DMSO-d6): 10.94 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.16 (d, 2H), 8.01 (s, 1H), 7.96 (d, 2H), 4.21(s, 3H), 4.09 (s, 3H). LCMS m / z = 430 [M+H]+. Example 19: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(2-morpholinopyrimidin-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-19):

[0306] To a- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 70 mg, 0.252 mmol) and 2- morpholino-5-pyrimidinylamine (45.4 mg, 0.252 mmol) in DCM (2 mL) were added DIPEA (0.22 mL, 1.26 mmol) and T3P® (0.375 mL, 1.26 mmol) under N2and the reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by column chromatography (12 g SNAP, neutral alumina) eluting with 2-3% MeOH in DCM to give the title compound as yellow solid (30 mg, 27%).1H NMR (400 MHz, DMSO- d6): 10.71 (s, 1H), 8.78 (s, 2H), 8.32 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 4.07 (s, 3H), 3.72-3.66 (m, 8H). LCMS m / z = 435 [M+H]+. - 115 -Attorney Docket No.15768.0041-00304 Example 20: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(1-(pyrimidin-2-yl)piperidin-4- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-29)

[0307] The m 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 1- (pyrimidin-2-yl)piperidin-4-amine, following a similar procedure to that described in Example 19 (I-19).1H NMR (400 MHz, DMSO-d6): 8.82 (d, 1H), 8.37 (d, 2H), 8.22 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 6.61 (t, 1H), 4.72-4.69 (m, 2H), 4.23-4.22 (m, 1H), 4.02 (s, 3H), 3.04 (t, 2H), 1.86- 1.83 (m, 2H), 1.71-1.62 (m, 2H). LCMS m / z = 433 [M+H]+. Example 21: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-27):

[0308] The titium 2-(1-methyl- 1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 1- (methylsulfonyl)piperidin-4-amine, following a similar procedure to that described in Example 19 (I-19).1H NMR (400 MHz, DMSO-d6): 8.87 (d, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 4.04 (s, 3H), 4.01-3.97 (m, 1H), 3.62-3.59 (m, 2H), 2.91-2.85 (m, 5H), 1.91-1.89 (m, 2H), 1.84-1.76 (m, 2H). LCMS m / z = 433 [M+H]+. Example 22: 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-52)

[0309] The t, , , ium 2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 1- (5-amino-2-pyridyl)-2-pyrrolidinone, following the procedure described in Example 26.1H NMR - 116 -Attorney Docket No.15768.0041-00304 (400 MHz, DMSO-d6): 10.86 (s, 1H), 8.85 (d, 1H), 8.37-8.33 (m, 2H), 8.26 (dd, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 4.08 (s, 3H), 4.01 (t, 2H), 2.59 (t, 2H), 2.09-2.02 (m, 2H). LCMS m / z = 432 [M+H]+. Example 23: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-((1-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)methyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-25):

[0310] To a -(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 100 mg, 0.359 mmol) in DCM (4 mL) was added (1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methanamine (71.3 mg, 0.359 mmol) under N2. DIPEA (0.2 mL, 1.08 mmol) and T3P® (0.7 mL, 1.08 mmol) were added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with 25% IPA in CHCl3 (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep-HPLC using X Bridge Shield RP18 (19*250) 10 m column eluting with 5 mM NH4CO3 in water and MeCN, to give the title compound as brown solid (12 mg, 8%).1H NMR (400 MHz, DMSO-d6): 9.07 (t, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.04 (s, 3H), 3.85 (d, 2H), 3.26-3.21 (m, 4H), 2.87- 2.84 (m, 2H), 2.41-2.35 (m, 1H), 2.07-2.01 (m, 2H), 1.62-1.56 (m, 5H), 1.44-1.35 (m, 2H), 1.23- 1.12 (m, 2H). LCMS m / z = 453 [M+H]+. Examples 24 to 30

[0311] The compounds in the following table were prepared from lithium 2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and the appropriate amine, following a similar procedure to that described in Example 23 (I-25). Cmpd No Name, Structure Amine, Data 7- 117 -Attorney Docket No.15768.0041-00304 I-51 N-(4-(1H-tetrazol-1-yl)phenyl)-2-(1- 4-(1H-tetrazol-1-yl)aniline methyl-1H-imidazol-5-yl)-6- white solid (32 mg, 30%), , - 6 , 7 - d,- 118 -Attorney Docket No.15768.0041-00304 1H NMR (400 MHz, DMSO-d6): 11.43 (s, 1H), 8.84 (d, 1H), 8.24 (s, 3 . ),Example 31: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(1-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-44)

[0312] To an icl)-6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) (100 mg, 0.360 mmol) and 1- (tetrahydro-2H-pyran-4-yl)-4-piperidylamine, hydrochloride (111 mg, 0.431 mmol) in DCM (10 mL, 156 mmol) were added T3P® (0.5 mL, 0.899 mmol) and DIPEA (0.3 mL, 1.8 mmol) under N2atmosphere and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with 25% IPA in CHCl3 (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 Mesh silica gel) using 6-7% MeOH in DCM to get the desired compound as beige solid (41 mg, 26%).1H NMR (400 MHz, DMSO-d6): 8.75 (br s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 4.02 (s, 3H), 3.87-3.80 (m, 3H), 3.29-3.23 (m, 2H), 2.96-2.85 (m, 2H), 2.20-2.05 (m, 2H), 1.89-1.70 (m, 7H), 1.48-1.44 (m, 2H). LCMS m / z = 439 [M+H]+. - 119 -Attorney Docket No.15768.0041-00304 Example 32: 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyrimidine-4-carboxamide (I-59)

[0313] The title lithium 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 6- (trifluoromethyl)pyridin-2-amine, following a similar procedure to that described in Example 31 (I-44).1H NMR (400 MHz, DMSO-d6): 11.21 (s, 1H), 8.45 (d, 1H), 8.26-8.20 (m, 3H), 7.99 (s, 1H), 7.78 (d, 1H), 4.08 (s, 3H). LCMS m / z = 417 [M+H]+. Example 33: 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)-N-(6- (trifluoromethyl)pyridin-3-yl)pyrimidine-4-carboxamide (I-60)

[0314] The tim lithium 2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and 6- (trifluoromethyl)pyridin-3-amine, following the procedure described in Example 31 (I-44).1H NMR (400 MHz, DMSO-d6): 11.16 (s, 1H), 9.24 (d, 1H), 8.59 (dd, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.04-8.01 (m, 2H), 4.08 (s, 3H). LCMS m / z = 417 [M+H]+. Example 34: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-28) S(trifluoromethyl)pyrimidine-4-carboxamido)piperidine-1-carboxylate:

[0315] The title compound was obtained as an off-white solid, 190 mg, 81%, from lithium 2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and (9H-fluoren-9-yl)methyl 4-aminopiperidine-1-carboxylate hydrochloride, following the procedure described in Example 19 (I-19). LCMS m / z = 577 [M+H]+. Step 2: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4-yl)-6- - 120 -Attorney Docket No.15768.0041-00304 (trifluoromethyl)pyrimidine-4-carboxamide:

[0316] To an ice-cold stirred solution of (9H-fluoren-9-yl)methyl 4-(2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamido)piperidine-1-carboxylate (0.2 g, 0.347 mmol) in DCM (4 mL) was added piperidine (0.5 mL, 5.2 mmol) under N2 and the reaction mixture stirred at rt for 5 h. The reaction mixture was concentrated under reduced pressure and the crudewas purified by prep-HPLC using X Bridge C18 (19*100) 10 m column, eluting with 5 mMNH4CO3 in water and MeCN to give the title compound as white solid (34 mg, 27%).1H NMR (400 MHz, DMSO-d6): 8.77 (d, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 4.04 (s, 3H), 3.92- 3.85 (m, 1H), 2.99-2.96 (m, 2H), 2.55-2.53 (m, 2H), 1.74-1.72 (m, 2H) 1.62-1.54 (m, 2H). LCMS m / z = 355 [M+H]+. Example 35: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(2-(methylsulfonyl)pyrimidin-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-35)

[0317] To a- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) (100 mg, 0.359 mmol) and 2- (methylsulfonyl)pyrimidin-5-amine (75 mg, 0.431 mmol) in DCM (5 mL) were added DIPEA (0.2 mL, 1.07 mmol) and T3P® (0.6 mL, 0.899 mmol) under N2and the reaction stirred at rt for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was triturated with DCM and Et2O to get the title compound as an off-white solid (51 mg, 35%).1H NMR (400 MHz, DMSO-d6): 11.35 (s, 1H), 9.51 (s, 2H), 8.33 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 4.08 (s, 3H), 3.43 (s, 3H). LCMS m / z = 428 [M+H]+. Examples 36 to 41

[0318] The compounds in the following table were prepared from lithium 2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and the appropriate amine, following a similar procedure to that described in Example 35 (I-35). Cmpd Name Structure Startin amine Data- 121 -Attorney Docket No.15768.0041-00304 (trifluoromethyl)pyrimidine-4-1H NMR (400 MHz, DMSO-d6): carboxamide 11.17 (s, 1H), 10.21 (s, 1H), 9.14 (d, d - 9 , 1- 4- 8- e,- 122 -Attorney Docket No.15768.0041-00304 3.23 (m, 2H), 2.80-2.77 (m, 2H), 2.17 (s, 3H), 1.90-1.87 (m, 2H), 1.65-1.59 , ),p y y y p p y y y imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-43)

[0319] To a- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) (60 mg, 0.216 mmol) and (1-(2- methoxyethyl)piperidin-4-yl)methanamine (45 mg, 0.259 mmol) in DMF (1 mL) were added HATU (123 mg, 0.324 mmol) and DIPEA (0.1 mL, 0.647 mmol) under N2and the reaction stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (20 mL) and extracted with 25% IPA in CHCl3(2 x 20 mL). The combined organic layer was washed with chilled brine solution (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by RP-HPLC using X Bridge C18 (19*100) 10µm in 5 mM NH4CO3in water and MeCN to give the title compound as brown solid (12 mg, 12%).1H NMR (400 MHz, DMSO-d6): 9.06 (t, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 4.04 (s, 3H), 3.38 (t, 2H), 3.23 (t, 2H), 3.19 (s, 3H), 2.84-2.81 (m, 2H), 2.40 (t, 2H), 1.89-1.84 (m, 2H), 1.61-1.54 (m, 3H), 1.21- 1.12 (m, 2H). LCMS m / z = 427 [M+H]+. - 123 -Attorney Docket No.15768.0041-00304 Example 43: Synthesis of N-((1-(cyanomethyl) piperidin-4-yl) methyl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide (I-41) Step rimidine-4-carboxamido)methyl)piperidine-1-carboxylate

[0320] The title compound was obtained as a yellow solid, 300 mg, 89%, from lithium 2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and tert- butyl 4-(aminomethyl)-1-piperidinecarboxylate, following a similar procedure to that described in Example 35, I-35. LCMS m / z = 469 [M+H]+. Step 2: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4-ylmethyl)-6-(trifluoromethyl) pyrimidine-4-carboxamide:

[0321] To an ice-cold stirred solution of tert-butyl 4-((2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamido)methyl)piperidine-1-carboxylate (300 mg, 0.640 mmol) in DCM (6 mL) was added TFA (2 mL) under N2and the reaction stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude was cooled to 0 °C, basified with aq. NaHCO3 solution (50 mL) and extracted with 25% IPA in CHCl3 (50 mL). The organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as yellow solid (170 mg, 72%). LCMS m / z = 369 [M+H]+. Step-3: Synthesis of N-((1-(cyanomethyl) piperidin-4-yl) methyl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide:

[0322] To an ice-cold stirred solution of 2-(1-methyl-1H-imidazol-5-yl)-N-(piperidin-4- ylmethyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (65 mg, 0.176 mmol) in MeCN (10 mL) were added K2CO3 (24.4 mg, 0.176 mmol) and DIPEA (0.03 mL, 0.176 mmol) under N2. Bromoacetonitrile (21 mg, 0.176 mmol) was added dropwise and the reaction mixture stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the crude was triturated using DCM and Et2O (10 mL) to give the desired product as an off white solid (35 mg, 48%).1H NMR (400 MHz, DMSO-d6): 9.09 (t, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 4.05 (s, 3H), 3.69 - 124 -Attorney Docket No.15768.0041-00304 (s, 2H), 3.28-3.25 (m, 2H), 2.79-2.77 (m, 2H), 2.11 (t, 2H), 1.71-1.62 (m, 3H), 1.28-1.19 (m, 2H). LCMS m / z = 408 [M+H]+. Example 44: Synthesis of N-(1-(cyanomethyl) piperidin-4-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide (I-47)

[0323] To a din-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (Example 34 (I-28), 70 mg, 0.198 mmol) in MeCN (4 mL) were added K2CO3 (41 mg, 0.296 mmol) and DIPEA (69 µL, 0.395 mmol) under N2. A solution of bromoacetonitrile (47 mg, 0.395 mmol) in MeCN (1 mL) was added dropwise at 0 °C and the reaction mixture stirred at rt for 1 h. The reaction was concentrated under reduced pressure. The crude was purified by flash column chromatography (neutral alumina) eluting with 2-5% MeOH in DCM to give the desired compound as an off-white solid (14 mg, 18%).1H NMR (400 MHz, DMSO-d6): 8.81 (d, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 4.04 (s, 3H), 3.87-3.82 (m, 1H), 3.74 (s, 2H), 2.84-2.82 (m, 2H), 2.31-2.25 (m, 2H), 1.83-1.77 (m, 4H). LCMS m / z = 394 [M+H]+. Example 45: Synthesis of N-((1-(2,2-difluoroethyl) piperidin-4-yl) methyl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide (I-50)

[0324] olyl)-6- (trifluoromethyl)-4-pyrimidinecarboxamide (Example 15 (I-18), 55 mg, 0.149 mmol) in MeCN (2 mL) was added K2CO3(31 mg, 0.224 mmol) under N2. A solution of 2,2-difluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (54 mg, 0.149 mmol) in MeCN (1 mL) was added and the reaction mixture stirred at rt for 10 min. The reaction mixture was filtered through a sintered funnel and the filtrate was concentrated under reduced pressure. The crude was purified by RP-HPLC purification using X Bridge Shield RP18 (19*250) 10 m in 5 mM NH4CO3 in water and MeCN to give the desired compound as pale yellow solid (10 mg, 15%).1H NMR (400 MHz, DMSO-d6): 9.09 (t, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 6.10 (tt, 1H), 3.25 (t, - 125 -Attorney Docket No.15768.0041-00304 2H), 2.89-2.86 (m, 2H), 2.67 (dt, 2H), 2.11-2.06 (m, 2H), 1.64-1.57 (m, 3H), 1.25-1.17 (m, 2H). LCMS m / z = 433 [M+H]+. Example 46: Synthesis of N-(1-cyanopiperidin-4-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-39)

[0325] To an ice- piperidin-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (Example 34 (I-28), 100 mg, 0.282 mmol) in DCM (10 mL) was added NaHCO3 (94.8 mg, 1.13 mmol) dissolved in water (3 mL). CNBr (60 mg, 0.564 mmol) was then added dropwise under N2and the reaction mixture stirred at rt for 2 h. The reaction was quenched with water (50 mL) and extracted with DCM (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by RP-HPLC using column X Bridge C18 (19*100) 10 m in 5 mM NH4CO3 in Water and MeCN to give the title compound as a white solid (14 mg, 12%).1H NMR (400 MHz, DMSO-d6): 8.91 (d, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 4.08-3.99 (m, 4H), 3.46-3.43 (m, 2H), 3.21-3.14 (m, 2H), 1.90-1.80 (m, 4H). LCMS m / z = 380 [M+H]+. Example 47: Synthesis of N-(1-(ethylsulfonyl) piperidin-4-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide (I-48)

[0326] To a-6- (trifluoromethyl)-4-pyrimidinecarboxamide (Example 34 (I-28), 70 mg, 0.198 mmol) in DCM (3 mL) were added Et3N (42 µL, 0.296 mmol) under N2. A solution of (chlorosulfonyl)ethane 4 (18 µL, 0.198 mmol) in DCM (2 mL) was added dropwise and the reaction mixture stirred at rt for 15 min. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 Mesh silica gel) eluting with 3-4% MeOH in DCM to give the desired compound as beige solid (14 mg, 16%).1H NMR (400 MHz, DMSO-d6): 8.89 (d, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 4.06 (s, 3H), 4.04-3.97 (m, 1H), 3.67-3.63 (m, 2H), 3.07 (q, 2H), 3.00-2.94 (m, - 126 -Attorney Docket No.15768.0041-00304 2H), 1.88-1.80 (m, 2H), 1.78-1.72 (m, 2H), 1.22 (t, 3H). LCMS m / z = 447 [M+H]+. Example 48: Synthesis of N-(6-(4,5-dihydro-1H-imidazol-2-yl)pyridin-3-yl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-45) Ste

[0327] To a stirred solution of 5-amino-2-pyridinecarbonitrile (500 mg, 4.2 mmol) in ethylenediamine (5 mL) was added P2S5 (1.12 g, 2.52 mmol) at rt under N2 and the reaction stirred at 120 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with 25% IPA in CHCl3(3 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as brown solid (490 mg, 72%). LCMS m / z = 163 [M+H]+. Step 2: Synthesis of tert-butyl 2-(5-aminopyridin-2-yl)-4,5-dihydro-1H-imidazole-1-carboxylate:

[0328] To a stirred solution of 6-(2-imidazolin-2-yl)-3-pyridylamine (480 mg, 2.96 mmol) in DMF (5 mL) were added Et3N (1.25 mL, 8.88 mmol) and Boc anhydride (1.02 mL, 4.44 mmol) at rt under N2and the reaction mixture stirred at rt for 4 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was washed with chilled brine solution (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as brown solid (600 mg, 77%). LCMS m / z = 263 [M+H]+. Step 3: Synthesis of tert-butyl 2-(5-(2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamido) pyridin-2-yl)-4,5-dihydro-1H-imidazole-1-carboxylate:

[0329] To an ice-cold stirred solution of lithium 2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 80 mg, 0.288 mmol) and tert-butyl 2- (5-amino-2-pyridyl)-2-imidazoline-1-carboxylate (189 mg, 0.719 mmol) in DMF (3 mL) were added DIPEA (0.2 mL, 0.863 mmol) and HATU (273 mg, 0.719 mmol) under N2 and the reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was - 127 -Attorney Docket No.15768.0041-00304 washed with chilled brine solution (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as brown solid (110 mg, 67%). LCMS m / z = 517 [M+H]+. Step 4: Synthesis of N-(6-(4,5-dihydro-1H-imidazol-2-yl) pyridin-3-yl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide:

[0330] To an ice-cold stirred solution of tert-butyl 2-(5-(2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl) pyrimidine-4-carboxamido) pyridin-2-yl)-4,5-dihydro-1H-imidazole-1- carboxylate (110 mg, 0.212 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise under N2and the reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure, the crude was cooled to 0 °C, basified using aq. NaHCO3solution (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep- HPLC using column X TERRA RP18 (19*250) 10 µm in 5 mM NH4CO3 in water and MeCN to give the desired compound as an off-white solid (12 mg, 14%).1H NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 9.10 (d, 1H), 8.38 (dd, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.10 (d, 8.8 Hz, 1H), 8.01 (s, 1H), 7.02 (br s, 1H), 4.08 (s, 3H), 3.64-3.62 (m, 4H). LCMS m / z = 417 [M+H]+. Example 49: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(methylsulfonamido)pyridin- 3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-24) Steethyl) pyrimidine-4-carboxamide:

[0331] The title compound was obtained as a yellow solid (200 mg, 47%) from ethyl 2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2) and tert- butyl (5-amino-2-pyridyl)carbamate, following the procedure described in Example 1 (I-1). LCMS m / z = 364 [M+H]+. Step 2: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(N- - 128 -Attorney Docket No.15768.0041-00304 (methylsulfonyl)methylsulfonamido)pyridin-3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide:

[0332] To a stirred solution of N-(6-aminopyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl) pyrimidine-4-carboxamide (200 mg, 0.551 mmol) in DCM (5 mL) was added TEA (0.3 mL, 1.65 mmol) at rt under N2 and the mixture then cooled to 0 °C. A solution of MsCl (74 mg, 0.661 mmol) in DCM (1 mL) was added dropwise and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by column chromatography (100-200 Mesh silica gel) eluting with 4-5% MeOH in DCM to give the title compound as white solid (120 mg, 42%). LCMS m / z = 520 [M+H]+. Step 3: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(methylsulfonamido)pyridin-3-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide:

[0333] To a stirred solution of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(N- (methylsulfonyl)methylsulfonamido)pyridin-3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (110 mg, 0.212 mmol) in THF (3 mL) was added TBAF (0.23 mL, 1 M in THF, 0.233 mmol) under N2and the reaction mixture stirred at rt for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep- HPLC using X TERRA RP18 (19*250) 10 m column eluting with 5 mM NH4CO3in water and MeCN to give the title compound as an off-white solid (35 mg, 38%).1H NMR (400 MHz, DMSO-d6): 10.79 (s, 1H), 10.62 (br s, 1H), 8.73 (d, 1H), 8.31 (s, 1H), 8.17 (dd, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.05 (d, 1H), 4.08 (s, 3H), 3.30 (s, 3H). LCMS m / z = 442 [M+H]+. Example 50: N-(6-(difluoromethyl)pyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-63)

[0334] To(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 60 mg, 0.216 mmol) in DCM was added 6-(difluoromethyl)-3-pyridylamine (31 mg, 0.216 mmol) under N2. DIPEA (0.1 mL, 0.64 mmol)) and T3P® (0.4 mL, 0.64 mmol) were added and the reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under - 129 -Attorney Docket No.15768.0041-00304 reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 M silica gel) eluting with 55-60 % EtOAc in heptane to give the desired product as white solid (17 mg, 20%).1H NMR (400 MHz, DMSO-d6): 11.05 (s, 1H), 9.15 (d, 1H), 8.50 (dd, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.80 (d, 1H), 7.11-6.84 (m, 1H), 4.08 (s, 3H). LCMS m / z = 399 [M+H]+. Example 51: 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(4-methylpiperazin-1- yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-62)

[0335] To an ice c -yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 120 mg, 0.431 mmol) and 4-(4- methyl-1-piperazinyl)cyclohexylamine·3HCl (106 mg, 0.345 mmol) in DCM (10 mL) were added DIPEA (0.4 mL, 2.16 mmol) and T3P® (0.7 mL, 1.08 mmol) under N2and the reaction mixture was stirred at rt for 16 h. The reaction was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by RP-HPLC using column X Bridge Shield RP18 (19*250) 10 µm in 5 mM NH4CO3in water and MeCN to give Peak 1, 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(4- methylpiperazin-1-yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide as a white solid (11 mg, 5%) and Peak 2, 2-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-(4-methylpiperazin-1- yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide as a white solid (12 mg, 5.6%).1H NMR (400 MHz, DMSO-d6): 8.72 (d, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.03 (s, 3H), 3.82-3.75 (m, 1H), 2.50-2.48 (m, 5H), 2.32-2.20 (m, 4H), 2.12 (s, 3H), 1.89-1.83 (m, 4H), 1.58- 1.49 (m, 2H), 1.36-1.27 (m, 2H). LCMS m / z = 452 [M+H]+. Example 52: Synthesis of methyl 5-(2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamido)picolinate (I-6)

[0336] To a sty y (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3), (200 mg, 0.72 mmol) and methyl 5- - 130 -Attorney Docket No.15768.0041-00304 amino-2-pyridinecarboxylate (164 mg, 1.08 mmol) in MeCN (4 mL) and DMF (1 mL) were added TCFH (404 mg, 1.44 mmol) and 1-methylimidazole (295 mg, 3.6 mmol) under N2 and the reaction mixture stirred at rt for 3 h. The reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (12 g SNAP, 100-200 Mesh silica gel) eluting with 3-3.2 % MeOH in DCM to give the desired compound as a white solid (130 mg, 44%).1H NMR (400 MHz, DMSO-d6): 11.14 (s, 1H), 9.18 (d, 1H), 8.53 (dd, 1H), 8.33 (s, 1H), 8.18-8.15 (m, 2H), 8.00 (s, 1H), 4.08 (s, 3H), 3.89 (s, 3H). LCMS m / z = 407 [M+H]+. Example 53: Synthesis of N-(6-aminopyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-5)

[0337] To a(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 2, 80 mg, 0.27 mmol) and tert-butyl (5- amino-2-pyridyl)carbamate (67 mg, 0.32 mmol) in toluene (4 mL) was added a solution of TMA in toluene (0.66 mL, 2 M, 1.33 mmol) at 0 °C under N2 and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was quenched with aq. NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with chilled brine solution (2 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (4 g SNAP, 100-200 silica gel) eluting with 3-5% MeOH in DCM to give the title product as yellow solid (9 mg, 9%).1H NMR (400 MHz, DMSO-d6): 10.47 (s, 1H), 8.33-8.31 (m, 2H), 8.11 (s, 1H), 7.98 (s, 1H), 7.78 (dd, 1H), 6.50 (dd, 1H), 5.95 (s, 2H), 4.07 (s, 3H). LCMS m / z = 364 [M+H]+. Alternative Synthesis of N-(6-aminopyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)- 6(trifluoromethyl)pyrimidine-4-carboxamide (I-5)y y y y y py midine- 4-carboxamido)pyridin-2-yl)carbamate: to an ice-cold solution of lithium 2-(1-methyl-5- - 131 -Attorney Docket No.15768.0041-00304 imidazolyl)-6-(trifluoromethyl)-4-pyrimidinecarboxylate (Intermediate 3, 0.2 g, 0.719 mmol) and tert-butyl (5-amino-2-pyridyl)carbamate (150 mg, 0.719 mmol) in MeCN (10 mL) and DMF (1 mL) were added TCFH (404 mg, 1.44 mmol) and NMI (0.3 mL, 3.6 mmol) under N2. The reaction mixture was stirred at rt for 6 h, then diluted with ice-cold water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with cold brine solution (2 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (4g SNAP, 100-200 M silica gel) eluting with 50- 55 % EtOAc in heptane to give the title product as yellow solid (220 mg, 66%).1H NMR (400 MHz, DMSO-d6): 10.79 (s, 1H), 9.86 (s, 1H), 8.72 (s, 1H), 8.34 (s, 1H), 8.21-8.25 (m, 2H), 8.00 (s, 1H), 7.85 (d, 1H), 4.08 (s, 3H), 1.48 (s, 9H). LCMS m / z = 464 [M+H]+.

[0338] Step 2: Synthesis of N-(6-aminopyridin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl) pyrimidine-4-carboxamide: to an ice-cold stirred solution of tert-butyl (5-(2-(1- methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamido)pyridin-2-yl)carbamate (220 mg, 0.475 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise under N2. The resulting reaction mixture was stirred at rt for 3h. The reaction mixture was concentrated under reduced pressure to remove excess of TFA, then cooled to 0°C, basified with aq. NaHCO3 solution (50 mL) and extracted with DCM (2 x 100 mL).The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the desired product as yellow solid (170 mg, 99%).1H NMR (400 MHz, DMSO-d6): 10.50 (s, 1H), 8.34-8.33 (m, 2H), 8.12 (s ,1H), 8.00 (s, 1H), 7.79 (dd, J = 8.8, 2.8 Hz, 1H), 7.50 (d, 1H), 5.98 (s, 2H) and 4.08 (s, 3H). LCMS m / z = 364 [M+H]+Example 54: 2-(1-methyl-1H-imidazol-5-yl)-N-(thiazolo[5,4-b]pyridin-2-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-61)

[0339] To an6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 70 mg, 0.252 mmol) and thiazolo[4,5-b]pyridin-2-amine (38 mg, 0.252 mmol) in DMF (1 mL) were added HATU (144 mg, 0.378 mmol) and DIPEA (0.2 mL, 0.755 mmol) under N2and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with 10% MeOH in DCM (50 mL). The organic layer was washed with chilled brine solution (50 - 132 -Attorney Docket No.15768.0041-00304 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crudewas purified by RP-HPLC purification using column X Select CSH C18 (19*250) 10 in 5mMNH4CO3in water and MeCN to give the desired compound as an off-white solid (10 mg, 10%).1H NMR (400 MHz, DMSO-d6): 8.37 (d, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.98-7.95 (m, 2H), 7.40-7.37 (m, 1H), 7.08 (br s, 1H), 4.10 (s, 3H). LCMS m / z = 406 [M+H]+. Example 55: Synthesis of N-(2-(dimethylamino)pyrimidin-5-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-15)

[0340] To an ic l)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 100 mg, 0.359 mmol) and 5-amino-2- (dimethylamino)pyrimidine (49.6 mg, 0.359 mmol) in DMF (3 mL) were added HATU (205 mg, 0.539 mmol) and DIPEA (0.18 mL, 1.07 mmol) under N2 and the reaction mixture stirred at rt for 5 h. The reaction mixture was diluted with ice-cold water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with chilled brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (4 g SNAP, 100-200 Mesh silica gel) eluting with 3-4% MeOH in DCM to give the title compound as yellow solid (20 mg, 15%).1H NMR (400 MHz, DMSO-d6): 10.65 (s, 1H), 8.71 (s, 2H), 8.32 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 4.07 (s, 3H), 3.14 (s, 6H). LCMS m / z = 393 [M+H]+. Example 56: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (I-16)

[0341] To an-6- (trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3, 100 mg, 0.359 mmol) in DCM (5 mL) was added 2-(trifluoromethyl)pyridin-4-amine (46 mg, 0.287 mmol) under N2 atmosphere. DIPEA (0.31 mL, 1.79 mmol) and T3P® (0.85 mL, 1.79 mmol) were added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (25 mL) and extracted with 25% IPA in CHCl3(2 x 25 mL). The combined organic layer was washed - 133 -Attorney Docket No.15768.0041-00304 with chilled brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (12 g SNAP, 100-200 Mesh silica gel) eluting with 4-5% MeOH in DCM to give the title compound as an off-white solid (66 mg, 44%)1H NMR (400 MHz, DMSO-d6): 11.23 (s, 1H), 8.77 (d, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.26 (d, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 4.07 (s, 3H). LCMS m / z = 417 [M+H]+. Example 57: Synthesis of N-(6-((2-methoxyethyl)amino)pyridin-3-yl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-22)

[0342] omethyl)-4-pyrimidinecarboxylate (Intermediate 5, 0.1 g, 0.360 mmol) and 5-amino-2-(2- methoxyethylamino)pyridine (72 mg, 0.431 mmol) in DMF (2 mL) were added T3P® (0.57 mL, 0.449 mmol) and DIPEA (0.188 mL, 1.08 mmol) under N2 and the reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (30 mL) and extracted with 25% IPA in CHCl3 (30 mL). The organic layer was washed with chilled brine solution (2 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep HPLC using X Bridge C18 (19*250) 10 m in 5 mM NH4CO3 in water and MeCN to give the title compound as a solid (42 mg, 28%).1H NMR (400 MHz, DMSO-d6): 10.49 (s, 1H), 8.38 (d, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.77 (dd, 1H), 6.63 (t, 1H), 6.57 (d, 1H), 4.07 (s, 3H), 3.46-3.41 (m, 4H), 3.27 (s, 3H). LCMS m / z = 422 [M+H]+. Example 58: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(methylamino)pyridin-3-yl)- 6-(trifluoromethyl)pyrimidine-4-carboxamide (I-23)

[0343] To an ictrifluoromethyl)- 4-pyrimidinecarboxylate (Intermediate 5, 0.1 g, 0.36 mmol) and 5-amino-2- (methylamino)pyridine (53.1 mg, 0.431 mmol) in DMF (3 mL) were added T3P (572 mg, 0.899 mmol) and DIPEA (0.188 mL, 1.08 mmol) under N2and the reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with 25% IPA - 134 -Attorney Docket No.15768.0041-00304 in CHCl3(50 mL). The organic layer was washed with chilled brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep HPLC in X Bridge C18 (19*100) 10 m using 5 mM NH4CO3in water and MeCN to give the title compound as brown solid (19 mg, 14%).1H NMR (400 MHz, DMSO): 10.49 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.80 (m, 1H), 6.54-6.49 (m, 2H), 4.07 (s, 3H) 2.78 (d, 3H). LCMS m / z = 378 [M+H]+. Example 59: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(methylcarbamoyl)pyridin-3- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-7)

[0344] T(trifluoromethyl)pyrimidine-4-carboxamido)picolinate (Example 52 (I-6), 80 mg, 0.2 mmol) in toluene (5 mL) was added 2 M solution of methylamine in THF (0.11 mL, 0.23 mmol) under N2. TMA (0.50 mL, 0.99 mmol) was added at 0 °C and the reaction mixture stirred at 90 °C for 3 h. The reaction mixture was quenched with aq. NH4Cl (25 mL) and extracted with 25% IPA in CH3Cl (3 x 25 mL). The combined organic layer was washed with chilled brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (4 g SNAP, 230-400 Mesh silica gel) eluting with 2% MeOH in DCM to give the title compound as white solid (25 mg, 32%).1H NMR (400 MHz, DMSO-d6): 11.05 (s, 1H), 9.13 (d, 1H), 8.75 (q, 1H), 8.48 (dd, 1H), 8.37 (d, 1H), 8.18 (s, 1H), 8.11 (d, 1H), 8.00 (s, 1H), 4.08 (s, 3H), 2.82 (d, 3H). LCMS m / z = 406 [M+H]+. Alternative Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(4-(methylcarbamoyl)phenyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-7) [03. , oromethyl)pyrimidine-4- carboxylic acid (582 g, 2.13 mol), 4-amino-N-methylbenzamide (320 g, 2.13 mol) and 2,6- lutidine (503 g, 4.69 mol) were charged to a reactor and the mixture cooled to 15±5oC. A solution - 135 -Attorney Docket No.15768.0041-00304 of TCFH in acetonitrile (0.44 M, 2.56 mol) was added, while maintaining the temperature at 15±5oC. The mixture was stirred for 4.5 h at 15±5oC. The reaction was quenched with aqueous ammonia (1%, 5.8 L) at 15±5oC. The product was isolated by filtration and the solid washed with a 2:1 mixture of acetonitrile and 1% aqueous ammonia solution (2.9 L). The filter cake was collected and dried in a stream of dry N2 to afford the title compound (860 g, 91.6% yield) as an off-white solid. LCMS m / z = 406 [M+H]+Example 60: Synthesis of 5-(2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine- 4-carboxamido)picolinic acid (I-12)

[0346] To a s(trifluoromethyl)pyrimidine-4-carboxamido)picolinate (I-6 (120 mg, 0.295 mmol) in DCE (4 mL) was added trimethyltin hydroxide (213 mg, 1.18 mmol) at rt under N2 and the reaction stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The crude was purified by RP-HPLC purification using X Bridge Shield RP18 (19*250) 10 m in 5 mM NH4CO3in water and MeCN to give the title compound as white solid (43 mg, 37%).1H NMR (400 MHz, DMSO-d6): 10.97 (br s, 1H), 9.12 (s, 1H), 8.43 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 4.08 (s, 3H). LCMS m / z = 393 [M+H]+. Example 61: 2-(1H-imidazol-1-yl)-N-(6-(methylcarbamoyl)pyridin-3-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-56)

[0347] To an iceethyl) pyrimidine-4- carboxylic acid (150 mg, 0.581 mmol) and 5-amino-N-methylpicolinamide (88 mg, 0.581 mmol) in DCM (10 mL) were added DIPEA (0.3 mL, 1.74 mmol) and T3P® (0.9 mL, 1.45 mmol) under N2and the reaction mixture was stirred at rt for 16 h. The reaction was diluted with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine solution (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 M silica gel) using eluents 8-10% MeOH in DCM to give the title compound as yellow solid (19 mg, 8%). - 136 -Attorney Docket No.15768.0041-00304 1H NMR (400 MHz, DMSO-d6): 11.17 (s, 1H), 9.12 (d, 1H), 9.09 (s, 1H), 8.76 (q, 1H), 8.47 (dd, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.13 (d, 1H), 7.26 (s, 1H) and 2.83 (d, 3H). LCMS m / z = 392 [M+H]+. Example 62: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-morpholinocyclohexyl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-57)

[0348] The title rom 2-(1H-imidazol-1-yl)-6-(trifluoromethyl) pyrimidine-4-carboxylic acid and (1r,4r)-4- morpholinocyclohexylamine hydrochloride, following the procedure described in Example 61 (I- 56).1H NMR (400 MHz, DMSO-d6): 9.03-8.99 (m, 2H), 8.21 (s, 1H), 8.17 (s, 1H), 7.21 (s, 1H), 3.85-3.80 (m, 1H), 3.64-3.50 (m, 4H), 3.32-3.31 (m, 4H), 2.23-2.18 (m, 1H), 2.32-2.27 (m, 2H), 1.91-1.88 (m, 4H), 1.61-1.52 (m, 2H), and 1.37-1.23 (m, 2H). LCMS m / z = 425 [M+H]+. Example 63: 2-(1H-imidazol-1-yl)-6-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4- yl)pyrimidine-4-carboxamide (I-58)

[0349] The title cm 2-(1H-imidazol-1- yl)-6-(trifluoromethyl) pyrimidine-4-carboxylic acid and 2-(trifluoromethyl)-4-pyridylamine, following a similar method to that described in Example 61 (I-56).1H NMR (400 MHz, DMSO- d6): 11.29 (s, 1H), 9.07 (s, 1H), 8.80 (d, 1H), 8.44 (d, 1H), 8.37 (s, 1H), 8.29-8.28 (m, 2H), 7.26 (s, 1H). LCMS m / z = 403 [M+H]+. Example 64: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-(6-(propylsulfonamido)pyridin- 3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-64)py y y yl)-6- - 137 -Attorney Docket No.15768.0041-00304 (trifluoromethyl)pyrimidine-4-carboxamide (Example 53, 0.3 g, 0.82 mmol) in DCM (8 mL) was added Et3N (0.34 mL, 2.48 mmol). The reaction mixture was stirred for 10 min before the addition of 1-(chlorosulfonyl)propane (0.09 mL, 0.82 mmol). The reaction mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by reverse phase-HPLC to yield the title product as an off white solid (42 mg, 11%).1H NMR (400 MHz, DMSO-d6): 10.78 (s, 1H), 10.57 (br s, 1H), 8.71 (d, 1H), 8.31 (s, 1H), 8.17 (dd, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.07 (d, 1H), 4.07 (s, 3H), 3.43 (t, 2H), 1.77-1.69 (m, 2H), 0.97 (t, 3H). LCMS m / z = 470 [M+H]+. Example 65: Synthesis of N-(6-(butylsulfonamido)pyridin-3-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-65) [03ridin-3- yl)-2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (Example 53) and butane-1-sulfonyl chloride, following the procedure described in Example 64.1H NMR (400 MHz, DMSO-d6): 8.66 (d, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 8.10 (dd, 1H), 7.99 (s, 1H), 6.99 (d, 1H), 4.07 (s, 3H), 3.39 (t, 2H), 1.69-1.62 (m, 2H), 1.42-1.33 (m, 2H), 0.85 (t, 3H). LCMS m / z = 484 [M+H]+. Example 66: Synthesis of N-(6-(ethylsulfonamido)pyridin-3-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-66) [03, aminopyridin-3- yl)-2-(1-methyl-1H-imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (Example 53) and ethanesulfonyl chloride, following the procedure described in Example 64. Purification by flash column chromatography (4 g SNAP, 100-200 M silica gel) eluting with 3-4% MeOH in DCM.1H NMR (400 MHz, DMSO-d6): 10.81 (s, 1H), 10.55 (s, 1H), 8.71 (s, 1H), 8.32 (s, 1H), - 138 -Attorney Docket No.15768.0041-00304 8.18-8.15 (m, 2H), 8.01 (s, 1H), 7.07 (d, 1H), 4.08 (s, 3H), 3.46 (q, 2H), 1.23 (t, 3H). LCMS m / z = 456 [M+H]+. Example 67: Synthesis of N-(6-(cyclopropanesulfonamido)pyridin-3-yl)-2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-67) [03(trifluoromethyl) pyrimidine-4-carboxamide (Example 53, 0.1 g, 0.275 mmol) in pyridine (8 mL) was added a solution of 1-(chlorosulfonyl)cyclopropane (193 mg, 1.38 mmol) in pyridine (0.5 mL) under N2. The reaction mixture was stirred at rt for 72 h, then concentrated under reduced pressure, diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 230-400 M silica gel) eluting with 10% MeOH in DCM to yield the title product as a yellow solid (22 mg, 19%).1H NMR (400 MHz, DMSO-d6): 10.81 (s, 1H), 10.58 (s, 1H), 8.73 (s, 1H), 8.34 (s, 1H), 8.19-8.16 (m, 2H), 8.03 (s, 1H), 7.14 (d, 1H), 4.08 (s, 3H), 3.05 (m, 1H), 1.08-1.00 (m, 4H). LCMS m / z = 468 [M+H]+. Example 68: Synthesis of N-(2-isopropoxypyrimidin-5-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl) pyrimidine-4-carboxamide (I-68) [03ifluoromethyl)-4- pyrimidinecarboxylate (Intermediate 3, 60 mg, 0.216 mmol) and 2-isopropoxy-5- pyrimidinylamine (23 mg, 0.151 mmol) in DCM (6 mL) were added T3P® (0.3 mL, 0.539 mmol) and DIPEA (0.1 mL, 0.647 mmol) under N2. The reaction mixture was stirred at rt for 16 h, then diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 M silica gel) eluting with 4-6% MeOH in DCM, to yield the title product as a pale-yellow solid - 139 -Attorney Docket No.15768.0041-00304 (37 mg, 42%).1H NMR (400 MHz, DMSO-d6): 10.89 (s, 1H), 8.97 (s, 2H), 8.32 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 5.23-5.17 (m, 1H), 4.07 (s, 3H), 1.33 (d, 6H). LCMS m / z = 408 [M+H]+. Examples 69-76

[0355] The compounds in the following table were prepared from lithium 2-(1-methyl-1H- imidazol-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxylate (Intermediate 3) and the appropriate amine, following a similar procedure to that described in Example 68. Cmpd No Name, Structure Amine, Data I-69 N-([2,2'-bipyrimidin]-5-yl)-2-(1- 2,2'-bipyrimidinyl-5-ylamine ), , s, , 2- 140 -Attorney Docket No.15768.0041-00304 yl)pyrimidine-4-carboxamide (m, 2H), 1.85-1.75 (m, 2H). LCMS m / z = 487 [M+H]+. , 0 - s, 5 ne ),- 141 -Attorney Docket No.15768.0041-00304 carboxamide 8.11 (dd, 1H), 8.01 (s, 1H), 7.12- 6.85 (t, 1H), 4.07 (s, 3H). LCMS , 4 (s,Example 77: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(piperazin-1- yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-77)p y ess o e -uy - , -- - - e y- - ao--y -- - 142 -Attorney Docket No.15768.0041-00304 (trifluoromethyl)pyrimidine-4-carboxamido)cyclohexyl)piperazine-1-carboxylate

[0357] The title product was obtained as a brown solid (120 mg, 62%), from lithium 2-(1- methyl-5-imidazolyl)-6-(trifluoromethyl)-4-pyrimidinecarboxylate (Intermediate 3) and tert-butyl 4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylate, following the procedure described in Example 68, and was used in Step 2 without purification. LCMS m / z = 538 [M+H]+.

[0358] Step 2: Synthesis of 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(piperazin-1- yl)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide

[0359] To an ice-cold solution of tert-butyl 4-((1r,4r)-4-(2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamido)cyclohexyl)piperazine-1-carboxylate

[0360] (110 mg, 0.205 mmol) in DCM (3 mL) was added TFA (1 mL) under N2. The reaction mixture was stirred at rt for 1 h, then concentrated under reduced pressure, triturated with Et2O and dried under reduced pressure. The crude was purified by reverse phase-HPLC using X Bridge Shield RP18 (19*250) 10µ column, eluting with 5mM ammonium bicarbonate in water and acetonitrile to give the title product as a white solid (20 mg, 22%).1H NMR (400 MHz, DMSO-d6): 8.72 (d, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 4.03 (s, 3H), 3.79-3.76 (m, 1H), 2.66-2.64 (m, 4H), 2.41-2.39 (m, 4H), 2.22-2.16 (m, 1H), 1.89-1.82 (m, 4H), 1.57-1.49 (m, 2H), 1.37-1.29 (m, 2H). LCMS m / z = 438 [M+H]+. Example 78: Synthesis of N-(2-cyclopentylpyrimidin-5-yl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-78) [03uoromethyl)-4- pyrimidinecarboxylate (Intermediate 3, 60 mg, 0.216 mmol) and 2-cyclopentyl-5- pyrimidinylamine (35 mg, 0.216 mmol) in MeCN (4 mL) and DMF (0.1 mL) were added TCFH (121 mg, 0.431 mmol) and NMI (88 mg, 1.08 mmol) under N2. The reaction mixture was stirred at rt for 16 h, then diluted with ice-cold water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with cold brine solution (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was triturated with DCM and Et2O to yield the title product as an off-white solid (19 mg, 21%).1H NMR (400 MHz, DMSO-d6): 10.90 (s, 1H), 9.14 (s, 2H), 8.32 (d, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 4.08 (s, 3H), 3.37-3.35 (m, 1H), 2.07-2.01 (m, 2H), 1.90-1.83 (m, 2H) 1.79-1.72 (m, 2H), 1.70-1.62 (m, 2H). LCMS m / z = 418 [M+H]+. - 143 -Attorney Docket No.15768.0041-00304 Example 79: Synthesis of N-(2-(3-fluorophenyl)pyrimidin-5-yl)-2-(1-methyl-1H-imidazol-5- yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (I-79) m lithium 2-(1-methyl-5-imidazolyl)-6-(trifluoromethyl)-4-pyrimidinecarboxylate (Intermediate 3) and 2-(3- fluorophenyl)pyrimidin-5-amine, following the procedure described in Example 78.1H NMR (400 MHz, DMSO-d6): 11.16 (s, 1H), 9.40 (s, 2H), 8.34 (s, 1H), 8.24 (d, 1H), 8.20 (s, 1H), 8.09 (d, 1H), 8.02 (s, 1H), 7.62-7.57 (m, 1H), 7.41-7.37 (m, 1H), 4.09 (s, 3H). LCMS m / z = 444 [M+H]+. Example 80: Synthesis of N-(4-carbamoylphenyl)-2-(1-methyl-1H-imidazol-5-yl)-6- (trifluoromethyl)pyrimidine-4-carboxamide (I-80) [03rifluoromethyl)-4- pyrimidinecarboxylate (Intermediate 3, 60 mg, 0.216 mmol) and 4-aminobenzamide (44 mg, 0.324 mmol) in DMF (2 mL) were added HATU (205 mg, 0.539 mmol) and DIPEA (0.1 mL, 0.647 mmol) under N2. The reaction mixture was stirred at rt for 16 h, then diluted with ice cold water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with cold brine solution (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (4 g SNAP, 100-200 M silica gel) eluting with 5-6% MeOH in DCM to give the title compound as white solid (30 mg, 36%).1H NMR (400 MHz, DMSO-d6): 10.80 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.01-7.94 (m, 6H, 7.34 (br s, 1H), 4.10 (s, 3H). LCMS m / z = 391 [M+H]+. III. Biological Assays Assay 1: Fluorescence-based NAD+ Hydrolase Activity Assay with Human T Cell Line NH7-dCas9 Cells- Jurkat Clone

[0364] The following protocol was modified from the following references: de Oliveira et al. - 144 -Attorney Docket No.15768.0041-00304 (2018) Bio. Protoc.8(14): e2938-e2938; Matalonga et al. (2017) Cell Rep.18(5):1241-1255; Muller et al. (1983) Biochem J.212(2):459-464; and Schultzet et al. (2018). Meth. Mol. Bio. 1813:77-90.

[0365] NAD+ hydrolase activity of a human T cell line treated with test compounds was measured using a fluorescence-based assay. NH7-dCas9 cells (Jurkat clone) were provided by the Weissman Lab (UCSF 17004th St., Byers Hall, Room 403B, San Francisco, CA 94158- 2330). Briefly, cells were centrifuged, resuspended in 44 L PBS / 0.5x106cells and plated in a 96 well black plate (CORNING) at a density of 0.5 × 106per well.

[0366] Each test compound was received in a powder state and dissolved in DMSO as a 25 mM stock solution. Each test compound was serially diluted in order to generate a dose-response curve. The dilution series of each test compound in DMSO was prepared at 50 times the concentrations to be assayed. Each test compound was diluted to generate a 5-fold dilution series of 8 concentrations from 20 M to 0.256 nM in order to assay 8 final concentrations ranging from 400 nM to 25.6 pM. One L of the 50X concentration compound series was added to each well of the plate containing 0.5 x 106cells in PBS.

[0367] Each plate had the following intra plate controls: 3 wells containing cells treated with vehicle only (DMSO), and 3 wells containing only PBS (used as a background value).

[0368] The reaction was started by adding nicotinamide 1,N6-etheno-adenine dinucleotide (Sigma Aldrich) to reach a final concentration of 80 M. The samples were excited at 321 nm, and the emission of fluorescence was measured at 410 nm at 37 °C every minute for 1 h in a Clariostar® microplate reader (BMG LABTECH). NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence-time curve using the MARS data analysis software (BMG LABTECH). The data were uploaded in the Collaborative Drug Design (CDD) Software and for each compound the IC50 was calculated by the software. Each compound was tested in 2-3 independent experiments on 2-3 separate days to establish the reproducibility of the results. Assay 2: Fluorescence-based NAD+ Hydrolase Activity Assay with Human Recombinant CD38 Protein

[0369] This protocol was modified from the following references: (Muller et al. (1983); (Schultz et al. (2018); (Matalonga et al. (2017); and de Oliveira et al. (2018).

[0370] NAD+ hydrolase activity of the human recombinant CD38 protein treated with test compounds was measured using a fluorescence-based assay. Briefly, recombinant human CD38 Protein (R&D System) was resuspended in 44 L / well of Sucrose-Tris Buffer (Sucrose 0.25 M, Tris pH 7.440 mM) with HaltTMProtease and Phosphatase inhibitor cocktail (Thermo Scientific) - 145 -Attorney Docket No.15768.0041-00304 and plated in a 96-well black plate (CORNING) at a density of 10 ng / well.

[0371] Each test compound was received in a powder state and dissolved in DMSO as a 25 mM stock solution. Each test compound was serially diluted in order to generate a dose-response curve. The dilution series of each test compound in DMSO was prepared at 50X the concentrations to be assayed. Each test compound was diluted to generate a 5-fold dilution series of 8 concentrations from 20 M to 0.256 nM in order to assay 8 final concentrations ranging from ranging from 400 nM to 25.6 pM. One L of the 50X concentration compound series was added to each well of the plate containing 10 ng protein in Sucrose-Tris buffer.

[0372] Each plate had the following intra plate controls: 3 wells containing cells treated with vehicle only (DMSO), and 3 wells containing only PBS (used as a background value).

[0373] The reaction was started by adding nicotinamide 1,N6-etheno-adenine dinucleotide (Sigma Aldrich) to reach a final concentration of 80 µM. The samples were excited at 321 nm, and the emission of fluorescence was measured at 410 nm at 37 °C every minute for 30 min in a Clariostar® microplate reader (BMG LABTECH). NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence-time curve using the MARS data analysis software (BMG LABTECH). The data were uploaded in the Collaborative Drug Design (CDD) Software and for each compound the IC50 was calculated by the software. Each compound was tested in 2-3 independent experiments on 2-3 separate days to establish the reproducibility of the results. Assay 3: Fluorescence-Based NAD+ Hydrolase Activity Assay with Mouse Recombinant CD38 Protein

[0374] This protocol was modified from the following references: (Muller et al. (1983); (Schultz et al. (2018); (Matalonga et al. (2017); and de Oliveira et al. (2018).

[0375] NAD+ hydrolase activity of the mouse recombinant CD38 protein treated with test compounds was measured using a fluorescence-based assay. Briefly, recombinant mouse CD38 Protein (R&D System) was resuspended in 44 L / well of Sucrose-Tris Buffer (Sucrose 0.25 M, Tris pH 7.440 mM) with HaltTMProtease and Phosphatase inhibitor cocktail (Thermo Scientific) and plated in a 96-well black plate (CORNING) at a density of 2.5 ng / well.

[0376] Each test compound was received in a powder state and dissolved in DMSO as a 25 mM stock solution. Each test compound was serially diluted in order to generate a dose-response curve. The dilution series of each test compound in DMSO was prepared at 50X the concentrations to be assayed. Each test compound was diluted to generate a 5-fold dilution series of 8 concentrations from 20 M to 0.256 nM in order to assay 8 final concentrations ranging - 146 -Attorney Docket No.15768.0041-00304 from ranging from 400 nM to 25.6 pM. One L of the 50X concentration compound series was added to each well of the plate containing 2.5 ng protein in Sucrose-Tris buffer.

[0377] Each plate had the following intra plate controls: 3 wells containing cells treated with vehicle only (DMSO), and 3 wells containing only PBS (used as a background value).

[0378] The reaction was started by adding nicotinamide 1,N6-etheno-adenine dinucleotide (Sigma Aldrich) to reach a final concentration of 80 µM. The samples were excited at 321-15 nm, and the emission of fluorescence was measured at 410-20 nm at 37 °C every minute for 30 min in a Clariostar® microplate reader (BMG LABTECH). NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence-time curve using the MARS data analysis software (BMG LABTECH). The data were uploaded in the Collaborative Drug Design (CDD) Software and for each compound the IC50 was calculated by the software. Each compound was tested in two independent experiments on two separate days to establish the reproducibility of the results. Assay 4: Fluorescence-Based NAD+ Hydrolase Activity Assay with Rat Recombinant CD38 Protein

[0379] This protocol was modified from the following references (Muller et al. (1983); (Schultz et al. (2018); (Matalonga et al. (2017); and de Oliveira et al. (2018).

[0380] NAD+ hydrolase activity of the rat recombinant CD38 protein treated with test compounds was measured using a fluorescence-based assay. Briefly, recombinant rat CD38 Protein (Sino Biological) was resuspended in 44 L / well of Sucrose-Tris Buffer (Sucrose 0.25 M, Tris pH 7.440 mM) with HaltTMProtease and Phosphatase inhibitor cocktail (Thermo Scientific) and plated in a 96-well black plate (CORNING) at a density of 2.5 ng / well.

[0381] Each test compound was received in a powder state and dissolved in DMSO as a 25 mM stock solution. Each test compound was serially diluted in order to generate a dose-response curve. The dilution series of each test compound in DMSO was prepared at 50X the concentrations to be assayed. Each test compound was diluted to generate a 5-fold dilution series of 8 concentrations from 20 M to 0.256 nM in order to assay 8 final concentrations ranging from ranging from 400 nM to 25.6 pM. One L of the 50X concentration compound series was added to each well of the plate containing 2.5 ng protein in Sucrose-Tris buffer.

[0382] Each plate had the following intra plate controls: 3 wells containing cells treated with vehicle only (DMSO), and 3 wells containing only PBS (used as a background value).

[0383] The reaction was started by adding nicotinamide 1,N6-etheno-adenine dinucleotide (Sigma Aldrich) to reach a final concentration of 80 µM. The samples were excited at 321-15 - 147 -Attorney Docket No.15768.0041-00304 nm, and the emission of fluorescence was measured at 410-20 nm at 37 °C every minute for 30 min in a Clariostar® microplate reader (BMG LABTECH). NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence-time curve using the MARS data analysis software (BMG LABTECH). The data were uploaded in the Collaborative Drug Design (CDD) Software and for each compound the IC50 was calculated by the software. Each compound was tested in two independent experiments on two separate days to establish the reproducibility of the results. Assay 5: Fluorescence-based NAD+ Cyclase Activity Assay with Human Recombinant CD38 Protein

[0384] This protocol was modified from the de Oliveira et al., 2018 reference, supra.

[0385] NAD+ cyclase activity of the human recombinant CD38 protein treated with test compounds was measured using a fluorescence-based assay. Briefly, recombinant human CD38 Protein (R&D System) was resuspended in 44 L / well of Sucrose-Tris Buffer (Sucrose 0.25 M, Tris pH 7.440 mM) and plated in a 96-well black plate (CORNING) at a density of 125ng / well.

[0386] Each test compound was received in a powder state and dissolved in DMSO as a 25 mM stock solution. Each test compound was serially diluted in order to generate a dose-response curve. The dilution series of each test compound in DMSO was prepared at 50 times the concentrations to be assayed. Each test compound was diluted to generate a 5-fold dilution series of 8 concentrations from 50 M to 3.2 nM in order to assay 8 final concentrations ranging from 1 µM to 0.064 nM. One L of the 50X concentration compound series was added to each well of the plate containing 125 ng of protein in Sucrose-Tris buffer.

[0387] Each plate had the following intra plate controls: 3 wells containing cells treated with vehicle only (DMSO) and 3 wells containing only Sucrose-Tris buffer (used as a background value).

[0388] The reaction was started adding nicotinamide guanine dinucleotide (NGD+) (Sigma Aldrich) to reach a final concentration of 150 µM. The samples were excited at 337 nm, and the emission of fluorescence was measured at 442 nm at 37 °C every minute for 1 h in a Clariostar microplate reader (BMG LABTECH). NAD+ cyclase activity was calculated as the slope of the linear portion of the fluorescence-time curve using the MARS data analysis software (BMG LABTECH). The data were uploaded in the Collaborative Drug Design (CDD) Software, and for each compound the IC50was calculated by the software. For each plate, the z-factor was also calculated as a plate quality using the CDD software.

[0389] The compounds according to the disclosure that were tested had the following activity in - 148 -Attorney Docket No.15768.0041-00304 the aforesaid assays (Assays 1-5), as shown in Table 2. Table 2 Assays 1-5 Activity reported as Geometric mean IC50 (KEY: **** < 1 nM; *** 1-50 nM; ** 0.051-1 µM; * 1-10 µM; N.D. not- 149 -Attorney Docket No.15768.0041-00304 I-27 N.D. *** N.D. N.D. N.D. I 28 ND * ND ND ND- 150 -Attorney Docket No.15768.0041-00304 I-58 N.D. *** N.D. N.D. N.D. I 59 ND *** ND ND NDAssay 6: Stability in Human Hepatocytes

[0390] Cryopreserved hepatocytes were thawed by immersing vials into 37 ± 1 °C water bath and shaking gently for 75-90 seconds until the content was almost entirely melted. The hepatocytes were then resuspended in prewarmed tubes of cryopreserved hepatocytes recovery medium and centrifuged at 800 rpm at 22 °C for 5 minutes. After centrifugation, the supernatant was discarded from the tubes and 1 mL of 37 ± 1 °C pre-warmed hepatocytes incubation buffer was added. Total cell count and number of viable cells was determined using cell viability analyzer and hepatocytes suspensions were subsequently diluted to 0.25 million viable cells per - 151 -Attorney Docket No.15768.0041-00304 mL.

[0391] Stock solutions of test compounds were prepared at a final concentration of 720 M, and3.3 L from each stock solution was added to 796.6 L of hepatocytes cell suspension to reach afinal concentration of 3 M for test compounds. Plates were kept in the humidified CO2 incubator and incubated at 37 ± 1 °C with shaking.

[0392] 50 L of the hepatocyte mixture was quenched with 300 µL of acetonitrile at different time points (0, 5, 15, 30, 60, 120 and 180 minutes) then centrifuged for 10 min at 14,000 rpm, after which the supernatant was transferred into respective vials.

[0393] The supernatant was analyzed by LC-MS / MS using QExactive mass spectrometer instrument and Waters Acquity BEH (50 x 2.1 mm, 1.7 µm) column. The LC analysis employed a gradient elution method with mobile phase consisting of 0.2% Formic Acid in Milli-Q water (A) and acetonitrile (B) in a 98:2 ratio (v / v). The 0.6 mL / min elution profile transitioned from 2% B to 50% B in 0.2 min followed by a linear shift to 98% B in 0.4 min. Initial and final equilibration were set for 0.2 min each with a total run time of 1.5 min.

[0394] The compounds according to the disclosure that were tested had the following activity in the aforesaid assay (Assay 6), as shown in Table 3. Table 3 Assay 6 Activity reported as Av hClint (mL / min / 106cells) (KEY: *** < 1 6- 152 -Attorney Docket No.15768.0041-00304 I-13 * I-30 ** I-48 ** I-14 ** I-31 ** I-49 ** As

[0395] Caco 2 cell lines (ATCC # HTB-37) were split every other day at a split ratio of 1:3~1:5 and grown in Dulbecco's Modified Eagle Medium (GlutaMAX I, 4,500 mg / L D-glucose, sodium pyruvate) supplemented with 10% FBS in the presence of antibiotics. For transport studies, cells were seeded onto polycarbonate Transwell filter membranes (Millipore) at a density of 60,000 cells / well.24 h post seeding, medium was changed, and cells were cultured for another 21 days before transport experiments. For transport studies, donor solutions were prepared by diluting the stock solutions of test compounds in transport medium (HBSS buffer with 10 mM HEPES, pH 7.4). Receiver solutions were the same HBSS buffer with 10 mM HEPES, pH 7.4.

[0396] The transport of test compounds (5 M) incubated for 60 min was measured in duplicatein two directions [apical to basolateral (A B) and basolateral to apical (B A)]. Thepermeability coefficient for membrane transport of test compounds was determined using the following equation:

[0397] Papp (cm / sec) = (Vr / C0) (1 / S) (dC / dt)

[0398] (Papp = apparent permeability, Vr = volume of medium in the receiver chamber, C0 = Initial peak area ratio of the test drug, S = surface area of monolayer, dC / dt = drug PAR in the receiver chamber with time).

[0399] Area of 24-well = 0.7 cm2

[0400] Peak area ratio = Analyte peak area / IS peak area

[0401] The efflux ratio was defined as: Efflux ratio= Papp B-A / Papp A-B

[0402] The bioanalysis was done by LC-MS / MS using QExactive mass spectrometer instrument and Waters Acquity BEH (50 x 2.1 mm, 1.7 µm) column. The LC analysis employed a gradient elution method with mobile phase consisting of acetonitrile (A) and 0.2% Formic Acid in Milli-Q water (B) and in a 10:90 ratio (v / v). The column was equilibrated with 90% for 0.6 min. The 0.6 mL / min elution profile transitioned from 90% B to 10% B at 0.6 min and was held at 10% B for 1.1 min followed by a shift to 90% B in 0.1 min.

[0403] The compounds according to the disclosure that were tested had the following activity in - 153 -Attorney Docket No.15768.0041-00304 the aforesaid assay (Assay 7), as shown in Table 4. Table 4 Assay 7 Activity reported as A-B (10-6cm / sec) (KEY: * < 110-6cm / sec; ** 1-5 10-6m / *** >510-6m / ) 7Assay 8: CYP3A4 Inhibition

[0404] Microsomes were thawed on ice and microsomal suspension was prepared in potassium phosphate buffer. The probe substrate Midazolam (Hangzhou Pharma, cat# 5946-96-8) was added to the above microsomal suspension to get a final concentration of 2.5 M and mixed gently by inversion at 37 ± 1 °C for 5 minutes.

[0405] 801 L of the above incubation mixture was added into three polypropylene tubes labelled “Test”, “Test control” and “Positive control”: 0.9 L of the test compound (10 mM) was - 154 -Attorney Docket No.15768.0041-00304 spiked into respective tubes while 0.9 L of DMSO was spiked to the tube labelled “Test control”. The reference inhibitor ketoconazole (Sigma Aldrich, Cat# K1003) was added to the tube labelled “Positive control”. Two aliquots (2 x 270 L) of each of the above incubation mixtures were transferred into aptly labelled tubes and incubated in shaking water bath at 37 ± 1 °C for 5 minutes.

[0406] The reaction was started by adding 30 L of 10 mM NADPH to all samples and incubate at 37 ± 1 °C for 10 minutes. After completion of incubation time, the reactions were stopped by adding 300 L of quenching solution.

[0407] The Supernatant was collected and injected onto the LC-MS / MS system to estimate metabolite formation for the probe substrate. The bioanalysis was done by LC-MS / MS using QExactive mass spectrometer instrument and Waters Acquity BEH (50 x 2.1 mm, 1.7 µm) column. The LC analysis employed a gradient elution method with mobile phase consisting of 0.2% Formic Acid in Milli-Q water (A) and acetonitrile (B) and in a 5:95 ratio (v / v). The 0.6 mL / min elution profile transitioned from 50% B to 98% B in 0.7 min and was held for 0.3 min at 98% B followed by a shift to 5% B in 1.8 min. Initial and final equilibration was done with 5% B for 0.2 min each with a total run time of 2 min.

[0408] The percent of inhibition was calculated as follow: [1-(test area ratio / control area ratio)]*100

[0409] The compounds according to the disclosure that were tested had the following activity in the aforesaid assay (Assay 8), as shown in Table 5. Table 5 Assay 8 Activity reported as inhibition of CYP3A4 at 10 M (%) 8- 155 -Attorney Docket No.15768.0041-00304 I-9 ** I-26 ** I-44 ** I-10 ** I-27 ** I-45 *** Assa

[0410] The in vivo efficacy of Compound I-7 against the mouse CD38 enzyme was tested in mice after oral administration and determined by plasma unbound concentration (pharmacokinetic analysis) and Mass Spec (MS) analysis of NAD+ metabolites levels in liver and spleen tissues. The main CD38 substrate, NAD+, and the 2 main products of the CD38- mediated NAD+ hydrolysis, NAM and ADPR, were measured.

[0411] Briefly, 8-12 weeks old mice (male C57BL6 / J) were fasted for 4 hr and compound Compound I-7 was administered via oral gavage at a concentration of 15 mg / kg. Diet was replaced 2 h post compound administration. Mice were humanely euthanized for blood, liver and spleen tissue harvesting at 2 h, 4 h, 8 h, and 24 h post-dosing. A vehicle control (0.5% w / v Tween 80 + 99.5% of 0.05% Methylcellulose in water) was included to assess baseline NAD+ metabolites levels.

[0412] The procedure for plasma unbound concentration analysis was performed following standard methodology. Briefly, blood samples were placed on ice immediately after collection and centrifuged within 30 min at 4 °C for 5 min at 8,000 rpm to obtain plasma. Plasma was then immediately frozen to -80 °C or lower until assayed. A sub-sample (0.1 mL) of each dosing formulation will be taken from the syringe or gavage used for formulation administration and transferred to a polypropylene tube and stored at -20 °C or lower until analysed.

[0413] The Pharmacokinetic analysis to measure unbound Compound I-7 plasma concentration was performed following appropriate methodology. Briefly, the test compound was extracted from plasma by using pre-optimized extraction procedure and extracted samples were quantified along with calibration standards and quality control (QC) samples (high, mid, and low level QCs) by LC-MS / MS. The pharmacokinetics of the test compound were calculated on mean - 156 -Attorney Docket No.15768.0041-00304 concentration value for 3 animals (per time point) using Phoenix WinNonlin. Plasma concentrations less than limit of quantification were not considered for calculation. Data were reported as individual / mean plasma concentration vs. time.

[0414] The procedure for liver and spleen tissue sample preparation and UPLC-MS / MS methods were adapted from the following references: Trammell et al. (2013) Comput. Struct. Biotechnol. J.4(5): e201301012; Margier et al. (2023) Cells 12(1):108.

[0415] NAD+ and related metabolites were extracted from pre-weighed frozen liver and spleen with 80% ice-cold methanol containing internal standard mix (13C NAD+ and13C NAM, Cambridge Isotope Laboratories). Briefly, frozen tissues were homogenized in a bullet blender (Next Advance bead homogenizer) in 80% methanol for 2 cycles of 2 min. Following complete homogenization, samples were vortexed for 10 sec and incubated for 30 min on ice. Upon centrifugation at 18,000 rcf for 10 min, the supernatant was dried in a speed vacuum. The final dried pellet was resuspended in starting buffer conditions for subsequent LCMS analysis.

[0416] A targeted, liquid chromatography-mass spectrometry (LCMS / MS) analysis was applied to measure NAD+, NAM and ADPR in liver and spleen tissues. Data acquisition was executed using a QExactive mass spectrometer connected to a Vanquish LC system (Thermo Scientific). Separation of target metabolites was achieved through a Hypercarb column (5 mm, 100 × 2.1 mm, Thermo Scientific) operated at a 60 °C. Mobile phase A was composed of 7.5 mM ammonium acetate with 0.05% (v / v) ammonium hydroxide, while mobile phase B consisted of 0.05% (v / v) ammonium hydroxide in acetonitrile. A linear gradient was applied over 12 min at a flow rate of 0.250 mL / min: starting with 5% B for the 1.0 min, followed by a 60% B phase for the next 6 min, 90% B for the subsequent 1.5 min, and concluding with 5% B for the final 4.4 min.

[0417] For the QExactive Mass Spectrometer, the settings included sheath gas flow rate of 45, auxiliary gas flow rate of 2, spray voltage of 3.75 kV, capillary temperature of 320 °C, S-lens RF level of 55, and probe temperature of 120 °C. Data acquisition was optimized in positive mode FullMS1-ddMS2 (Top4) and involved targeted single and parallel ion monitoring (tSIM-PRM) within a scan range of 50–750 m / z.

[0418] Metabolite identification was confirmed through matching MS1 / MS2 spectra and retention times with standards run in parallel. The normalized area under the curve (AUC) was determined for each metabolite from MS1 extracted ion chromatograms. Data analysis was carried out using Freestyle and Excalibur QuanBrowser (Thermo Scientific). Absolute quantification was achieved by constructing a 10-point calibration curve using metabolite standards. - 157 -Attorney Docket No.15768.0041-00304

[0419] A single 15 mg / kg oral administration dose of Compound I-7 was able to increase NAD+ levels and to decrease NAM and ADPR levels in liver (FIG. 1A-1C) and spleen (FIG.2A-2C) showing direct correlation with unbound plasma exposure. Assay 10: In Vivo Efficacy of Compound I-16 Against CD38 in mouse

[0420] The in vivo efficacy of Compound I-16 against the mouse CD38 enzyme was tested in mice after oral administration and determined by plasma unbound concentration (pharmacokinetic analysis) and Mass Spec (MS) analysis of NAD+ metabolites levels in liver and spleen tissues. The main CD38 substrate, NAD+, and the 2 main products of the CD38- mediated NAD+ hydrolysis, NAM and ADPR, were measured.

[0421] Briefly, 8-12 weeks old mice (male C57BL6 / J) were fasted for 4 h and compound Compound I-16 was administered via oral gavage at a concentration of 30 mg / kg. Diet was replaced 2 h post compound administration. Mice were humanely euthanized for blood, liver and spleen tissue harvesting at 2 h, 4 h, 8 h, and 24 h post-dosing. A vehicle control (0.5% w / v Tween 80 + 99.5% of 0.05% Methylcellulose in water) was included to assess baseline NAD+ metabolites levels.

[0422] The procedure for plasma unbound concentration analysis was performed following standard methodology. Briefly, blood samples were placed on ice immediately after collection and centrifuged within 30 min at 4 °C for 5 min at 8,000 rpm to obtain plasma. Plasma was then immediately frozen to -80 °C or lower until assayed. A sub-sample (0.1 mL) of each dosing formulation will be taken from the syringe or gavage used for formulation administration and transferred to a polypropylene tube and stored at -20 °C or lower until analyzed.

[0423] The Pharmacokinetic analysis to measure unbound Compound I-16 plasma concentration was performed following appropriate methodology. Briefly, the test compound was extracted from plasma by using pre-optimized extraction procedure and extracted samples were quantified along with calibration standards and quality control (QC) samples (high, mid, and low level QCs) by LC-MS / MS. The pharmacokinetics of the test compound were calculated on mean concentration value for 3 animals (per time point) using Phoenix WinNonlin. Plasma concentrations less than limit of quantification were not considered for calculation. Data were reported as individual / mean plasma concentration vs. time.

[0424] The procedure for liver and spleen tissue sample preparation and UPLC-MS / MS methods were adapted from the following references: Trammell et al. (2013) Comput. Struct. Biotechnol. J.4(5): e201301012; Margier et al. (2023) Cells 12(1):108.

[0425] NAD+ and related metabolites were extracted from pre-weighed frozen liver and spleen with 80% ice-cold methanol containing internal standard mix (13C NAD+ and13C NAM, - 158 -Attorney Docket No.15768.0041-00304 Cambridge Isotope Laboratories). Briefly, frozen tissues were homogenized in a bullet blender (Next Advance bead homogenizer) in 80% methanol for 2 cycles of 2 min. Following complete homogenization, samples were vortexed for 10 sec and incubated for 30 min on ice. Upon centrifugation at 18,000 rcf for 10 min, the supernatant was dried in a speed vacuum. The final dried pellet was resuspended in starting buffer conditions for subsequent LCMS analysis.

[0426] A targeted, liquid chromatography-mass spectrometry (LCMS / MS) analysis was applied to measure NAD+, NAM and ADPR in liver and spleen tissues. Data acquisition was executed using a QExactive mass spectrometer connected to a Vanquish LC system (Thermo Scientific). Separation of target metabolites was achieved through a Hypercarb column (5 mm, 100 × 2.1 mm, Thermo Scientific) operated at a 60 °C. Mobile phase A was composed of 7.5 mM ammonium acetate with 0.05% (v / v) ammonium hydroxide, while mobile phase B consisted of 0.05% (v / v) ammonium hydroxide in acetonitrile. A linear gradient was applied over 12 min at a flow rate of 0.250 mL / min: starting with 5% B for 1.0 min, followed by a 60% B phase for the next 6 min, 90% B for the subsequent 1.5 min, and concluding with 5% B for the final 4.4 min.

[0427] For the QExactive Mass Spectrometer, the settings included sheath gas flow rate of 45, auxiliary gas flow rate of 2, spray voltage of 3.75 kV, capillary temperature of 320 °C, S-lens RF level of 55, and probe temperature of 120 °C. Data acquisition was optimized in positive mode FullMS1-ddMS2 (Top4) and involved targeted single and parallel ion monitoring (tSIM-PRM) within a scan range of 50–750 m / z.

[0428] Metabolite identification was confirmed through matching MS1 / MS2 spectra and retention times with standards run in parallel. The normalized area under the curve (AUC) was determined for each metabolite from MS1 extracted ion chromatograms. Data analysis was carried out using Freestyle and Excalibur QuanBrowser (Thermo Scientific). Absolute quantification was achieved by constructing a 10-point calibration curve using metabolite standards.

[0429] A single 30 mg / kg oral administration dose of Compound I-16 was able to increase NAD+ levels and to decrease NAM and ADPR levels in liver (FIG.3A-3C) and spleen (FIG.4A- 4C) showing direct correlation with unbound plasma exposure. EQUIVALENTS

[0430] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

[0431] Those skilled in the art will appreciate further features and advantages of the invention - 159 -Attorney Docket No.15768.0041-00304 based on the above-described disclosures, aspects, and embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety. - 160 -

Claims

Attorney Docket No.15768.0041-00304 CLAIMS 1. A compound of Formula I: I), an acceptable salt of the omer of the compound of FormulaI, or an acceptable salt of the tautomer of the compound of Formula I, wherein: n is 0 or 1; RNis selected from H and C1-C6alkyl; Ring A is selected from C6-C10 aryl, C3-C10 cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10fused bicyclic, wherein 0 to 4 atoms of the 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic are independently O, S, N, or NRA, and wherein the C6-C10aryl, C3-C10cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, and C4-C10 fused bicyclic are each optionally substituted with one or more RA; each RAis independently selected from H, -CN, halo, optionally substituted C1-C6alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -SRA1, -S(O)2NRA2RA3, -S(O)2RA1, -S(O)RA1, -NRA2S(O)2RA1, -NRA2RA3, -C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6aryl, and optionally substituted 5-6 membered heteroaryl; wherein the optionally substituted 5-9 membered heterocycloalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6aryl, and optionally substituted 5-6 membered heteroaryl are each independently optionally substituted with one to three substituents selected from C1-C6alkyl, oxo, and halogen; wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 fluoroalkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted 5-9 membered heterocycloalkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; - 161 -Attorney Docket No.15768.0041-00304 each RA2and RA3is independently selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6alkoxy; Ring B is selected from nd each RBis independent alkyl;provided that the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer thereof is not selected fro ,, ,- 162 -Attorney Docket No.15768.0041-00304 , ,, tautomers thereof, and acceptable salts of any of the foregoing.

2. The compound, tautomer, or acceptable salt of claim 1, wherein the compound, tautomer, or acceptable salt is not a compound of Formula E-i: i), an acceptable salt of the coa tautomer of the compound of Formula E-i, or an acceptable salt of the tautomer of the compound of Formula E-i, wherein: ,, , , , ,,, , (C1-C6alkyl)2N-, HOC(O)-, (C1-C3 alkyl)(O)(C=O)-, (C1-C3 alkyl)-O-(C1-C3 alkyl)-NH-, HO-(C1-C3 alkyl)-N(C1-C3alkyl)-, (C1-C3alkyl)O(C1-C3alkyl)-N(C1-C3alkyl)-, (C1-C3alkyl)-(C=O)-NH-, (C1-C3 alkyl)-(C=O)-N(C1-C3 alkyl)-, H2N-(C=O)-, and (C1-C3 alkyl)2N-(C=O)-; - 163 -Attorney Docket No.15768.0041-00304 B1 is selected from ndR1bis selected fro3. The compound, tautomer, or acceptable salt of claim 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-ii: (E-ii), an acceptable salt of th a tautomer of the compound ofFormula E-ii, or an acceptable salt of the tautomer of the compound of Formula E-ii, wherein: Ring A2is selected from 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, C6 cycloalkyl, and C7-C10 cycloalkyl, wherein the 4-8 membered heterocycloalkyl, C3-C5 cycloalkyl, and C7-C10cycloalkyl are each optionally substituted with R2aor wherein the C6 cycloalkyl is substituted with R2a; each R2ais independently selected from -CN, halo, optionally substituted C1-C6 alkyl, C1- C6haloalkyl, C1-C6cyanoalkyl, -OR21a, -SR21a, -S(O)2NR22aR23a, -S(O)2R21a, -S(O)R21a, -NR21aR23a, -C(O)R21a, -C(O)OR21a, -C(O)NR22aR23a, and 5-8 membered heterocycloalkyl; wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each R21ais independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; and each R22aand R23ais independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy.

4. The compound, tautomer, or acceptable salt of claim 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-iii: - 164 -Attorney Docket No.15768.0041-00304 (E-iii), an acceptable salt utomer of the compound ofFormula E-iii, or an acceptable salt of the tautomer of the compound of Formula E-iii, wherein: L is selected from a bond and CH2; R31ais independently selected from H and methyl; R32ais independently selected from H and C1-C4 alkyl; or R31aand R32atogether with the nitrogen atom to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may optionally be substituted with fluoro; Ring B3is selected from nd each R3bis independent alkyl.

5. The compound, tautomer, or acceptable salt of claim 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-iv: v), an acceptable salt of thetautomer of the compound of Formula E-iv, or an acceptable salt of the tautomer of the compound of Formula E-iv, wherein: Ring A4is selected from C4-C9 cycloalkyl, phenyl, pyridinyl, and 4-9 membered heterocycloalkyl; wherein the C4-C9 cycloalkyl is optionally substituted with -OH, halo, C1-C6 alkyl optionally substituted with C1-C6alkoxy, C1-C6haloalkyl, C1-C6alkoxy optionally substituted with C1-C6 alkoxy, C(O)OC1-C6 alkyl, and pyridinyl; wherein the phenyl is optionally substituted with one or more halo; wherein the 4-9 membered heterocycloalkyl is optionally substituted with halo, C1-C6alkyl, C(O)OC1-C6alkyl, and C(O)C1-C6alkyl; and - 165 -Attorney Docket No.15768.0041-00304 wherein the pyridinyl is optionally substituted with halo or C1-C6alkyl; Ring B4is selected from nd each R4bis independent 6 alkyl.

6. The compound, tautomer, or acceptable salt of claim 1, wherein the compound, acceptable salt of the compound, tautomer, or acceptable salt of the tautomer is not a compound of Formula E-v: v), an acceptable salt o mer of the compound ofFormula E-v, or an acceptable salt of the tautomer of the compound of Formula E-v, wherein: Ring A5is selected C3-C7cycloalkyl, wherein the C3-C7cycloalkyl is optionally substituted with one or two groups selected from halo, C1-C4alkyl, C1-C4haloalkyl, -NHSO2C1- C4 alkyl, and -SO2C1-C4 alkyl; R5ais independently selected from H and C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with C1-C4alkoxy; n is 0 or 1; Ring B5is selected from nd each R5bis independentalkyl.

7. The compound, tautomer, or acceptable salt of any one of claims 1-6, wherein n is 1.

8. The compound, tautomer, or acceptable salt of any one of claims 1-6, wherein n is 0.

9. The compound, tautomer, or acceptable salt of any one of claims 1-8, wherein RNis selected from H and methyl.

10. The compound, tautomer, or acceptable salt of any one of claims 1-8, wherein RNis H.- 166 -Attorney Docket No.15768.0041-00304 11. The compound, tautomer, or acceptable salt of any one of claims 1-8, wherein RNis methyl.

12. The compound, tautomer, or acceptable salt of any one of claims 1-11, wherein Ring A is selected from cyclohexyl, quinuclidinyl, phenyl, pyridinyl, pyrimidinyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidinyl, wherein each of the foregoing is optionally substituted with RA.

13. The compound, tautomer, or acceptable salt of any one of claims 1-11, wherein Ring A is , .

14. The compound, tautomer, or acceptable salt of any one of claims 1-11, wherein Ring A is ,15. The compound, tautomer, or acceptable salt of any one of claims 1-11, wherein Ring A is , ,- 167 -Attorney Docket No.15768.0041-00304 16. The compound, tautomer, or acceptable salt of any one of claims 1-11, wherein Ring A is .. , , , ing A is , , , ,- 168 -Attorney Docket No.15768.0041-00304 , ,18. The compound, tautomer, or acceptable salt of any one of claims 1-16, wherein each RAis independently selected from H, -CN, -OH, halo, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -ORA1, -S(O)2NRA2RA3, -S(O)2RA1, -NRA2S(O)2RA1, -NRA2RA3, - C(O)RA1, -C(O)ORA1, -C(O)NRA2RA3, cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, pyrrolidinyl, oxadiazolyl, tetrazolyl, 4,5-dihydro-1H-imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl, wherein the cyclopentyl, piperidine, piperazinyl, morpholinyl, pyrazolyl, pyrrolidinyl, oxadiazolyl, tetrazolyl, 4,5-dihydro-1H-imidazolyl, tetrahydropyran, pyridinyl, pyrimidinyl, and imidazolyl are each independently optionally substituted with one to three substituents selected from C1-C6 alkyl, oxo, and halogen; - 169 -Attorney Docket No.15768.0041-00304 wherein the optionally substituted C1-C6alkyl is optionally substituted with C1-C6alkoxy or 5-6 membered heteroaryl; each RA1is independently selected from H, optionally substituted C1-C6alkyl, and C1-C6alkoxy, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy; and each RA2and RA3is independently selected from H and optionally substituted C1-C6alkyl, wherein the optionally substituted C1-C6 alkyl is optionally substituted with C1-C6 alkoxy.

19. The compound, tautomer, or acceptable salt of any one of claims 1-16, wherein each RAis independently selected from H, F, -CN, -OH, Me, Et, n-Pr, i-butyl, -CHF2, -CF3, -CH2CHF2, - CH2CN, -C(O)OH, -C(O)OMe, -C(O)CH2OMe, -C(O)NH2, -C(O)NHMe, -Oi-Pr, -S(O)2NHMe, Me,20. The compound, tautomer, or acceptable salt of any one of claims 1-16, wherein each RAis independently selected from H, F, -CN, -OH, Me, Et, n-Pr, i-butyl, -CHF2, -CF3, -CH2CHF2, - , ,- 170 -Attorney Docket No.15768.0041-00304 ,21. The compound, tautomer, or acceptable salt of any one of claims 1-16, wherein each RAis independently selected from -CN, -OH, -CHF2, -CF3, -CH2CHF2, -CH2CN, NH2, -NHMe, - r, -22. The compound, tautomer, or acceptable salt of any one of claims 1-21, wherein Ring B is selected from .

23. The compound, tautomer, or acceptable salt of any one of claims 1-21, wherein Ring B is .

24. The compound, tautomer, or acceptable salt of any one of claims 1-21, wherein Ring B is .

25. A compound selected from: - 171 -Attorney Docket No.15768.0041-00304- 172 -Attorney Docket No.15768.0041-00304- 173 -Attorney Docket No.15768.0041-00304- 174 -Attorney Docket No.15768.0041-00304- 175 -Attorney Docket No.15768.0041-00304- 176 -Attorney Docket No.15768.0041-00304- 177 -Attorney Docket No.15768.0041-00304- 178 -Attorney Docket No.15768.0041-00304, . - 179 -Attorney Docket No.15768.0041-00304 26. A composition comprising one or more compound(s), tautomer(s), and / or acceptable salt(s) of any one of claims 1 to 25 and an acceptable carrier.

27. The composition of claim 26, further comprising one or more additional therapeutic agent(s).

28. The composition of claim 27, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, an inhibitor ofCCR2 and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid 17- dehydrogenase (HSD17B13)inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin-sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrates, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin-receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid-lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta-adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT)inhibitor, an immunomodulator, anti-IL-6 antibody, an anti-TNF- antibody, an NSAID, adisease-modifying antirheumatic drug (DMARD), a steroid, methotrexate, an anti-IL-1 agent, aJAK inhibitor, an interferon, an 11 -hydroxy steroid dehydrogenase-1 (11 .-HSD type 1)inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, an MCR-4 agonist, a cholecystokinin- A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte-stimulating hormone analog, a 5HT2c agonist, a melanin concentrating - 180 -Attorney Docket No.15768.0041-00304 hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent.

29. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject that benefits from modulation of the level of NAD+ and / or a related metabolite thereof and / or wherein CD38 is upregulated.

30. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to small lung cell carcinoma, renal clear cell carcinoma, chronic lymphocytic leukemia, multiple myeloma, hypertension, hypoxic pulmonary vasoconstriction, cardiac hypertrophy, congestive heart failure, stroke, Alzheimer's disease, bipolar disorder, schizophrenia, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, optic neuropathy, epilepsy, idiopathic pulmonary fibrosis, viral- induced fibrosis of the lung, infection-induced fibrosis of the lung, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity, sarcopenic obesity, sarcopenia, dyslipidemia, diabetes, diabetic neuropathy, insulin resistance, pancreatitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, steatosis, non-alcoholic steatohepatitis (NASH), postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin hyperpigmentation, UV skin damage, psoriasis, hidradenitis suppurativa, X-ray-induced DNA damage, periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, neurodegeneration, peripheral - 181 -Attorney Docket No.15768.0041-00304 neuropathies associated with chemotherapy, a mitochondrial myopathy, or a disease, disorder, orcondition mediated by TNF- or IL-6.

31. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition related to aging.

32. The compound, tautomer, acceptable salt, or composition of claim 31, wherein the disease, disorder, or condition related to aging is or is related to a chronic age-related disease, disorder, or condition.

33. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to aging, a age-related chronic disease, inflammation, cancer, a cardiovascular disorder, a neurological disorder, a pulmonary disorder, a fibrotic disease, SARS, COVID-19, a metabolic disorder, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, arthritis, ataxia-telangiectasia, irritable bowel syndrome, colitis, gout, end stage renal disease, hearing loss, a liver disorder, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, a disease of the skin, damage caused by exposure to radiation, a periodontal disease, Leber's hereditary amaurosis, a sleep disorder, exercise intolerance, or a chronic disease associated with cell death.

34. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to a fibrotic disease, disorder, or condition of the lung, heart, or kidney.

35. The compound, tautomer, or acceptable salt, or composition of claim 34, wherein the fibrotic disease is diabetic nephropathy, chronic kidney disease, infection-induced fibrosis of the lung or a virus-induced infection of the lung. - 182 -Attorney Docket No.15768.0041-00304 36. The compound, tautomer, or acceptable salt of any one of claims 1 to 25, or the composition of any one of claims 26 to 28, wherein the compound, tautomer, or acceptable salt or the composition is for treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is or is related to multiple myeloma.

37. The compound, tautomer, acceptable salt, or composition of claim 36, wherein the treatment further comprises administering an immuno-oncology drug to the subject.

38. The compound, tautomer, acceptable salt, or composition of claim 29, wherein the modulation is an increase in the level of NAD+ and / or a related metabolite thereof.

39. The compound, tautomer, acceptable salt, or composition of claim 29, wherein the modulation is a decrease in the level of NAD+ and / or a related metabolite thereof.

40. The compound, tautomer, acceptable salt, or composition of claim 29, wherein the NAD+ and / or related metabolite thereof is selected from the group consisting of NAD+, NMN, ADPR, cADPR, NAM, NAAD, NAADP, NR, and MNAM.

41. A method of treating a disease, disorder, or condition in a subject that benefits from modulation of the level of NAD+ or a related metabolite thereof and / or wherein CD38 is upregulated in a subject comprising administering to the subject an effective amount of the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28.

42. The method of claim 41, further comprising administering to the subject one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28.

43. The method of claim 42, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, an inhibitor ofCCR2 and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid 17- dehydrogenase (HSD17B13)inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, an SGLT2 inhibitor, a PPAR - 183 -Attorney Docket No.15768.0041-00304 agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin-sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrates, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin-receptor blocker, an acetyl-CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid-lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta-adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT)inhibitor, an immunomodulator, anti-IL-6 antibody, an anti-TNF- antibody, an NSAID, adisease-modifying antirheumatic drug (DMARD), a steroid, methotrexate, an anti-IL-1 agent, aJAK inhibitor, an interferon, an 11 -hydroxy steroid dehydrogenase-1 (11 .-HSD type 1)inhibitor, a stearoyl-CoA desaturase-1 (SCD-1) inhibitor, an MCR-4 agonist, a cholecystokinin- A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte-stimulating hormone analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent.

44. The method of claim 42, wherein the one or more additional therapeutic agent(s) are selected from sarilumab, tocilizumab, etanercept, adalimumab, and infliximab. - 184 -Attorney Docket No.15768.0041-00304 45. The method of claim 43 or 44, wherein the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28 is administered to the subject in one, two, or three daily dose(s).

46. The method of any one of claims 42 to 45, wherein the subject is a mammal.

47. The method of any one of claims 42 to 45, wherein the subject is a human.

48. The method of any one of claims 42 to 45, wherein the subject is an animal.

49. The method of any one of claims 42 to 45, wherein the subject is a domestic animal, wherein the domestic animal is selected from a rabbit, a bird, a cat, a dog, a fish, a rat, a tortoise, and a reptile.

50. The method of any one of claims 42 to 45, wherein the subject is a working animal or a farm animal, wherein the working animal is selected from cattle, yaks, and horses; and wherein the farm animal is selected from sheep, pigs, cows, chickens, goats, geese, ducks, and llamas.

51. A kit comprising the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28 and instructions for use thereof.

52. The kit of claim 51, further comprising one or more additional therapeutic agent(s).

53. The kit of claim 52, wherein the one or more additional therapeutic agent(s) are selected from an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, a GLP-1 receptor agonist, an FXR agonist, a CB1 antagonist, an ASK1 inhibitor, an inhibitor of CCR2and / or CCR5, a PNPLA3 inhibitor, a hydroxysteroid 17- dehydrogenase (HSD17B13) inhibitor,a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, an SGLT2 inhibitor, a PPAR agonist, an AMPK activator, an SCD1 inhibitor, an MPO inhibitor; an insulin-sensitizing agent, a FGF21 analog, metformin, an omega-3-acid ethyl ester , a fibrate, an HMG CoA-reductase inhibitor, ezetimibe, probucol, ursodeoxycholic acid, a TGR5 agonist, an FXR agonist, vitamin E, betaine, pentoxifylline, a CB1 antagonist, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, an SGLT2 inhibitor, phentermine, topiramate, a GLP-1 receptor agonist, a GIP receptor agonist, a dual GLP-1 receptor / glucagon receptor - 185 -Attorney Docket No.15768.0041-00304 agonist, a dual GLP-1 receptor / GIP receptor agonist, an angiotensin-receptor blocker, an acetyl- CoA carboxylase (ACC) inhibitor, a BCKDK inhibitor, a ketohexokinase (KHK) inhibitor, an ASK1 inhibitor, a branched-chain alpha keto acid dehydrogenase kinase inhibitor (BCBK inhibitor), an inhibitor of CCR2 and / or CCR5, a PNPLA3 inhibitor, a DGAT1 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, a SCD1 inhibitor, an MPO inhibitor, an acetylcholinesterase inhibitor, a dopamine receptor agonist, an immuno-oncology drug, a DOPA decarboxylase inhibitor, a monoamine oxidase (MAO) inhibitor, a muscarinic receptor agonist, an amyloid-lowering or -inhibiting agent, an antibody to amyloid-ß, amyloid-ß or a fragment thereof, a beta-adrenergic receptor blocking agent (beta blocker), a calcium channel blocker, a catechol O-methyltransferase (COMT) inhibitor, animmunomodulator, anti-IL-6 antibody, an anti-TNF- antibody, an NSAID, a disease-modifyingantirheumatic drug (DMARD), a steroid, methotrexate, an anti-IL-1 agent, a JAK inhibitor, aninterferon, an 11 -hydroxy steroid dehydrogenase-1 (11 .-HSD type 1) inhibitor, a stearoyl-CoAdesaturase-1 (SCD-1) inhibitor, an MCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor, -3 adrenergic agonists, a dopamine agonist, a melanocyte- stimulating hormone analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin agonist, a galanin antagonist, a lipase inhibitor, an anorectic agent, a neuropeptide-Y antagonist, a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid agonist or antagonist, an orexin antagonist, a glucagon-like peptide-1 agonist, a ciliary neurotrophic factor, a human agouti-related protein (AGRP) inhibitor, a ghrelin antagonist, a histamine H3 antagonist or inverse agonist, a neuromedin U agonist, a MTP / ApoB inhibitor, an opioid antagonist, an orexin antagonist, a neuroprotective drug, a trophic factor, a nutraceutical product, and a sympathomimetic agent.

54. The kit of claim 52 or 53, wherein the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28 and the one or more additional therapeutic agent(s) are in separate containers.

55. The kit of claim 52 or 53, wherein the compound, tautomer, or acceptable salt of any one of claims 1 to 25 or the composition of any one of claims 26 to 28 and the one or more additional therapeutic agent(s) are in the same container.

56. The kit of claim 54 or 55, wherein the container is a bottle, vial, or blister pack, or a combination thereof. - 186 -