Heteroaryl amide inhibitors of CD38

Abstract

Heteroaryl amide inhibitors of CD38, and methods for making and using same in the treatment of diseases and disorders, are disclosed.

Description

Technical Field

[0001]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 089,818, filed October 9, 2020, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to biochemistry and medicine. More specifically, the present disclosure relates to novel compounds for treating diseases by modulating the levels of cellular NAD+ and its related metabolites by inhibiting the CD38 enzyme, their preparation processes, and pharmaceutical formulations and methods.

Background Art

[0002]

[0003] Nicotinamide adenine dinucleotide (NAD+) is a biochemical substance found in all cells that play important roles in redox enzyme reactions. NAD+ and its related pyridine nucleotides NADH, nicotinamide adenine dinucleotide phosphate (NADP+), and NADPH are all recognized as major redox carriers in all organisms. These pyridine dinucleotides control the redox state of the cytosol and mitochondria and are major participants in monitoring the metabolic state of cells (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).

[0003]

[0004] In addition to its role as a cofactor for redox enzymes, NAD+ is also a substrate for various enzymes and is consumed in the process of donating its adenosine diphosphate (ADP) ribose to acceptor molecules or in the processes of hydrolysis or cyclization. Enzymes that are major consumers of NAD+ are ADP ribosyltransferases (i.e., the poly(ADP-ribose) polymerase (PARP) and ADP-ribosyltransferase (ART) families of enzymes), sirtuins (Sirt1-7), and ADP ribosyl cyclase / hydrolase (CD38 / CD157). These enzymes are involved in pathways that control Ca2+ signaling, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. Thus, both NAD+ and its phosphorylated analogs NADP and nicotinic acid adenine dinucleotide phosphate (NAADP), which are all derived from NAD+, also act as signaling molecules. NAD+ is also a component of the circadian cycle with daily oscillations that link cellular metabolism to chromatin remodeling and gene transcription. Exercise and calorie restriction are known to increase NAD+ levels, while aging and obesity decrease cellular NAD+ levels.

[0004]

[0005] Cellular NAD+ is produced by de novo synthesis pathways from tryptophan, or by the Preiss-Handler pathway, and / or by salvage synthesis pathways from precursors such as nicotinic acid (niacin), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) that are taken up by the cell. Regulation of cellular NAD+ levels can be achieved by blocking NAD+ consumption by inhibiting enzymes that consume NAD+. CD38 is one such NAD+-consuming enzyme and has been reported to be a major cellular NAD+ consumer. CD38, also known as an ADP-ribosyl cyclase, is a type II membrane-anchored enzyme. CD38 efficiently catalyzes the breakdown of NAD+ into nicotinamide (NAM) and ADP-ribose (ADPR), and hydrolyzes NAADP to ADPR phosphate (ADPRP). CD38 acts as a cyclase that converts NAD+ into cyclic ADPR (cADPR). Finally, ADPR is also a breakdown product of cADPR hydrolysis mediated by CD38.

[0005]

[0006] ADP-ribose (ADPR) and cyclic ADPR (cADPR) are metabolites of NAD+ generated by CD38-mediated hydrolysis or cyclization and play important roles as intracellular Ca2+ mobilizing second messengers. cADPR is mainly involved in stimulating Ca2+ release from the endoplasmic reticulum via ryanodine receptors, while ADPR activates the plasma membrane cation channel TRPM2 (transient receptor potential melastatin 2) and promotes calcium entry into the cell. Aberrant TRPM2 activation has been shown to induce abnormal intracellular Ca2+ accumulation and cell death in various cell types including neurons and is involved in several neuropathies. In particular, activation of TRPM2 has been associated with diseases such as ischemia-reperfusion injury, bipolar disorder, Alzheimer's disease, neuropathic pain, and Parkinson's disease.

[0006]

[0007] Nicotinamide (NAM) is NAD +It is a precursor and an important molecule involved in energy metabolism. NAM is converted to nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). Alternatively, NAM is irreversibly methylated by the 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 cancer.

[0007]

[0008] Although NAM supplementation has shown positive effects, high levels of NAM can exert negative effects through multiple pathways such as inhibition of PARP and sirtuins, as well as changes in methyl metabolism. It has been shown that NAM supplementation causes significant decreases in insulin sensitivity, neurotoxicity, and hepatotoxicity in human subjects.

[0008]

[0009] Certain heteroaryl amides, such as N-(3-chloro-2-methylpyridin-4-yl)-6-imidazol-1-ylpyridine-2-carboxamide, pubchem.ncbi.nlm.nih.gov / compound / 99607495 are known, but the biological data of the compounds have not been reported. International Patent Publication WO2015 / 187499 mentions certain unrelated reverse amides as ASK1 inhibitors. International Patent Publication WO2009 / 014637 mentions certain benzimidazolyl pyridines as protein kinase inhibitors. U.S. Patent No. 7,919,487 mentions certain heteroaryl hydrazones.

[0009]

[0010] Therefore, there remains a need for novel inhibitors of CD38 and for the treatment of diseases or disorders where modulation of cellular NAD+ and its related metabolite levels would be beneficial.

Summary of the Invention

[0010]

[0011] The present disclosure provides novel compounds, their preparation processes, pharmaceutical formulations, and methods for treating diseases by modulating the levels of cellular NAD+ and its related metabolites by inhibiting the CD38 enzyme.

[0011]

[0012] The present disclosure relates to a compound of formula I

[0012]

Chemical formula

[0013] or a pharmaceutically acceptable salt, ester, or prodrug thereof, or to a compound of formula I *

[0014]

Chemical formula

[0015] or a pharmaceutically acceptable salt, ester, or prodrug thereof. (wherein, when the compound is of formula I, -X-Y-Z- is =CR 1 -CR 2 =CR 3 -、=N-CR 2 =CR 3 -、=CR 1 -N=CR 3 - or =CR 1 -CR 2 =N-; when the compound is of formula I * X-Y-Z- is CR 1 -CR 2 =C, N-CR 2 =C, or CR 1 -N=C; R 1is selected from the group consisting of H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkoxy-; (C1-C6)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 2 is H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C6)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3)alkyl, -CF3, (C1-C3)alkoxy, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3)alkyl; each R 4 is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5is selected from the group consisting of (C1-C3) alkyl, perfluoro (C1-C3) alkyl, HO-(C2-C4) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3) alkyl; (C1-C3) alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; W is

[0016]

Chemical formula

[0017] and R 8 is H, -CH3, or -CF3; Het is a heterocyclic ring of the formula

[0018]

Chemical formula

[0019] ; Each R 9 is H, halo, (C1-C6) alkyl, -CF3, (C1-C6) alkoxy, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O((C1-C3) alkyl)-(NR 11 )-, R 13-(C=O)-(NR 11 )- and (R 11 )2N-(C=O)- independently selected from; Each R 10 is H, (C1-C3) alkyl, -CF3, -OCH3, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O-((C1-C3) alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )-, and (R 11 )2N-(C=O), independently selected from; R 11 is independently H or (C1-C3) alkyl; R 12 is H or (C1-C3) alkyl; R 13 is (C1-C3) alkyl)

[0013] In some embodiments of the compounds of formula I and I * , Het is, Formula i:

[0020]

Chemical formula

[0021] Formula ii:

[0022]

Chemical formula

[0023] Formula iii:

[0024]

Chemical formula

[0025] Formula iv:

[0026]

Chemical formula

[0027] Formula v:

[0028] [Chem.]

[0029] Formula vi:

[0030] [Chem.]

[0031] Formula vii:

[0032] [Chem.]

[0033] Formula viii:

[0034] [Chem.]

[0035] or Formula ix:

[0036] [Chem.]

[0037] is the ring of.

[0014] In a specific embodiment of the compound of formula I and I containing any of the above compounds, R * is -CH3 or -CF3; W is 8 Formula (a): Formula (a):

[0038] [Chem.]

[0039] Formula (b):

[0040] [ka]

[0041] Formula (c):

[0042] [ka]

[0043] Formula (d):

[0044] [ka]

[0045] Formula (e):

[0046] [ka]

[0047] or Formula (f):

[0048] [ka]

[0049] It is a compound of the formula:

[0015] Formula I and I, which include any of the above compounds * In some embodiments of the compound of formula (I), R 1 is selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -OCH3, and -OCF3.

[0050]

[0016] Formula I and I, which include any of the above compounds * In certain embodiments of the compound of: R 2is selected from the group consisting of H, (C1-C6) alkyl, (C1-C6) alkoxy, and perfluoro (C1-C6) alkyl, perfluoro (C1-C6) alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; each R 4 is independently H or (C1-C3) alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from the group consisting of (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3) alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3.

[0051] In some embodiments of the compound of Formula 1 comprising any of the above compounds, R 3 is selected from the group consisting of H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, and (R 7 )2N-; R 7 is H or (C1-C3)alkyl.

[0052]

[0018] In certain embodiments, R 1 is selected from the group consisting of H, F, -CH3, and -OCH3.

[0019] In some embodiments of the compounds of Formula I and I * comprising any of the above compounds, R 1 is H.

[0053]

[0020] In certain embodiments of the compounds of Formula I and I * comprising any of the above compounds, R 2 is selected from the group consisting of H, (C1-C3)alkyl, (C1-C3)alkoxy-, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy-, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C3)alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; each R 4is independently (C1-C3) alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from (C1-C3) alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and 6-10 membered aryl; (C1-C3) alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and 6-10 membered aryl are optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently (C1-C3) alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3.

[0054]

[0021] In certain embodiments of the compounds of Formula I and I comprising any of the above compounds, R * is selected from methoxy-, cyclopropoxy- or R 2 -(C(R 5 )2)-O-; each R 4 is H; R 4 is selected from the group consisting of C1-alkyl and tetrahydropyran, and said C1-alkyl is substituted with -OCH3. 5 is selected from the group consisting of C1-alkyl and tetrahydropyran, and said C1-alkyl is substituted with -OCH3.

[0055]

[0022] In some embodiments of the compounds of Formula I and I comprising any of the above compounds, R * is selected from the group consisting of H, F, -CH3, -OCH3, or H2N-. In certain embodiments, R 3 is H. 3 is H.

[0056]

[0023] In some embodiments of the compounds of Formula I and I, comprising any of the above compounds * in some embodiments of the compounds of Formula I and I, R 9 is selected from the group consisting of H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, R 12 O((C1-C3)alkyl)-(NR 11 )-, -CO2R 12 , and (R 11 )2N-(C=O)-; each R 11 is independently selected from H and (C1-C3)alkyl; R 12 is H or (C1-C3)alkyl.

[0057]

[0024] In certain embodiments, at least one R 9 is selected from the group consisting of F, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN; in certain embodiments, at least one R 9 is -CF.

[0058]

[0025] In some embodiments of the compounds of Formula I and I, comprising any of the compounds of Formula (iii) and Formula (a)-(f), * at least one R 10 is H; in certain embodiments, R 10 is H.

[0059]

[0026] In certain embodiments of the compounds of Formula I and I, comprising any of the above compounds, Het is a ring of Formula iii: *

[0060]

Chemical Formula

[0061] (wherein one R 9 is H and the other R 9 is -CF3, and R 10 ​​is H)

[0027] In some embodiments of the compounds of formula I and I containing any of the above compounds, R * is H. 8 is H.

[0062]

[0028] In some embodiments of the compounds of formula I and I containing any of the above compounds, -X-Y-Z- is =CR * -CR 1 -CR 2 =CR 3 - or =N-CR 2 =CR 3 -, and in certain embodiments, -X-Y-Z- is =CR 1 -CR 2 =CR 3 -.

[0063]

[0029] In some embodiments of the compounds of formula I containing any of the compounds described in any of the compounds of formula (iii) and formula (a), the compound is of formula 1A:

[0064]

Chemical formula

[0065] is a compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, Formula I * The compound of is a compound of formula I * A

[0066]

Chemical formula

[0067] is a compound or a pharmaceutically acceptable salt, ester, or prodrug thereof. (Wherein, -X-Y-Z- of formula IA is =CR 1 -CR 2 =CR 3 - or =N-CR 2 =CR 3-and; Formula I * -X-Y-Z- of A is CR 1 -CR 2 =C or =N-CR 2 =C; R 1 is selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -OCH3, and -OCF3; R 2 is H, (C1-C6) alkyl, (C1-C6) alkoxy-, and perfluoro (C1-C6) alkyl, perfluoro (C1-C6) alkoxy-, cycloalkyl, cycloalkyl-O, heterocycloalkyl, aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C6) alkyl, cycloalkyl, cycloalkyl-O, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; each R 4 is independently H or (C1-C3) alkyl; R 5 is selected from the group consisting of (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3)alkyl; R 8 is H, -CH3, or -CF3; R 9 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, R 12 O((C1-C3)alkyl)-(NR 11 )-, -CO2R 12 , and (R 11 )2N-(C=O)-; Each R 11 is independently selected from the group consisting of H and (C1-C3)alkyl; R 12 is H or (C1-C3)alkyl)

[0030] In some embodiments of the compound of formula I comprising any one of the compounds of formula (ii) and formula (a), the compound is of formula 1B:

[0068]

Chemical formula

[0069] is a compound of or a pharmaceutically acceptable salt, ester, or prodrug thereof, The compound of formula I * is a compound of formula I * B

[0070]

Chemical formula

[0071] is a compound or a pharmaceutically acceptable salt, ester, or prodrug thereof. (wherein Formula I * -X-Y-Z- of B is CH-CR 2 =C or N-CR 2 =C; R 2 is H, (C1-C3)alkyl, (C1-C3)alkoxy, and perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy-, cycloalkyl, heterocycloalkyl, aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; each R 4 is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from the group consisting of (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3)alkyl; R 8 is H, -CH3, or -CF3; R 9 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, -(NR 10 )-((C1-C3)alkyl)-OR 11 , -CO2R 11 and -(C=O)-N(R 10 )2 selected from the group consisting of; R 10 is H or (C1-C3)alkyl; R 11 is (C1-C3)alkyl)

[0031] In a particular embodiment, the compound is 6-(1H-imidazol-1-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 6-(1H-imidazol-1-yl)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 2-(1H-imidazol-1-yl)-6-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-imidazol-1-yl)-4-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 4-cyclopropoxy-6-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 6-(1H-imidazol-1-yl)-N-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine, 6-(1H-imidazol-1-yl)-N-(pyridin-4-yl)pyrimid[5,4-d]pyrimidin-4-amine, 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-imidazol-1-yl)-4-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 2-(3-methyl-4H-3l4-imidazol-4-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-hydroxy-2-methylpropoxy)-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, and pharmaceutically acceptable salts, esters, or prodrugs thereof.,

[0072]

[0032] In another aspect, the disclosure provides a therapeutically effective amount of Formula I or I containing any of the above compounds, *Provided is a pharmaceutical composition comprising a compound of formula I or I

[0073]

[0033] In another aspect, the present disclosure provides a method of treating a subject suffering from a disease or medical disorder in which modulation of NAD+ levels or levels of related metabolites thereof is beneficial, the method comprising administering to the subject an amount of a pharmaceutical formulation effective to modulate the levels of NAD+ or related metabolites thereof, the formulation comprising a therapeutically effective amount of a compound of formula I or I * as described above, and a pharmaceutically acceptable carrier, and optionally comprising another agent that modulates the levels of NAD+ or related metabolites thereof.

[0074]

[0034] In some embodiments, the disease or disorder is non-alcoholic steatohepatitis, aging, chronic aging conditions, senescence, immunometabolism, sepsis, inflammation, infection, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, lupus, erythematosus, Crohn's disease, ulcerative colitis, psoriasis vulgaris, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis, cardiac fibrosis, cancer, multiple myeloma, cardiovascular disorders, neuropathy, infertility, follicle loss, reduction in the quality and quantity of oocytes, ovarian senescence, transient receptor potential melastatin 2 (TRPM2) regulation, calcium flux regulation, ischemia-reperfusion injury, bipolar disorder, Alzheimer's, neuropathic pain, Parkinson's disease, coronary artery, obesity, type 2 diabetes, hepatotoxicity, lung disorders, metabolic disorders, 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, liver disorders, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin diseases, radiation exposure-induced damage, periodontal disease, Leber hereditary cataract, sleep disorders, exercise intolerance, chronic diseases associated with cell death, and chemotherapy-related neurodegeneration, peripheral neuropathy, etc., or is associated therewith. In certain embodiments, the disease or disorder is non-alcoholic steatohepatitis, etc., or is associated therewith. In other embodiments, the disease or disorder is an age-related disease or disorder, etc., or is associated therewith. In still other embodiments, the disease or disorder is a fibrotic disease of the digestive system, lung, heart, kidney, liver, or lung, etc., or is associated therewith. In a particular embodiment, the disease or disorder is multiple myeloma, etc., or is associated therewith, and the method further comprises administering an immuno-oncology agent to a subject in need thereof.

[0075]

[0035] In another aspect, the present disclosure provides the use of a pharmaceutical formulation comprising a compound of Formula 1, such as any of the above compounds, for treating a disease or disorder in a subject in which modulation of the level of NAD+ or its related metabolites is beneficial. In some embodiments, the pharmaceutical formulation comprising a compound of Formula 1, such as any of the above compounds, is used for treating a disease or disorder in a subject in which inhibition of CD38 is beneficial. In certain embodiments, the disease or disorder is or is associated with aging and the like.

[0076]

[0036] In certain embodiments, the pharmaceutical formulation is used for treating a disease or disorder selected from small cell lung cancer, 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, virus-induced pulmonary fibrosis, infection-induced pulmonary fibrosis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity, sarcopenic obesity, 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, fatty liver, 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 hereditary cataract, sleep disorder, exercise intolerance, and chemotherapy-related neurodegeneration and peripheral neuropathy.

[0077]

[0037] In other specific embodiments, the pharmaceutical preparation is used to treat a disease or disorder selected from aging, age-related chronic diseases, inflammation, cancer, cardiovascular disorders, neuropathies, lung disorders, fibrotic diseases, SARS, COVID-19, metabolic disorders, 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, liver disorders, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin diseases, radiation exposure-induced damage, periodontal disease, Leber hereditary cataract, sleep disorders, exercise intolerance, chronic diseases associated with cell death.

[0078]

[0038] In a specific embodiment, the use is the treatment of multiple myeloma, and the treatment further comprises treating the subject with an immuno-oncology drug. In another specific embodiment, the use is the treatment of non-alcoholic steatohepatitis (NASH), and in certain embodiments, the treatment of NASH uses 2-(1H-imidazol-1-yl)-6-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide.

[0079]

[0039] These aspects and embodiments, and others, are disclosed in more detail herein.

Brief Description of the Drawings

[0080]

[0040] The accompanying drawings illustrate embodiments of the present disclosure and, together with the above general description and the following detailed description, serve to explain the principles of the present disclosure.

Fig. 1A

[0041] Figure 1A shows the in vitro functional potency of Compound 35 in human CD38+ cells as measured by a NAD hydrolase activity assay in primary human activated CD4+ T cells. The concentration-response plot represents the mean + standard deviation of % inhibition values at each concentration tested in biological replicates with n = 3 in one experiment.

Fig. 1B

[0042] Figure 1B shows the in vitro functional potency of compound 35 in human CD38+ cells, measured by NAD hydrolase activity assay in primary human M1 macrophages. The concentration-response plot represents the mean (+ / -) standard deviation of % inhibition values at each concentration tested with biological replicates at n = 3 in one experiment.

Fig. 2A

[0043] Figure 2A shows the in vitro efficacy of compound 35 in the human 3D NASH model, measured by the release of the inflammatory marker IP-10 / CXCL10. The response plot represents the mean (+ / -) standard deviation of the measured values of each cytokine / chemokine released into the supernatant under each condition tested with biological replicates at n = 6 in one experiment. By unpaired t-test, compared to NASH samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 2B

[0044] Figure 2B shows the in vitro efficacy of compound 35 in the human 3D NASH model, measured by the release of the inflammatory marker IL-10. The response plot represents the mean (+ / -) standard deviation of the measured values of each cytokine / chemokine released into the supernatant under each condition tested with biological replicates at n = 6 in one experiment. By unpaired t-test, compared to NASH samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 2C

[0045] Figure 2C shows the in vitro efficacy of compound 35 in the human 3D NASH model, measured by the release of the inflammatory marker MIP-1α / CCL3. The response plot represents the mean (+ / -) standard deviation of the measured values of each cytokine / chemokine released into the supernatant under each condition tested with biological replicates at n = 6 in one experiment. By unpaired t-test, compared to NASH samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 2D

[0046] ]Figure 2D shows the in vitro efficacy of compound 35 in a human 3D NASH model as measured by the release of the inflammatory marker TNFα. The response plots represent the mean (+ / -) standard deviation of the measured values of each cytokine / chemokine released into the supernatant under each condition tested with biological replicates at n = 6 in a single experiment. By unpaired t-test, compared to the NASH samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 3A

[0047] ]Figures 3A - 3D show the in vivo efficacy of oral administration of compound 35 (3 mg / kg) against CD38 in an aged mouse model as measured by liver NAD+ (Figure 3A), NMN (Figure 3B), NAM (Figure 3C), and ADPR (Figure 3D) levels. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 3 in a single experiment. By one-way ANOVA, compared to the vehicle sample, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 3B

Fig. 3C

Fig. 3D

Fig. 4A

[0048] Figures 4A - 4D show the in - vivo efficacy of oral administration of compound 35 (10 mg / kg) against CD38 in an aged mouse model, as measured by liver NAD+ (Figure 4A), NMN (Figure 4B), NAM (Figure 4C), and ADPR (Figure 4D) levels. Response plots represent the mean (+ / -) standard deviation of measured values of NAD+ metabolites under each condition tested with n = 3 in one experiment. By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p < 0.0001.

Fig. 4B

Fig. 4C

Fig. 4D

Fig. 5

[0049] Figure 5 shows the in vitro efficacy of compound 32 in human CD38+ cells, as measured by NAD - hydrolase activity assay in primary human M1 macrophages. The response plots represent the mean (+ / -) standard deviation of the % inhibition values at each concentration tested with n = 3 biological replicates in one experiment.

Fig. 6A

[0050] ]Figures 6A - 6D show the in vivo efficacy of short - term oral administration of compound 32 (3 and 10 mg / kg) against CD38 in an obese mouse model, as measured by liver NAD+ (Figure 6A), NMN (Figure 6B), NAM (Figure 6C), and ADPR (Figure 6D) levels. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 3 in one experiment (Example 32). By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p<0.0001.

Fig. 6B

[0050] ]Figures 6A - 6D show the in vivo efficacy of short - term oral administration of compound 32 (3 and 10 mg / kg) against CD38 in an obese mouse model, as measured by liver NAD+ (Figure 6A), NMN (Figure 6B), NAM (Figure 6C), and ADPR (Figure 6D) levels. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 3 in one experiment (Example 32). By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p<0.0001.

Fig. 6C

[0050] ]Figures 6A - 6D show the in vivo efficacy of short - term oral administration of compound 32 (3 and 10 mg / kg) against CD38 in an obese mouse model, as measured by liver NAD+ (Figure 6A), NMN (Figure 6B), NAM (Figure 6C), and ADPR (Figure 6D) levels. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 3 in one experiment (Example 32). By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p<0.0001.

Fig. 6D

Fig. 7A

[0051] Figures 7A - 7D show the in vivo efficacy of a long - term oral administration of compound 32 (10 mg / kg) against CD38 in an obese mouse model as measured by liver NAD+ (Figure 7A), NMN (Figure 7B), NAM (Figure 7C), and ADPR (Figure 7D) levels. Response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 8 - 10 in one experiment (Example 33). By one - way ANOVA, compared to the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p < 0.0001.

Fig. 7B

Fig. 7C

Fig. 7D

Fig. 8A

[0052] Figures 8A-8D show the in vivo efficacy of long-term oral administration of compound 32 (3 and 10 mg / kg) against CD38 in an aged mouse model, as measured by liver NAD+ (Figure 8A), NMN (Figure 8B), NAM (Figure 8C), and ADPR (Figure 8D) levels. Response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 4 in one experiment (Example 34). By one-way ANOVA, compared with the vehicle sample, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 8B

Fig. 8C

Fig. 8D

Fig. 9

[0053] Figure 9 shows the in vitro efficacy of compound 39 in human CD38+ cells, measured by NAD - hydrolase activity assay in primary human M1 macrophages. The response plots represent the mean (+ / -) standard deviation of the % inhibition values at each concentration tested with n = 3 biological replicates in one experiment.

Fig. 10A

[0054] Figures 10A - 10D show the in - vivo efficacy of the short - term oral administration of compound 39 (3 and 10 mg / kg) against CD38 in an obese mouse model, measured by liver NAD+ (Figure 10A), NMN (Figure 10B), NAM (Figure 10C), and ADPR (Figure 10D) levels. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 3 in one experiment. By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p < 0.0001.

Fig. 10B

Fig. 10C

Fig. 10D

Fig. 11A

[0055] Figures 11A - 11D show the in - vivo efficacy of long - term oral administration of compound 39 (10 mg / kg) against CD38 in an obese mouse model, measured by liver NAD+ (Figure 11A), NMN (Figure 11B), NAM (Figure 11C), and ADPR (Figure 11D) levels. Response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolites under each condition tested with n = 8 - 10 in one experiment. By one - way ANOVA, compared with the vehicle sample, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p < 0.0001.

Fig. 11B

Fig. 11C

Fig. 11D

Fig. 12A

[0056] Figures 12A - 12D show the in vivo efficacy of compound 39 (3 and 10 mg / kg) in an aged murine model, as measured by liver NAD+ (Figure 12A), NMN (Figure 12B), NAM (Figure 12C), and ADPR (Figure 12D) levels. Response plots represent the mean (+ / -) standard deviation of measured values of NAD+ metabolites under each condition tested with n = 3 - 4 in one experiment. By one - way ANOVA, compared to the vehicle sample, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 12B

Fig. 12C

Fig. 12D

Fig. 13A

[0057] Figures 13A - 13C show the quantification of cytokines in plasma for IL - 6 (Figure 13A), TNFα (Figure 13B), and IP - 10 (Figure 13C). The response plots represent the mean (+ / -) standard deviation of the measured cytokine levels for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the LPS samples at each time point, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 13B

Fig. 13C

Fig. 14A

[0058] Figures 14A - 14C show the MS analysis of NAD+ (Figure 14A), NAM (Figure 14B), and ADPR (Figure 14C) levels in spleen tissue. The response plots represent the mean (+ / -) standard deviation of the measured NAD+ metabolite levels for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the vehicle samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 14B

Fig. 14C

Fig. 15A

[0059] Figures 15A - 15C show the MS analysis of NAD+ (Figure 15A), NAM (Figure 15B), and ADPR (Figure 15C) levels in liver tissue. The response plots represent the mean (+ / -) standard deviation of the measured values of NAD+ metabolite levels under each condition tested with n = 4 in one experiment. By one - way ANOVA, compared with the LPS sample at each time point, *, p≤0.05; **, p≤0.01; ***, p≤0.001; ****, p < 0.0001.

Fig. 15B

Fig. 15C

Fig. 16

[0060] Shows CD38 expression in spleen tissue. Response plots represent the mean (+ / -) standard deviation of measurements of CD38 gene expression for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the LPS sample at each time point, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 17A

[0061] Figures 17A - 17I show the expression of MIP1α (Figure 17A), MIP2 (Figure 17B), TNFα (Figure 17C), RANTES (Figure 17D), MCP1 (Figure 17E), IL - 1β (Figure 17F), IL - 6 (Figure 17G), IP - 10 (Figure 17H), and IFNγ (Figure 17I) in the spleen. Response plots represent the mean (+ / -) standard deviation of measurements of gene expression for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the LPS sample at each time point, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 17B

Fig. 17C

Fig. 17D

Fig. 17E

Fig. 17F

Fig. 17G

Fig. 17H

Fig. 17I

Fig. 18

[0062] Shows CD38 expression in the liver. The response plots represent the mean (+ / -) standard deviation of the measured CD38 gene expression for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the LPS samples at each time point, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 19A

[0063] Figures 19A - 19I show the expression of MIP1α (Figure 19A), MIP2 (Figure 19B), TNFα (Figure 19C), RANTES (Figure 19D), MCP1 (Figure 19E), IL - 1β (Figure 19F), IL - 6 (Figure 19G), IP - 10 (Figure 19H), and IFNγ (Figure 19I) in the liver. The response plots represent the mean (+ / -) standard deviation of the measured gene expression for each condition tested with n = 4 in one experiment. By one - way ANOVA, compared to the vehicle samples, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 19B

Fig. 19C

Fig. 19D

Fig. 19E

Fig. 19F

Fig. 19G

Fig. 19H

Fig. 19I

Fig. 20A

[0064] Figures 20A - 20B show the in vitro efficacy of compound 32 in human CD38+ T cell lines as measured by total calcium flux analysis. The data in Figure 20B are presented as the mean AUC ± s.d. of n = 3 independent experiments. By unpaired t - test, compared to the untreated WT sample, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 20B

Fig. 21A

[0065] Figures 21A - 21B show the in vitro efficacy of compound 39 in human CD38+ T cell lines as measured by total calcium flux analysis. The data in Figure 21B are presented as the mean AUC ± s.d. of n = 3 independent experiments. By unpaired t - test, compared to the untreated WT sample, *, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001; ****, p < 0.0001.

Fig. 21B

Mode for Carrying Out the Invention

[0081]

[0066] The disclosures of patents, patent applications, and publications referred to herein are hereby incorporated by reference in their entirety to more fully describe the state of the art known to those of ordinary skill in the art at the time of the invention described and claimed herein. This disclosure shall control in the event of any conflict between the patents, patent applications, and publications and this disclosure.

[0082]

[0067] 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 first definition provided for a group or term herein applies to that group or term throughout this specification, individually or as part of another group, unless otherwise indicated.

[0083]

[0068] 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 compounds.

[0084]

[0069] As used in the present invention, "optional" or "optionally" means that the event, situation, or substituent described thereafter may or may not occur, and that the description includes examples in which the event or situation occurs and examples in which it does not occur.

[0085]

[0070] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range and the recited endpoints.

[0071] As used herein, the terms "about" or "approximately" refer to measurable values such as parameters, amounts, temporal durations, etc., and include variations of and from a particular value, by way of example, variations of and from a particular value of + / - 10% or less, + / - 5% or less, + / - 1% or less, + / - 0.5% or less, and + / - 0.1% or less, to the extent such variations are appropriate in the inventions being disclosed. It should be understood that the value itself represented by the modifier "about" or "approximately" is also specifically and preferably disclosed.

[0086]

[0072] Whenever a numerical range is used in this application, for example, when 1 - 6 is used in the definition of "alkyl", an alkyl group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.

[0087] As used herein, the term "alkyl" includes straight and branched chain and saturated aliphatic hydrocarbons containing 1, 3, 4, 5, and 6 carbon atoms. For example, as used herein, the term "(C1-C6)alkyl" and the alkyl moieties of other groups referred to herein (e.g., (C1-C6)alkoxy) are straight or branched chain radicals of 1, 2, 3, 4, 5, and 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl) optionally substituted with 1, 2, 3, 4, or 5 suitable substituents. As used herein, "alkyl" also includes aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond and 2, 3, 4, 5, and 6 carbon atoms. For example, as used herein, the term "(C2-C6)alkyl" includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.; meaning a straight or branched chain unsaturated radical of 2-6 carbon atoms optionally substituted with 1-5 suitable substituents. Compounds of formulas I-I * When the compound of formula I-I contains an alkenyl group, the alkenyl group can exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0088] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated (non-aromatic) monocyclic or bicyclic hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) having from 1, 2, 3, 4, and 5 suitable substituents, by way of example and not limitation, H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl1-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3, and -OCF3, which is optionally substituted. The cycloalkyl group may have from 3 to 12 carbon atoms in the ring, by way of example, from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 6 carbon atoms, or 3, 4, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, the monocyclic cycloalkyl group may have from 3 to 6 carbon atoms in the ring, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl. In another embodiment, cycloalkyl may optionally contain one, two, or more non-cumulative non-aromatic double or triple bonds.

[0089] As used herein, the term "heterocycloalkyl" includes monocyclic, bridged, polycyclic or fused polycyclic saturated or unsaturated non-aromatic 3- to 13-membered rings, for example 3- to 10-membered rings, or 3- to 6-membered rings, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13-membered rings, containing one or more heteroatoms selected from O, S and N. Examples of such heterocycloalkyl rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiadinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, etc. Further non-limiting examples of heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, 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-tetrahydrothiadin-2-yl, 1,3-tetrahydrothiadin-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl, etc. The heterocycloalkyl ring is optionally substituted with 1 to 5 suitable substituents, or 1 to 3 substituents, or 1, 2, 3, 4, or 5 substituents, for example, but not limited to, H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3, and -OCF3.

[0090] As used herein, the term "aryl" is defined to include fully conjugated π-electron systems of all-carbon monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups. An aryl group has 6 to 12, 6 to 10, or 6, 8, 9, 10, or 12 carbon atoms in the ring. One non-limiting exemplary aryl group is a phenyl ring of 6 carbon atoms. As used herein, the term aryl means an aromatic group containing 6 to 10 or 6 to 12 carbon atoms, such as, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl, etc. The aryl group is optionally substituted with 1 to 5 suitable substituents, more preferably 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.

[0091] As used herein, the term "heteroaryl" is defined to include monocyclic or fused polycyclic aromatic heterocyclic groups having one or more heteroatoms selected from O, S, and N within the ring. Heteroaryl groups contain 5 to 12 ring atoms, for example 5 to 10 ring atoms, 5 to 8 ring atoms, or 6, 7, 8, 9, 10, 11, or 12 ring atoms, including 1 to 5 heteroatoms selected from O, S, and N. For example, as used herein, the term heteroaryl refers to an aromatic group containing at least one ring heteroatom selected from O, S, and N and 1 to 11 carbon atoms, for example 2 to 9 carbon atoms, 3 to 8 carbon atoms, or 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms, including, 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. Heteroaryl groups are optionally substituted with 1 to 5 suitable substituents, 1 to 3 substituents, including, but not limited to, H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3, and -OCF3.

[0092]

[0078] The term "alkoxy" refers to alkyl-O-, where alkyl is as defined herein.

[0079] The term "alkylaminoalkyl" refers to an -alkyl-NR-alkyl group.

[0093]

[0080] The term "amino" refers to -NH2 or -NRR' groups.

[0081] The term "aminoalkyl" refers to an -alkyl-NRR' group.

[0082] "Aminocarbonyl" refers to -C(O)NRR'.

[0094]

[0083] The term "arylalkyl" refers to an -alkylaryl, where alkyl and aryl are as defined herein.

[0084] The term "aryloxy" refers to both -O-aryl and -O-heteroaryl groups, as defined herein.

[0095]

[0085] The term "carbonyl" refers to -(C=O)R.

[0086] The term "C-carboxyl" refers to a -(C=O)OR or RO(C=O) group.

[0087] The term "carboxylic acid" refers to a C-carboxyl group where R is hydrogen.

[0096]

[0088] The term "cyano" refers to a -CN group.

[0089] The term "dialkylamino" refers to an -N(alkyl)2 or NR2 group.

[0090] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0097]

[0091] The term "hydroxy" refers to an -OH group.

[0092] The term "N-amide" refers to a -R'(C=O)NR group.

[0093] The term "perfluoroalkyl group" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms.

[0098]

[0094] As used herein, the terms "one compound of formula I" or "a plurality of compounds of formula I", e.g., compounds of formulae IA - IH, or a pharmaceutically acceptable salt, ester, or prodrug thereof, encompass all forms of the compounds of formula I, including the compounds of formulae IA - IH, as well as all of their hydrates, solvates, isomers, crystalline and amorphous forms, polymorphs, enantiomers, metabolites, and prodrugs.

[0099]

[0095] As used herein, the term "prodrug" means a derivative of a known direct-acting agent, the derivative having improved delivery characteristics and therapeutic value compared to the drug and being converted to the active drug by an enzyme or chemical process.

[0100]

[0096] As used in the present invention, the phrase "pharmaceutically acceptable" means those compounds, substances, compositions and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically in humans.

[0101]

[0097] This disclosure relates to novel heterocyclic amides of Formula I and I * and to pharmaceutical formulations containing these heterocyclic amides, as well as to their use and synthesis.

[0098] The compound of Formula I, having the following structure:

[0102]

Chem.

[0103] or a pharmaceutically acceptable salt, ester, or prodrug thereof, Compound of Formula I * has the following structure:

[0104]

Chem.

[0105] or a pharmaceutically acceptable salt, ester, or prodrug thereof. (wherein, When the compound is of formula I, -X-Y-Z- is =CR 1 -CR 2 =CR 3 -、=N-CR 2 =CR 3 -、=CR 1 -N=CR 3 - or =CR 1 -CR 2 =N-; When the compound is of formula I * -X-Y-Z- is =CR 1 -CR 2 =C-, =N-CR 2 =C- or =CR 1 -N=C-; R 1 is selected from the group consisting of H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkoxy-, and (C1-C6)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 2 is H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-, and (C1-C6)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3is H, halo, (C1-C3)alkyl, -CF3, (C1-C3)alkoxy, -OCF3 or (R 7 )2N-, where R 7 is H or (C1-C3)alkyl; n is an integer from 1 to 3; each R 4 is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from the group consisting of (C1-C3)alkyl, perfluoro(C1-C3)alkyl, HO-(C2-C4)alkyl, cycloalkyl, heterocycloalkyl, and aryl, and (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3)alkyl, and (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; W is

[0106]

Chemical formula

[0107] and R 8 is H, -CH3, or -CF3; Het is of the formula

[0108]

Chem.

[0109] is a complex ring; Each R 9 is independently selected from H, halo, (C1-C6)alkyl, -CF3, (C1-C6)alkoxy, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O((C1-C3)alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )- and (R 11 )2N-(C=O)-; Each R 10 is independently selected from H, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O-((C1-C3)alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )-, and (R 11 )2N-(C=O); Each R 11 is independently H or (C1-C3)alkyl; R 12 is H or (C1-C3)alkyl; R 13 is (C1-C3)alkyl)

[0099] The compounds of formula I - I * may exist, for example, in the form of pharmaceutically acceptable salts such as acid addition salts and base addition salts of the compounds of formula I. As used herein, the term "pharmaceutically acceptable salts" includes salts of acidic or basic groups that may be present in the compounds of formula I, unless otherwise indicated.

[0110]

[0100] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetates, adipates, aspartates, benzoates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, cyclamates, edisyates, esylates, formates, fumarates, gluceptates, glucuronates, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrobromides / bromides, hydroiodides / iodides, isethionates, lactates, malates, maleates, malonates, mesylates, methyl sulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharinates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, and xinafoates.

[0111]

[0101] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For a general review of suitable salts, see Stahl and Wermut (2011) Pharmaceutical Salts: Properties, Selection, and Use, (2nd Revised Edition) pp. 1 - 388 (Wiley - VCH), the entire content of which (and specifically the sections regarding suitable salts) is hereby incorporated by reference in its entirety into this specification.

[0112]

[0102] Compounds according to the present disclosure can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a substance lacks long-range order at the molecular level and may exhibit physical properties of a solid or a liquid depending on temperature. Such substances may not exhibit a characteristic X-ray diffraction pattern, exhibit solid properties, but are formally described as liquids. Upon heating, a change from solid to liquid occurs, which is typically characterized by a secondary state change ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has a regular internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with defined peaks. Such substances also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is typically characterized by a primary phase change ("melting point").

[0113]

[0103] Compounds according to the present disclosure can also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound according to the present disclosure and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

[0114]

[0104] The currently accepted classification system for organic hydrates is a system that defines isolated site hydrates, channel hydrates, or metal-ion coordinated hydrates (see Polymorphism in Pharmaceutical Solids, (1995) Morris (ed. H. G. Brittain, Marcel Dekker), the entire content of which (and in particular the sections regarding isolated site hydrates, channel hydrates, or metal-ion coordinated hydrates) is hereby incorporated by reference in its entirety into this specification. An isolated site hydrate is one in which water molecules are isolated from direct contact with each other by intervening organic molecules. In a channel hydrate, the water molecules are within lattice channels where they are adjacent to other water molecules. In a metal-ion coordinated hydrate, the water molecules are bonded to metal ions.

[0115]

[0105] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometric amount regardless of humidity. However, when the solvent or water is weakly bound, as in the case of channel hydrates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometric amounts will be standard.

[0116]

[0106] Formula I or I *Compounds and multicomponent complexes (other than salts and solvates) in which the compound and at least one other component are present in stoichiometric or non-stoichiometric amounts are also included within the scope of the present disclosure. This type of complex includes inclusion compounds (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular components bonded via non-covalent interactions, but may also be complexes of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, recrystallization from a solvent, or physically grinding the components together (see Almarsson et al. (2004) Chem. Commun. 1889-1896), the entire content of which (especially the part regarding the preparation of co-crystals by melt crystallization, recrystallization from a solvent, or grinding) is hereby incorporated by reference in its entirety into this specification. A general review of multicomponent complexes is described in Haleblia (1975) J. Pharm. Sci. 64 (8):1269-1288, the entire content of which is hereby incorporated by reference in its entirety into this specification.

[0117]

[0107] Compounds according to the present disclosure may also exist in an intermediate state (mesophase or liquid crystal) when exposed to suitable conditions. An intermediate state is intermediate between a true crystalline state and a true liquid state (either a melt or a solution). An intermediate state resulting from a change in temperature is described as "thermotropic", and one resulting from the addition of a second component, for example, but not limited to, water or another solvent is described as "lyotropic". Compounds having the potential to form lyotropic mesophases are described as "amphiphilic" and have an ionic polar head group (e.g., but not limited to, -COO - Na + , -COO - K + or -SO3 - Na + ) or a non-ionic polar head group (e.g., but not limited to, -N - N +It consists of molecules having (CH3)3). For more information, see Hartshorne and Stuart (1970) Crystals and the Polarizing Microscope (1970) 4th Edition (Edward Arnold), the entire content of which (and in particular the sections on intermediate compounds) is hereby incorporated by reference in its entirety into this specification.

[0118]

[0108] As used herein, all references to compounds of Formulas I - I * include references to salts, solvates, multicomponent complexes and liquid crystals thereof, as well as salts of such solvates, multicomponent complexes and liquid crystals thereof.

[0119]

[0109] Compounds according to the present disclosure include compounds of Formulas I - I * as defined above, for example, all polymorphs and crystal habits thereof as defined below, prodrugs thereof and isomers thereof (including optical isomers, geometric isomers and tautomers), as well as isotopically labeled compounds of Formula I.

[0120]

[0110] The present disclosure also relates to prodrugs of compounds of Formula I. Accordingly, certain derivatives of compounds of Formulas I - I * which may have little or no pharmacological activity per se, upon administration in vivo or topically, are converted into compounds of Formulas I - I * and can have the desired activity, for example, by cleavage by hydrolysis. Such derivatives are referred to as "prodrugs" (see, for example, Higuchi et al. (1987) "Pro - drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series; Bioreversible Carriers in Drug Design, Pergamon Press, edited by E. B. Roche, American Pharmaceutical Association), the entire content of which (in particular the sections on prodrugs) is hereby incorporated by reference in its entirety into this specification.

[0121]

[0111] The prodrugs according to the present disclosure are produced, for example, by replacing suitable functional groups present in the compounds of Formulas I to I with certain moieties known to those skilled in the art as "pro-moieties" (see Bundgaard (1985) Design of Prodrugs (Elsevier, 1985)), the entire content of which (and specifically the sections regarding pro-moieties) is hereby incorporated by reference in its entirety into this specification. *

[0112] Some non-limiting examples of the prodrugs according to the present disclosure include the following:

[0122]

[0112] Some non-limiting examples of the prodrugs according to the present disclosure include the following: (i) When the compound of Formula I or I * contains a carboxylic acid functional group that is preferably functionalized with a metabolically labile group (ester, carbamate, etc.); (ii) When the compound of Formula I or I * contains an alcohol functional group that is preferably functionalized with a metabolically labile group (ether, ester, carbamate, acetal, ketal, etc.); and (iii) When the compound of Formula I or I * contains a primary or secondary amino functional group that is preferably functionalized with a metabolically labile group, such as a hydrolyzable group (amide, carbamate, urea, phosphonate, sulfonate, etc.), or contains an amide.

[0123]

[0113] Further examples of substituents according to the foregoing examples and examples of other prodrug types can be found in the references described above.

[0114] The compounds of Formulas I to I * may have asymmetric carbon atoms and may exist as two or more stereoisomers. The carbon-carbon bonds of the compounds of Formulas I to I * are represented herein by solid lines

[0124]

Chemical Formula

[0125] , solid wedge shape

[0126]

Chem.

[0127] , or dashed wedge shape

[0128]

Chem.

[0129] can be represented using. The use of a solid line to represent a bond to an asymmetric carbon atom means that all possible stereoisomers (e.g., a particular enantiomer, racemic mixture, etc.) at that carbon atom are included. The use of a solid line or dashed wedge shape to represent a bond to an asymmetric carbon atom means that only the indicated stereoisomers are included. Compounds of formulas I - I * may contain two or more asymmetric carbon atoms. In those compounds, the use of a solid line to represent a bond to an asymmetric carbon atom means that all possible stereoisomers are included. For example, unless otherwise stated, compounds of formulas I - I * are intended to exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to represent a bond to one or more asymmetric carbon atoms in a compound of formula I or I * and the use of a solid line or dashed wedge shape to represent a bond to other asymmetric carbon atoms in the same compound means that a mixture of diastereomers is present.

[0130]

[0115] Compounds of formulas I - I *The stereoisomers of the compounds 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 compounds that exhibit two or more types of isomerism; and mixtures thereof (such as racemates and diastereomer pairs). Also included are acid addition salts or base addition salts in which the counterion is optically active, for example d-lactate or l-lysine, or racemates, for example dl-tartrate or dl-arginine.

[0131]

[0116] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (true racemate), in which case a single homogeneous form of crystal containing both enantiomers in equimolar amounts is produced. The second type is a racemic mixture or conglomerate, in which case two forms of crystals each containing a single enantiomer are produced in equimolar amounts.

[0132]

[0117] The compounds of formula I - I * may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of formula I - I * may exist in several tautomeric forms including enol and imine forms, as well as keto and enamine forms, and their geometric isomers and mixtures. All such tautomeric forms are included within the scope of the compounds of formula I. Tautomers exist as a mixture of a tautomeric set in solution. In the solid state, usually one tautomer is dominant. Even when one tautomer is described, the present disclosure includes all tautomers of the compounds of formula I.

[0133]

[0118] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of formula I - I * in which one or more atoms are replaced by atoms having the same atomic number but a different atomic weight or mass number than the atomic weight or mass number that is dominant in nature.

[0134] Examples of isotopes suitable for inclusion in the compounds according to the present disclosure include hydrogen isotopes, such as, 2 H and 3 H, etc., carbon isotopes, such as, 11 C, 13 C and 14 C, etc., chlorine isotopes, such as, 36 Cl, etc., fluorine isotopes, such as, 18 F, etc., iodine isotopes, such as, 123 I and 125 I, etc., nitrogen isotopes, such as, 13 N and 15 N, etc., oxygen isotopes, such as, 15 O, 17 O and 18 O, etc., phosphorus isotopes, such as, 32 P, etc., and sulfur isotopes, such as, 35 S, etc., but are not limited thereto.

[0135]

[0120] Certain isotope-labeled compounds of Formula I, such as those incorporating radioactive isotopes, etc., are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in terms of the ease of their incorporation and rapid detection means.

[0136]

[0121] Substitution with heavier isotopes, such as but not limited to deuterium, i.e., 2 H, etc., can provide certain therapeutic advantages resulting from greater metabolic stability, such as an increase in the half-life in vivo or a decrease in the required dose.

[0137]

[0122] Substitution with positron-emitting isotopes, such as, 11 C, 18 F, 15 O and 13 N, etc., is useful in positron emission tomography (PET) experiments for testing substrate receptor occupancy. 123 I, 124 I,125 I or 99m Substitution with isotopes such as Tc is useful in single photon emission computed tomography (SPECT).

[0138]

[0123] Formulas I - I * The isotope-labeled compounds of can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotope-labeled reagents in place of the unlabeled reagents previously utilized, or by similar processes described in the accompanying examples and preparations.

[0139]

[0124] Furthermore, certain compounds of Formulas I - I * can themselves act as prodrugs of other compounds of Formula I.

[0125] Metabolites of the compounds of Formula I, i.e., compounds formed in vivo by administration of the compounds of Formula I, are also included within the scope of the present disclosure.

[0140]

[0126] The compounds of Formulas I and IA - IH can be prepared according to the following reaction schemes and attendant considerations. Unless otherwise indicated, R 1 ~R 13 , W, X, Y, Z, Het, and n, and structural formulas I - I * are as defined above in the following reaction schemes and considerations. Generally, the compounds of the present disclosure can be manufactured by processes including processes similar to those known in the chemical arts in view of the descriptions contained herein. Certain processes for manufacturing the compounds of the present disclosure are provided as further features of the present disclosure and are shown by the following reaction schemes. Other processes can be described in the experimental section.

[0141]

[0127] In the preparation of the compounds of Formulas I - I * some of the preparative methods useful in the preparation of the compounds described herein are remote functional groups (e.g., Formulas I - I *Note that the protection of primary amines, secondary amines, and carboxyls in the precursor may sometimes be required. The need for such protection varies depending on the nature of the remote functional groups and the conditions of the preparation method. The need for such protection can be easily determined by those skilled in the art. The use of such protection / deprotection methods is also within the scope of the techniques in the art. See Greene (1991) Protective Groups in Organic Synthesis (John Wiley & Sons, New York), the entire content of which is hereby incorporated by reference in its entirety into this specification.

[0142]

[0128] For example, a particular compound contains a primary amine or carboxylic acid functional group that, if left unprotected, may interfere with reactions at other sites in the molecule. Thus, such functional groups can be protected by suitable protecting groups that can be removed in subsequent steps. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (by way of example and not limitation, for amines, N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl, and for carboxylic acids, lower alkyl or benzyl esters, etc.), which generally do not chemically react under the described reaction conditions and can be removed without chemically altering other functional groups in the compound. * Other functional groups in the compound can be removed without chemically changing them.

[0143]

Chemical formula

[0144]

[0129] Scheme 1 refers to the preparation of the compound of formula I from a bromoheteroaryl acid or ester of formula IV or a chloroheteroaryl acid or ester (although bromo is shown, it may be replaced by chloro). Referring to Scheme 1, the compound of formula IV is commercially available or can be prepared by methods well known to those skilled in the art. Without limitation, to a stirred solution of an activated carboxylate where P is, for example but not limited to, an ethyl ester, in a polar solvent such as DMSO, copper(I) iodide (0.2 equiv), L-proline (0.4 equiv), potassium carbonate (2 equiv) and W-H, imidazole, pyrazole, triazole or thiazole (1.5 equiv) are added. The reaction mixture may be heated at between about 80 °C to about 110 °C, or at about 100 °C, for about 4 hours to about 24 hours, or about 16 hours. The reaction mixture is then cooled to room temperature, diluted with ice-cold water, extracted with a solvent such as, without limitation, ethyl acetate, dried and evaporated under reduced pressure to afford the compound of formula III.

[0145]

[0130] The compound of formula III can be saponified to afford the compound of formula II by treatment with an excess of lithium hydroxide monohydrate in a solvent mixture such as, without limitation, THF, methanol and water. The reaction mixture can be stirred at room temperature for about 8 hours to about 24 hours, or about 16 hours. The aqueous layer is acidified using 1N HCl to adjust the pH to about 2 and subsequently evaporated to dryness under reduced pressure to afford the compound of formula II.

[0146] The compound of formula II can be converted to the title compound of formula I by dissolving it in DMF, followed by adding an excess of N,N-diisopropylethylamine, i.e., Hunig's base or DIPEA, and an excess of HATU, i.e., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, and then adding the desired amino-Het. The reaction mixture may be stirred at room temperature for about 8 hours to about 24 hours, or about 16 hours. The reaction can be quenched by adding water and then extracted with an organic solvent such as, but not limited to, ethyl acetate to obtain the title compound of formula I.

[0147]

[0132] Alternatively, the compound of formula I can be prepared from the compound of formula V by a so-called Stille reaction with tributylstannyl-W where W is imidazolyl, pyrazolyl, triazolyl or thiazolyl. A solution of the bromo or chloro intermediate of formula V is dissolved in a polar solvent such as, but not limited to, DMF, and then tetrakis(triphenylphosphine)palladium(0) (catalyst) is added. The reaction mixture is purged with nitrogen gas for 5 minutes and then sealed and can be heated to about 80 °C to about 110 °C or about 100 °C for about 4 to about 24 hours or about 16 hours. After the reaction is complete, the mixture is cooled to room temperature, quenched with water, and then extracted with a solvent such as, but not limited to, ethyl acetate, and the compound of formula I can be obtained after drying and evaporation.

[0148]

[0133] The compound of formula V can be prepared from the compound of formula IV by a reaction of Het-NH2 in a solvent such as, but not limited to, toluene with a solution of trimethylaluminum in toluene. The reaction mixture can be stirred at about 100 °C for about 1 hour using a CEM (registered trademark) microwave. Next, the completed reaction mixture is cooled to room temperature, quenched with water, and then extracted with ethyl acetate to obtain the compound of formula V.

[0149]

[0134] Formula I to I having a chiral center *The compounds may exist as stereoisomers such as racemates, enantiomers, or diastereomers. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, a racemate (or racemate precursor) can be reacted with a suitable optically active compound, such as an alcohol, or if the compound contains acidic or basic groups, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. Compounds of Formulas I - I * The chiral compounds (and their chiral precursors) of formula I can be obtained in enantiomerically enriched form by chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 - 50% isopropanol, typically 2% - 20%, and 0 - 5% alkylamine, or 0.1% diethylamine. Concentrating the eluate gives a concentrated mixture. The stereoisomeric conglomerate can be a moiety, acid or base such as, but not limited to, tartaric acid or 1 - phenylethylamine. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization and by conventional techniques known to those skilled in the art (see, for example, Elie (1994) Stereochemistry of Organic Compounds (Wiley, New York), the entire disclosure of which (and specifically the sections relating to the separation of stereoisomeric conglomerates) is incorporated herein by reference).

[0150]

[0135] When the compound of formula I or I * contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. The salts of the present disclosure can be prepared according to methods known to those skilled in the art.

[0151]

[0136] Compounds of formula I or I which are essentially basic * can form a wide variety of salts with various inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but it is useful to first isolate the compounds of the present disclosure from the reaction mixture as pharmaceutically unacceptable salts, and then simply convert this pharmaceutically unacceptable salt to the free base compound by treatment with an alkaline reagent, and thereafter convert the free base of this pharmaceutically unacceptable salt to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present disclosure can be prepared by treating the basic compound with a substantially equivalent amount of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, but not limited to, methanol or ethanol. Evaporation of the solvent gives the desired solid salt. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate inorganic or organic acid to the solution.

[0152]

[0137] Compounds of formula I - I which are essentially acidic *The compounds can form base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. All of these salts are prepared by prior art. The chemical bases used as reagents for preparing the pharmaceutically acceptable base salts of the present disclosure are those that form non-toxic base salts with the acidic compounds of Formula I. These salts can be prepared by treating 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 an alkaline earth metal hydroxide, by any suitable method. These salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness, for example, under reduced pressure. Alternatively, it can also be prepared by mixing a lower alkanolic solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric amounts of the reagents can be used to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0153] When the compound of formula

[0138] is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or 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, pyranosidic acid, such as, but not limited to, glucuronic acid or galacturonic acid, α-hydroxy acid, such as, but not limited to, citric acid or tartaric acid, amino acid, such as, but not limited to, aspartic acid or glutamic acid, aromatic acid, such as, but not limited to, benzoic acid or cinnamic acid, sulfonic acid, such as, but not limited to, p-toluenesulfonic acid or ethanesulfonic acid, etc.

[0154]

[0139] The pharmaceutically acceptable salts of the compounds of formula I - I * can be prepared, for example, (i) by reacting the compound of formula I or I * with the desired acid or base; (ii) by using the desired acid or base to remove an acid- or base-labile protecting group from a suitable precursor of the compound of formula I or I * or to open a suitable cyclic precursor, such as a lactone or lactam; or (iii) by reaction with a suitable acid or base or by using a suitable ion exchange column to convert one salt of the compound of formula I or I * to another salt. These salts can be prepared by

[0155]

[0140] These reactions are typically carried out in solution. The resulting salt can be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to hardly ionized.

[0156]

[0141] Certain compounds of Formula 1 according to the present disclosure can exist in two or more crystalline forms (“polymorphs”). Polymorphs can be prepared by crystallization under various conditions, for example, different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various cooling modes ranging from very rapid cooling to very slow cooling during crystallization.

[0157]

[0142] Polymorphs can also be obtained by heating or melting a compound according to the present disclosure and subsequently cooling it either gradually or rapidly. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or other such techniques. Polymorphs can be prepared according to techniques well known to those skilled in the art.

[0158]

[0143] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0144] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of a racemate (or a racemate of a salt or derivative), for example, using chiral high-performance liquid chromatography (HPLC).

[0159]

[0145] Alternatively, a racemate (or a racemate precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of Formula I or I * contains an acidic or basic moiety, with a base or an acid such as, but not limited to, 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers is separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art.

[0160]

[0146] The chiral compounds (and their chiral precursors) according to the present disclosure can be obtained in enantiomerically enriched form by chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of 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 a hydrocarbon containing about 0.1% diethylamine, typically heptane or hexane. When the eluate is concentrated, a concentrated mixture is obtained.

[0161]

[0147] When either racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which case a single homogeneous form of crystal containing both enantiomers in equimolar amounts is produced. The second type is a racemic mixture or conglomerate, in which case two forms of crystals each containing a single enantiomer are produced in equimolar amounts.

[0162]

[0148] Both crystal forms present in the racemic mixture have the same physical properties, but may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art (see, for example, Elie et al., (1994) Stereochemistry of Organic Compounds (Wiley)), the entire content of which is hereby incorporated by reference in its entirety as described above (specifically, the section regarding the separation of racemic mixtures). Compounds of formulae I - I * are not limited to the specific enantiomers shown and it will be understood that all stereoisomers and mixtures thereof are also included.

[0163]

[0149] The present disclosure also includes isotopically labeled compounds of formula I in which one or more atoms are replaced by atoms having the same atomic number but an atomic weight or mass number different from the atomic weight or mass number ordinarily found in nature. Formulae I - I *The isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or, alternatively, by analogous processes described herein using appropriate isotopically labeled reagents in place of the unlabeled reagents utilized.

[0164]

[0150] Compounds of formulae I - I * The compounds of formulae I - I are evaluated for their biopharmaceutical properties, such as, but not limited to, solubility and solution stability (across pH), permeability, etc., in order to select an appropriate dosage form and route of administration for the proposed indication.

[0165]

[0151] Compounds of formulae I - I * The compounds of formulae I - I are useful for modulating or inhibiting the NAD+ hydrolase activity of the CD38 protein. Accordingly, these compounds are useful for the prevention and / or treatment of conditions associated with NAD+ depletion and dysregulation of NAD+ - related metabolites, such as, but not limited to, aging, obesity, diabetes, cancer, heart disease, asthma, and inflammation.

[0166]

[0152] The present disclosure also relates to pharmaceutical compositions comprising a compound of formula I or I * or a pharmaceutically acceptable salt, ester, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0167]

[0153] The compounds of formula 1 according to the present disclosure intended for pharmaceutical use can be incorporated into pharmaceutical formulations. They may be incorporated into these formulations in the form of crystalline or amorphous products. The compounds can exist, for example, as solid plugs, powders, or films obtained by methods such as, but not limited to, precipitation, crystallization, lyophilization, spray drying, or evaporation to dryness. For this purpose, microwave or radio frequency drying can be used.

[0168]

[0154] These compounds can be administered alone, in combination with one or more other compounds according to the present disclosure, and / or in coformulation, and / or in combination with one or more other drugs (or as any combination or coformulation thereof), and / or in coformulation. Generally, they are administered as a combination, formulation, or coformulation with one or more pharmaceutically acceptable excipients. For example, but not limited to, the compounds disclosed herein can be coformulated with one or more supplements and / or inhibitors such as NAD supplements and JAK inhibitors.

[0169]

[0155] The term "excipient" is used herein to describe any component other than the compounds according to the present disclosure. The choice of excipient depends largely 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.

[0170]

[0156] For example, in such pharmaceutical formulations, the compounds according to the present disclosure can be combined with soluble polymeric substances, such as, but not limited to, cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the aforementioned modes of administration.

[0171]

[0157] For example, drug-cyclodextrin complexes can be useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an adjuvant, i.e., as a carrier, diluent, or solubilizing agent. For example, α-, β-, and γ-cyclodextrins are commonly used for these purposes, and examples thereof can be found in International Patent Application Nos. WO91 / 11172, WO94 / 02518, and WO98 / 55148 (specifically, from line 25 of page 3 to line 8 of page 6, inclusive). The entire contents of WO91 / 11172, WO94 / 02518, and WO98 / 55148 (specifically, the cyclodextrins from line 25 of page 3 to line 8 of page 6, inclusive) are hereby incorporated by reference in their entirety into this specification.

[0172]

[0158] Pharmaceutical compositions suitable for the delivery of the 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 can be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), the entire contents of which (particularly the sections related to pharmaceutical compositions and methods for their preparation) are hereby incorporated by reference in their entirety into this specification.

[0173]

[0159] The pharmaceutical formulations according to the present disclosure can be administered orally. Oral administration can include swallowing the formulation such that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration where the compound enters the bloodstream directly from the mouth.

[0174]

[0160] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, by way of example and not limitation, tablets; soft or hard capsules containing multi-particles or nanoparticles, liquids, or powders; troches (including those containing liquids); chewing gums; gels; rapid-dissolution dosage forms; films; ovules; sprays; and buccal / mucoadhesive patches.

[0175]

[0161] Examples of liquid preparations include suspensions, solutions, syrups, and elixirs. Such preparations can be used as fillers for soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying and / or suspending agents. Liquid preparations can also be prepared, for example, by reconstitution of a solid from a sachet.

[0176]

[0162] The compounds according to the present disclosure can 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 content of which (and specifically the portions related to fast-dissolving, fast-disintegrating dosage forms) is hereby incorporated by reference in its entirety into this specification.

[0177]

[0163] In the case of tablet dosage forms, depending on the dosage, the compound of formula I or I * can constitute from about 1% to about 80% by weight of the dosage form, or from about 5% to about 60% by weight of the dosage form. In addition to the compound of formula I, tablets generally contain a disintegrant. Non-limiting examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant constitutes from about 1% to about 25% by weight of the dosage form, or from about 5% to about 20% by weight of the dosage form.

[0178]

[0164] Binders are generally used to impart adhesiveness to tablet formulations. Suitable binders include, but are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate, but are not limited thereto.

[0179]

[0165] Tablets may also optionally contain surfactants such as, but not limited to, sodium lauryl sulfate and polysorbate 80, and glidants such as, but not limited to, silicon dioxide and talc. When present, the surfactant can constitute from about 0.2 wt% to about 5 wt% of the tablet, and the glidant can constitute from about 0.2 wt% to about 1 wt% of the tablet.

[0180]

[0166] Tablets also generally contain lubricants such as, but not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally constitute from about 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 3 wt% of the tablet.

[0181]

[0167] Other useful ingredients include, but are not limited to, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, flavorings and flavor enhancers, saliva stimulants, cooling agents, co-solvents (including oils), skin softeners, bulking agents, antifoaming agents, and surfactants.

[0182] Exemplary tablets contain up to about 80% of the compound of formula I, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant.

[0183]

[0169] The tablet blend may be compressed directly or by roller to form tablets. The tablet blend or a portion of the blend may alternatively be wet granulated, dry granulated, or melt granulated, melt solidified, or extruded prior to tableting. The final formulation may include one or more layers, may or may not be coated, and may be encapsulated.

[0184]

[0170] Tablet formulation is discussed in Lieberman et al., (1980) Pharmaceutical Dosage Forms: Tablets, Volume 1, (Marcel Dekker, New York,), the entire content of which (and specifically the sections related to tablet formulation) is hereby incorporated by reference in its entirety into this specification.

[0185]

[0171] Consumable oral films for human or animal use are typically flexible water-soluble or water-swellable thin film dosage forms that can dissolve rapidly or be mucoadhesive, and typically contain a compound of formula I, a film-forming polymer, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation may perform more than one function.

[0186]

[0172] The compound of formula I or I * may be water-soluble or water-insoluble. Water-soluble compounds constitute about 1 wt% to about 80 wt%, or about 20 wt% to about 50 wt% of the solute. Compounds with low solubility may constitute a greater proportion of the composition, typically up to about 88 wt% of the solute. Alternatively, the compound of formula I or I * may be in the form of multiparticulate beads.

[0187]

[0173] The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrophilic colloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of about 30% to about 80% by weight.

[0188]

[0174] The films according to the present disclosure can be prepared by evaporation drying of a thin aqueous film coated on a peelable backing support or paper. This can be carried out in a drying oven or tunnel, for example, in combination with a coater dryer, or by freeze-drying or evacuation.

[0189]

[0175] Solid formulations for oral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0190]

[0176] Suitable modified release formulations for the purposes of the present disclosure are described in U.S. 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, where the reference to "dalifenesin" should be read as referring to the compounds of formula I of the present disclosure) are hereby incorporated by reference in their entirety. Details of other suitable release technologies such as high energy dispersions, osmotic particles, and coated particles can be found in Verma et al. (2001) Pharm. Technol. On-line, 25(2):1-14, the entire contents of which (and in particular, the sections on suitable release technologies including high energy dispersions and osmotic and coated particles) are hereby incorporated by reference in their entirety. The use of chewing gum to achieve controlled release is described in International Patent Publication WO00 / 35298, the entire contents of which are hereby incorporated by reference in their entirety.

[0191]

[0177] Formula I or I according to the present disclosure *Pharmaceutical preparations containing the compound of the present invention can also be administered directly into bloodstream, muscle, or internal organs.Exemplary suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.Devices suitable for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0192]

[0178] Parenteral formulations are typically aqueous solutions which may contain excipients such as, but not limited to, salts, carbohydrates and buffering agents (preferably pH 3-9), although for some applications, parenteral formulations may be formulated as sterile nonaqueous solutions or as a dry form for use with a suitable vehicle such as, but not limited to, sterile pyrogen-free water.

[0193]

[0179] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0180] Formula I-I used in the preparation of parenteral pharmaceutical formulations * The solubility of the compounds can be increased by the use of appropriate formulation techniques, such as, but not limited to, the incorporation of solubility enhancers. 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, the compounds according to the present disclosure can be formulated as suspensions or as solid, semi-solid or thixotropic solutions for administration as implanted depots that provide modified release of the active compound. Non-limiting examples of such formulations include drug-coated stents, and semi-solids and suspensions containing drug-loaded poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

[0194]

[0181] The pharmaceutical formulations according to the present disclosure can also be administered topically to the skin or mucosa, (intradermally) to the skin, or transdermally. Typical formulations for this purpose include, but are not limited to, gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include, but are not limited to, alcohols, 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 content of which (and in particular the sections regarding penetration enhancers) is hereby incorporated by reference in its entirety.

[0195]

[0182] Other non-limiting means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis and delivery by micro needles or needleless (e.g., Powderject™, Bioject™, etc.) injection.

[0196]

[0183] Formulations for topical administration may be formulated for immediate and / or modified release. Exemplary modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

[0197]

[0184] The formula I~I according to the present disclosure *A pharmaceutical preparation containing the compound can be administered nasally or by inhalation, for example, in the form of dry powder from a dry powder inhaler (alone, as a mixture, for example, as a dry blend with lactose, or as mixed component particles mixed with a phospholipid such as phosphatidylcholine, although not limited thereto), or, although not limited thereto, using a suitable propellant such as 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane, or without using a propellant, as an aerosol spray agent from a pressurized container, pump, spray, atomizer (or preferably an atomizer that generates fine mist using electrohydrodynamics) or nebulizer, or as a nasal drop. In the case of nasal use, the powder may contain a bioadhesive, although not limited thereto, for example, chitosan or cyclodextrin as an example.

[0198]

[0185] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound according to the present disclosure, for example, ethanol, an aqueous ethanol solution, or a suitable alternative agent, solvent, propellant for dispersion, solubilization, or sustained release of the active substance, and an optional surfactant, for example, although not limited thereto, sorbitan trioleate, oleic acid, or oligolactic acid.

[0199]

[0186] Before use in dry powder or suspension formulations, the pharmaceutical preparation is micronized to a size suitable for delivery by inhalation (for example, less than about 5 microns). This can be achieved by any suitable grinding method such as, but not limited to, spiral jet milling, fluidized bed jet milling, supercritical fluid treatment for forming nanoparticles, high - pressure homogenization, or spray drying.

[0200] Capsules (e.g., made of gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for use with an inhaler or insufflator can be formulated to contain a powder mixture of a compound according to the present 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. Lactose can be anhydrous or in the form of the monohydrate. Other exemplary excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0201]

[0188] Exemplary pharmaceutical formulations for use with an atomizer that uses electrohydrodynamics to generate a fine mist can contain from about 1 μg to about 20 mg of a compound according to the present disclosure per actuation, and the actuation volume can vary from about 1 μl to about 100 μl. Exemplary formulations include a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative exemplary solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0202]

[0189] Suitable flavorants such as, but not limited to, menthol and levomenthol, or sweeteners such as, but not limited to, saccharin or sodium saccharin can be added to formulations according to the present disclosure intended for inhalation / intranasal administration.

[0203]

[0190] Formulations for inhalation / intranasal administration can be formulated to provide immediate and / or modified release, for example, using PGLA. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0204]

[0191] In the case of dry powder inhalers and aerosols, the dosage unit can be determined by a valve that delivers a metered amount. The units according to the present disclosure are provided, for example, as metered doses or "puffs" containing from about 0.01 μg to about 100 mg of a compound of formula I. The total daily dosage ranges from about 1 μg to about 200 mg and can be administered as a single dose or divided over the course of a day, and in some cases, over several days.

[0205]

[0192] The pharmaceutical formulations according to the present disclosure can be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a conventional suppository base, but various alternatives can be used as appropriate. The formulations for rectal / vaginal administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0206]

[0193] The pharmaceutical formulations according to the present 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 ophthalmic and otic 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. Polymers, such as, but not limited to, cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, can be incorporated together with preservatives such as, but not limited to, benzalkonium chloride. Such formulations can also be delivered by iontophoresis. The formulations for ophthalmic / otic administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, or programmed release.

[0207]

[0194] Since the present disclosure has aspects related to the treatment of the diseases / conditions described herein by combinations of active ingredients that can be administered separately, the present disclosure also relates to combining separate pharmaceutical compositions in kit form. Such a kit comprises two separate pharmaceutical compositions: a compound of formula I or I * or a salt thereof, and the second compound as described above. The kit includes means for containing the separate compositions, such as, but not limited to, a container, a divided bottle, or a divided foil packet. The kit includes instructions for 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), when administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0208]

[0195] A non-limiting example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of a relatively hard 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 packaged. Next, the tablets or capsules are placed in the recesses, and the sheet of the relatively hard material is sealed against the plastic foil on the side of the foil opposite to the direction in which the recesses are 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 can be such that the tablets or capsules can be removed from the blister pack by applying manual pressure to the recesses, thereby forming an opening at the location of the recesses in the sheet. The tablets or capsules can then be removed through the opening.

[0209]

[0196] For example, memory aids can be provided on the kit in the form of numbers next to the tablets or capsules, whereby the numbers correspond to the days of the regimen on which the tablets or capsules so designated are to be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday", "Week 2, Monday, Tuesday", etc. Other variations of the memory aid will readily become apparent. "Daily dose" can be a single tablet or capsule to be taken on a given day, or a plurality of tablets or capsules. Also, formula I or I * The daily dose of the compound can consist of one tablet or capsule, but the daily dose of the second compound can consist of a plurality of tablets or capsules, and vice versa. The memory aid can reflect this.

[0210]

[0197] In another particular embodiment according to the present disclosure, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. To further facilitate compliance with the regimen, the dispenser can be equipped with a memory aid. Non-limiting examples of such a memory aid are mechanical counters that indicate the number of daily doses dispensed. Another non-limiting example of such a memory aid is a liquid crystal readout, or a battery-powered microchip memory combined with an audible reminder signal that reads out, for example, the date on which the last daily dose was taken and / or reminds of the date for taking the next dose.

[0211]

[0198] The present disclosure is a method for treating, delaying, or preventing a disease in a subject, such as a mammal, including but not limited to a human, the method comprising administering to a subject in need of treatment, delay, or prevention of the disease a therapeutically effective amount of a compound of formula I or I * or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0212]

[0199] Formula I or I *The compounds are also useful for modulating or inhibiting the NAD hydrolase activity of the CD38 protein. Accordingly, the present disclosure provides for the prevention, delay and / or treatment of conditions associated with NAD+ depletion and dysregulation of NAD+ metabolites, such as aging (e.g., age-related chronic diseases), cancer, cardiovascular disorders, neuropathies, pulmonary disorders, fibrotic diseases, metabolic disorders, inflammation, liver disorders, and skin diseases, and for the identification of the compounds of Formulas I-I * as cell surface markers of blood cancers such as multiple myeloma (see Chin et al. (2018) Trends Pharmacol. Sci. 39(4):424-436). The method includes administering to a subject in need of treatment, delay, or prevention of a disease, a therapeutically effective amount of a compound of Formula I or I * or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0213]

[0200] Furthermore, the present disclosure provides for the use of the compounds of Formulas I-I * for the prevention and / or treatment of cancers such as small cell lung cancer, renal clear cell carcinoma, chronic lymphocytic leukemia, and multiple myeloma.

[0214]

[0201] The role of CD38 dysfunction in cancer has been demonstrated, for example, in small cell lung cancer (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).

[0215]

[0202] This disclosure relates to the use of compounds of Formula I-I for the prevention and / or treatment of cardiovascular disorders such as hypertension, hypoxic pulmonary vasoconstriction, cardiac hypertrophy, congestive heart failure, and stroke. * This includes the use of the compounds.

[0216]

[0203] The role of CD38 inhibition in cardiovascular disorders such as hypertension has been described (see, for example, Thai et al. (2009) Am. J. Renal Physiol. 297(1):F169-76. Hypoxic pulmonary vasoconstriction is described in Wilson et al. (2001) J. Biol. Chem. 276(14): 11180-8. Cardiac hypertrophy / CHF is described in Pillai et al. (2010) J. Biolog. Chem. 285(5): 3133-3144. The role in stroke is described in Choe et al. PLoS One (2011), 6(5):e19046.

[0217]

[0204] This disclosure also relates to the use of compounds of Formula I-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, and epilepsy. Accordingly, the agents described herein can be used as neuroprotective agents. The compounds of Formula I-I * can also be administered to tissues or organs that are likely to encounter cell death. *

[0218]

[0205] Neurological disorders have also been demonstrated to be mediated by CD38 dysfunction in Alzheimer's disease, etc., as described by Gong Bing, et al. (2013) Neurobiol. Aging 34(6):1581-1588. Neurocognitive impairment and CD38 are described, for example, by Banerjee et al. (2008) J. Neuroim. Pharmacol. 3(3):154-164. CD38 dysfunction in bipolar disorder / schizophrenia is described, for example, by Christoforou (2007) Mol. Psych.12(11);1011-1025. The role in Huntington's disease is described by Weydt (2009) Mol. Neurodeg.4:3. Dysfunction in amyotrophic lateral sclerosis is described by Lawton et al. (2012) Amyotrophic Lateral Sclerosis 13(1):110-118, and in Parkinson's disease (see, for example, Aoyama et al. (2001)Neurosci.Lett.298(1):78-80). Multiple sclerosis is described by Penberthy et al. (2009) Curr. Pharm. Design15(1):64-99. Optic nerve disorders are described by Kitaoka et al., (2009) J. Neuropathol. Exp. Neurol. 68(8):915-927. Epilepsy is described as a CD38 disorder, for example, by Kinton Lucy et al. (2002) Ann. Neurol. 51(6);740-749.

[0219]

[0206] The present disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of lung disorders such as idiopathic pulmonary fibrosis, cystic fibrosis, COVID-19, SARS, asthma, and chronic obstructive pulmonary disease (COPD). The present disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of fibrotic diseases such as idiopathic pulmonary fibrosis and cystic fibrosis. * * of the compounds.

[0220] ​

[0207] Lung disorders have CD38 dysfunction, as described for idiopathic pulmonary fibrosis by O’Neill et al. (1994) Expt. Lung Res. 20(1):41-56. Their role in cystic fibrosis is described by Wetmore et al. (2010) J. Biolog. Chem. 285(40):30516-30522. Asthma is described by Kang et al. (2006) Curr. Res. Med. Rev. 2(2):143-156. COPD is described by Hageman et al. (2003) Free Radical Biol. Med. 35(2):140-148.

[0221]

[0208] The present disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of metabolic disorders such as metabolic syndrome, obesity, sarcopenic obesity, dyslipidemia, diabetes (such as type I diabetes), diabetic neuropathy, insulin resistance, infection-induced and virus-induced pulmonary fibrosis, and pancreatitis. *

[0222]

[0209] The use of compounds of Formulas I-I for the prevention and / or treatment of obesity can include a subject that has obesity or is at high risk of developing it (e.g., a mammal at high risk of developing diet-induced obesity). A mammal can be identified as having obesity or being at risk of developing obesity using standard clinical techniques. For example, analysis of a human's family history or eating habits can be used to determine whether a human is likely to develop an obese condition. As described in the specification, a mammal identified as having or being prone to develop an obese condition can be treated by administering a compound of Formula I. *

[0223]

[0210] The dysfunction of CD38 in metabolic disorders is described in Metabolic Syndrome, Escande Carlos et al. (2013) Diabetes 62(4):1084 - 1093. Obesity / sarcopenia is described in Maria et al. (2007) FASEB J. 21(13):3629 - 3639. Dyslipidemia is described in Surakka Ida et al. (2011) PLoS Gen. 7(10):e1002333. The dysfunction in diabetes is described in Arya et al. (2004) Am. J. Hum. Gen. 74(2):272 - 282, and the dysfunction in diabetic neuropathy is described in Geeta et al. (2010) Neuropharmacol. 58(3):585 - 592. CD38 in insulin resistance is described in Yoshino et al. (2011) Cell Metab.14(4):528 - 536. CD38 in type I diabetes is described in Elliott. et al. (1993) Annals NY Acad. Sci. 696: 333 - 341. Pancreatitis is described in Chan et al. (2011) Antiox. Redox Sig. 15(10):2743 - 2755.

[0224]

[0211] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The dysfunction of CD38 in acute lung injury / ARDS is described, for example, in Su et al. (2007) Eur. Res. J. 30(2):199 - 204. * The dysfunction of CD38 in acute lung injury / ARDS is described, for example, in Su et al. (2007) Eur. Res. J. 30(2):199 - 204.

[0225]

[0212] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of hyperphosphatemia. See Takahashi et al. (2004) Kidney Int. 65(3):1099 - 1104 for hyperphosphatemia. * See Takahashi et al. (2004) Kidney Int. 65(3):1099 - 1104 for hyperphosphatemia.

[0226]

[0213] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of alcohol intolerance. *including the use of the compound. For alcohol intolerance, see, for example, Larson et al. (2005) J. Biol. Chem. 280(34):30550-30556.

[0227]

[0214] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of lupus. For lupus, see, for example, Gonzalez-Escribano et al. (2004) Hum. Immunol (2004) 65(6):660-4; Pavon et al. (2013) Cytokine 62(2):232-243. * including the use of the compound. For lupus, see, for example, Gonzalez-Escribano et al. (2004) Hum. Immunol (2004) 65(6):660-4; Pavon et al. (2013) Cytokine 62(2):232-243.

[0228]

[0215] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of arthritis such as rheumatoid arthritis. The role of CD38 in rheumatoid arthritis is described in Jorge Postigo et al. (2012) PLoS One 7(3):e33534. * including the use of the compound. The role of CD38 in rheumatoid arthritis is described in Jorge Postigo et al. (2012) PLoS One 7(3):e33534.

[0229]

[0216] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of ataxia telangiectasia. The role of CD38 in ataxia telangiectasia is described in Stern et al. (2012) J. Biol. Chem. 277(1):602-608. * including the use of the compound. The role of CD38 in ataxia telangiectasia is described in Stern et al. (2012) J. Biol. Chem. 277(1):602-608.

[0230]

[0217] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of irritable bowel syndrome and colitis. CD38 dysfunction is involved in irritable bowel syndrome and colitis, for example, Durnin et al. (2012) J. Physiol. (Oxford, UK) 590(8):1921-1941. * including the use of the compound. CD38 dysfunction is involved in irritable bowel syndrome and colitis, for example, Durnin et al. (2012) J. Physiol. (Oxford, UK) 590(8):1921-1941.

[0231]

[0218] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of gout. *It includes the use of the compound. See Nik Cummings et al., European Journal of Human Genetics (2010), 18(11), pages 1243-1247.

[0232]

[0219] This disclosure includes the use of the compound of formula I for the prevention and / or treatment of end-stage renal disease. The role of CD38 in end-stage renal disease is described in Freedman et al. (2005) Nephrol. Dialysis, Transpl. 20(4):712-718.

[0233]

[0220] This disclosure includes the use of the compound of formula I-I * for the prevention and / or treatment of hearing loss. Hearing loss is described in Someya et al. (2010) Cell 43(5):802-812.

[0234]

[0221] This disclosure includes the use of the compound of formula I-I * for the prevention and / or treatment of liver disorders such as fatty liver and non-alcoholic steatohepatitis (NASH). Liver disorders such as fatty liver and NASH are mediated by CD38, for example, Choi et al. (2013) Aging Cell 2(6):1062-1072.

[0235]

[0222] This disclosure includes the use of the compound of formula I-I * for the prevention and / or treatment of postmenopausal osteoporosis. The progression of postmenopausal osteoporosis disease is described in Drummond et al. (2006) J. Bone Mineral Met. 24(1):28-35.

[0236]

[0223] This disclosure includes the use of the compound of formula I-I * for the prevention and / or treatment of reproductive disorders or diseases. Regarding the recovery of oocyte quality and the improvement of ovulation rate and reproductive ability, it is described in Bertoldo et al., (2020) Cell Rep 30(6): 1670-1681.

[0237]

[0224] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of Hartnup disease. For Hartnup disease and CD38, see Jepson et al., (1960) Met. Basis Inherited Dis. pp. 1338 - 64. Hansen's disease is described in Dhople et al. (1985) Microbio. Letts. 28(109):17 - 20. * For Hartnup disease and CD38, see Jepson et al., (1960) Met. Basis Inherited Dis. pp. 1338 - 64. Hansen's disease is described in Dhople et al. (1985) Microbio. Letts. 28(109):17 - 20.

[0238]

[0225] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of tuberculosis. The role of CD38 in tuberculosis is described in Vilcheze et al. (2010) Mol. Microbiol. 76(2):365 - 377. * The role of CD38 in tuberculosis is described in Vilcheze et al. (2010) Mol. Microbiol. 76(2):365 - 377.

[0239]

[0226] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of leishmaniasis. The role of CD38 in leishmaniasis is described in Michels et al. (2011) Mol. Microbiol. 82(1):4 - 8. * The role of CD38 in leishmaniasis is described in Michels et al. (2011) Mol. Microbiol. 82(1):4 - 8.

[0240]

[0227] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of muscular dystrophy. For muscular dystrophy and CD38, see Goody et al. (2012) PLoS Biology 10(10):e1001409. * For muscular dystrophy and CD38, see Goody et al. (2012) PLoS Biology 10(10):e1001409.

[0241]

[0228] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of organ reperfusion injury. Organ reperfusion injury mediated by CD38 is described in Yan Ge et al. (2010) Biochem. Biophys. Res. Comm. 399(2):167 - 172. * Organ reperfusion injury mediated by CD38 is described in Yan Ge et al. (2010) Biochem. Biophys. Res. Comm. 399(2):167 - 172.

[0242]

[0229] This disclosure includes the use of compounds of formula I - I for the prevention and / or treatment of pellagra. *including the use of the compound. Pellagra is also a CD38-mediated disease, for example, Williams et al. (2007) Med. Hypoth. 69(3): 618-628.

[0243]

[0230] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of skin diseases such as hyperpigmentation, UV skin damage, and psoriasis. * including the use of the compound.

[0231] Skin diseases are associated with the dysfunction of NAD and CD38. For example, hyperpigmentation 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). Similarly, NAD dysfunction is involved in psoriasis (see Wozniacka et al. (2007) Skin Pharmacol. Physiol. 20(1): 37-42).

[0244]

[0232] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of damage caused by radiation exposure such as X-ray-induced DNA damage by promoting NAD+-regulated DNA repair and / or cell survival. This disclosure includes a method of promoting DNA repair in cells. Cells that may be exposed to conditions that can cause DNA damage, such as cells exposed to radiation, can be protected by contacting them with a compound of Formula I or I * before, during, and / or after exposure to a DNA damaging agent. *

[0245]

[0233] Protection from radiation exposure is described, for example, in Caibin et al. (2012) Internat. J. Physiol. Pathophysiol. Pharmacol. 4(1): 1-9.

[0246]

[0234] This disclosure includes the use of compounds of Formulas I-I for the prevention and / or treatment of periodontal disease. * ​It includes the use of the compound. The role of CD38 in periodontal disease has also been reported, for example, by Fujita et al. (2005) J. Periodontol. 76(11):1960-1965.

[0247]

[0235] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of Leber's hereditary cataract. Leber's hereditary cataract has also been reported, for example, by Koenekoop et al. (2012) Nat. Gen. 44(9):1035 - 1039. * It includes the use of the compound. Leber's hereditary cataract has also been reported, for example, by Koenekoop et al. (2012) Nat. Gen. 44(9):1035 - 1039.

[0248]

[0236] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of sleep disorders. The involvement of NAD+ in sleep disorders has also been reported (see Robinson et al. (1977) Biol. Psych. 12(1):139 - 143). * It includes the use of the compound. The involvement of NAD+ in sleep disorders has also been reported (see Robinson et al. (1977) Biol. Psych. 12(1):139 - 143).

[0249]

[0237] This disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of exercise intolerance. Exercise intolerance has also been reported (see, for example, Glick (1966) Am. J. Physiol. 210(6):1215 - 1221). * It includes the use of the compound. Exercise intolerance has also been reported (see, for example, Glick (1966) Am. J. Physiol. 210(6):1215 - 1221).

[0250]

[0238] Compounds of Formulas I - I extend the lifespan of cells and protect cells from stress. Accordingly, this disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of diseases associated with cell death, such as chronic diseases, for example, but not limited to, diseases associated with neuronal cell death or muscle cell death. In addition, this method can be used to prevent or reduce neurodegeneration and peripheral neuropathy associated with chemotherapy, such as, but not limited to, cancer chemotherapy (e.g., treatment with taxol or cisplatin). * Compounds of Formulas I - I extend the lifespan of cells and protect cells from stress. Accordingly, this disclosure includes the use of compounds of Formulas I - I for the prevention and / or treatment of diseases associated with cell death, such as chronic diseases, for example, but not limited to, diseases associated with neuronal cell death or muscle cell death. In addition, this method can be used to prevent or reduce neurodegeneration and peripheral neuropathy associated with chemotherapy, such as, but not limited to, cancer chemotherapy (e.g., treatment with taxol or cisplatin). * It includes the use of the compound. In addition, this method can be used to prevent or reduce neurodegeneration and peripheral neuropathy associated with chemotherapy, such as, but not limited to, cancer chemotherapy (e.g., treatment with taxol or cisplatin).

[0251]

[0239] The compounds of Formulas I - I described herein *The compounds can be administered to a subject to whom calorie restriction or its effects are beneficial. The subject can be a subject suffering from an aging disease such as stroke, heart disease, arthritis, hypertension. They can also be administered to treat metabolic diseases such as, but not limited to, insulin resistance or other precursor symptoms of type II diabetes, type II diabetes or their complications. Depending on the method, the insulin sensitivity of the subject may increase or the insulin level may decrease. The method can include administering to a subject in need of treatment, such as a subject, a pharmaceutically effective amount of an agent that increases the activity or protein level of proteins involved in the NAD+ salvage pathway, i.e., the synthesis of NAD+ and the breakdown of nicotinamide. A subject in need of such treatment can be a subject having insulin resistance or other precursor symptoms of type II diabetes, a subject having type II diabetes, or a subject likely to develop any of these conditions. For example, the subject can be a subject having insulin resistance, such as a subject having a high circulating level of insulin, and / or a subject having related conditions such as impaired glucose tolerance, high blood glucose levels and hypertension.

[0252]

[0240] Formulas I - I * The compounds can also be used to stimulate lipolysis, for example, to treat obesity and any condition resulting therefrom, or to reduce weight gain.

[0253]

[0241] The present disclosure provides a method for treating any of the conditions listed above in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, or prodrug thereof. The mammal can be a human in need of such treatment or prevention.

[0254] As used herein, the term "therapeutically effective amount" refers to the amount of a compound being administered that will, to some extent, alleviate one or more symptoms of the disease or condition being treated. With respect to the treatment of non-alcoholic steatohepatitis (NASH), a therapeutically effective amount refers to an amount having the effect of reducing or ameliorating the fat and scar tissue present in the liver and improving any of the biomarker measurements indicative of inflammation.

[0255] As used herein, the term "treating", unless otherwise indicated, means reversing, alleviating, inhibiting or preventing the progression of a disease or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating as defined immediately above for "treating", unless otherwise indicated. The term "treating" also includes, but is not limited to, adjuvant and neo-adjuvant treatment of a subject.

[0256]

[0244] Compounds of formulae I - I * may be affected by any method that enables delivery of the compound to the site of action. Such methods include oral, duodenal, parenteral injection (including intravenous, transdermal, subcutaneous, intramuscular, intra-vascular or infusion), intra-articular administration, intravitreal administration, topical, ocular, vaginal, rectal administration, and the like.

[0257]

[0245] The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus dose may be administered, doses may be administered in several divided portions over time, or the doses may be proportionally decreased or increased as indicated by the exigencies of the treatment situation. For ease of administration and uniformity of dosage, it is advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages for treating a mammalian subject; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect, together with a pharmaceutical carrier.

[0258]

[0246] Accordingly, one of ordinary skill in the art will understand that, based on the disclosure provided herein, the dosage and dosing regimen are adjusted according to methods well known in the art of therapy. That is, the maximum tolerated dose can be readily established, and the effective amount to provide a detectable therapeutic benefit to the patient can also be determined, as can the time requirements for administering each agent to provide a detectable therapeutic effect to the patient. Accordingly, while certain dosages and dosing regimens are exemplified herein, these examples in no way limit the dosages and dosing regimens that may be provided to a patient in the practice of this disclosure.

[0259]

[0247] The dosage value may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. For any subject, a particular dosing regimen can be adjusted over time according to individual needs and the professional judgment of the administrator of the composition or the person overseeing the administration. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, the dosage can be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or clinical laboratory values. Accordingly, the present disclosure encompasses dose titration within a patient determined by one of ordinary skill in the art. The determination of appropriate dosages and regimens for the administration of the active agent is well known in the relevant art and will be understood to be encompassed by one of ordinary skill in the art given the teachings disclosed herein.

[0260]

[0248] The amount of the compound of formula I or I * administered depends on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. Effective dosages are 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, given as a single or divided dose. For a 70 kg person, this corresponds 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 cases, dosage levels below the lower limit of the foregoing ranges may be sufficient, e.g., depending on the severity of the disorder being treated and the age and weight of the subject being treated, while in other cases, additional doses can be used without causing adverse side effects, provided that such additional doses are initially divided into several smaller doses for administration throughout the day.

[0261]

[0249] As used herein, the term "combination therapy" refers to administering a compound of formula I or I * together with at least one additional pharmaceutical or agent, either sequentially or simultaneously.

[0262]

[0250] The present disclosure includes the use of a combination of a compound of formula I or I * with one or more additional pharmaceutically active agents. When the combination of active agents is administered, they can be administered separately, or in a single dosage form, in combination, sequentially or simultaneously. Accordingly, the present disclosure also provides a first agent comprising (a) a compound of formula I or I * , or a pharmaceutically acceptable salt, ester, or prodrug of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, excipient, or diluent, in an amount of a pharmaceutical composition.

[0263]

[0251] Depending on the disease, disorder, or condition being treated, various pharmaceutically active agents can be selected for use in combination with the compounds of formula I - I * . Pharmaceutically active agents that can be used in combination with the compositions of the present disclosure include, but are not limited to, the following combination therapies.

[0264] In the treatment of non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD), combination therapies include, but are not limited to, combinations of agents such as acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, GLP-1 receptor agonists, FXR agonists, CB1 antagonists, ASK1 inhibitors, CCR2 and / or CCR5 inhibitors, PNPLA3 inhibitors, hydroxysteroid 17-β dehydrogenase (HSD17B13) inhibitors, DGAT1 inhibitors, FGF21 analogs, FGF19 analogs, SGLT2 inhibitors, PPAR agonists, AMPK activators, SCD1 inhibitors or MPO inhibitors; orlistat, TZDs and other insulin sensitizers, FGF21 analogs, metformin, omega-3 acid ethyl esters (e.g., Lovaza), fibrates, HMG CoA reductase inhibitors, ezetimibe, probucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, vitamin E, betaine, pentoxifylline, CB1 antagonists, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone and bupropion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin), phentermine, topiramate, GLP-1 receptor agonists, GIP receptor agonists, dual GLP-1 receptor / glucagon receptor agonists, dual GLP-1 receptor / GIP receptor agonists (tirzepatide), angiotensin receptor blockers, acetyl-CoA carboxylase (ACC) inhibitors, BCKDK inhibitors, ketohexokinase (KHK) inhibitors, ASK1 inhibitors, branched-chain alpha-ketoacid dehydrogenase kinase inhibitors (BCBK inhibitors), CCR2 and / or CCR5 inhibitors, PNPLA3 inhibitors, DGAT1 inhibitors, FGF21 analogs, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators, SCD1 inhibitors or MPO inhibitors.

[0265]

[0253] In the case of treating other disorders, combination therapies include, for example, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as, but not limited to, sibutramine), sympathomimetic agents, β-adrenergic agonists, dopamine agonists (such as, but not limited to, bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin-concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as, but not limited to, tetrahydrolipstatin, i.e., orlistat), anorectic agents (such as, but not limited to, bombesin agonists), neuropeptide-Y antagonists (such as, for example, NPY Y5 antagonists), PYY 3~36 (including its analogs), thyroid hormone-like agents, dehydroepiandrosterone or its analogs, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factor (such as, but not limited to, Axokine (trademark) available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company, Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP / ApoB inhibitors (such as, for example, but not limited to, intestinal-selective MTP inhibitors such as zilretapide), opioid antagonists, orexin antagonists, combinations such as naltrexone and bupropion, etc. are also included.

[0266]

[0254] The present disclosure also includes combination therapies for treating cancers such as, but not limited to, multiple myeloma. Such treatment agents include formula I or I *The combination with the compound and 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 is included.

[0267]

[0255] The combination therapy includes a neurodegenerative disorder therapeutic agent, namely, an acetylcholinesterase inhibitor such as donepezil hydrochloride, physostigmine salicylate, physostigmine sulfate, metrifonate, neostigmine, galanthamine, pyridostigmine, ambenonium, demarcarium, rivastigmine, ladostigil, galantamine hydrobromide, tacrine, tolserine, bernacrine maleate, memoquin, fupirtin A, phenserine, and edrophonium; amyloid-β or a fragment thereof, for example, but not limited to, Aβ conjugated to a pan HLA DR-binding epitope 1-15, antibodies against amyloid-β, such as, but not limited to, antibodies against amyloid-β such as bapineuzumab; agents that reduce or inhibit amyloid (including those that reduce amyloid production, accumulation, and fibrosis), such as, but not limited to, colostrinin, bisnorcymserine, pioglitazone, clioquinol, flurbiprofen, talenflurbil, nitrofurbiprofen, fenoprofen, ibuprofen, meclofenamic acid, sodium meclofenamate, indomethacin, diclofenac, sulindac, diflunisal, naproxen, ginkgo biloba extract, tramiprosate, eprodisate, and neprylisin; and dopamine receptor agonists, such as, but not limited to, apomorphine, bromocriptine, cabergoline, dihydroxyergotamine, dihydroergocryptine, phenoldopam, lisuride, pergolide, piribedil, pramipexole, quinpirole, ropinirole, rotigotine, and talipexole; levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (such as carbidopa, benserazide, α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine); monoamine oxidase (MAO) inhibitors, such as, but not limited to, selegiline, dimethylselegiline, brofaromine, phenelzine, tranylcypromine, moclobemide, befloxatone, safinamide, isocarboxazid, nialamide, rasagiline, iproniazid, iproclozide, troxatone, biferam, desoxypeganine, harmine, harmaline, linezolid, and pargyline; and combinations with muscarinic receptor (especially the M1 subtype) agonists, such as, but not limited to, bethanechol chloride, itamexiline, pilocarpine, arecoline, flutrethonium iodide, oxotremorine, subcomeline, and carbachol, etc.

[0268] [

[0256] ]Combination therapies include combinations with cardiovascular agents such as, but not limited to, beta-adrenergic receptor blockers (beta blockers), such as, but not limited to, carteolol, esmolol, labetalol, oxprenolol, pindolol, propranolol, sotalol, timolol, acebutolol, nadolol, metoprolol tartrate, metoprolol succinate, atenolol, and butoxamine; calcium channel blockers such as, but not limited to, nylidipine, diperdipine, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, lifarizidine, diltiazem, verapamil, and enecainide.

[0269] [

[0257] ]Combination therapies include combinations with anti-rheumatic arthritis agents such as, for example, symptomatic agents such as, but not limited to, NSAIDs and symptomatic agents such as acetaminophen / paracetamol, as well as disease-modifying anti-rheumatic drugs (DMARDs) for oral and parenteral administration such as, but not limited to, steroids, methotrexate, anti-IL-6, Il-1, and anti-TNFa antibodies, and both JAK inhibitors, etc.

[0270] [

[0258] ]In addition, combination therapies include combinations with catechol O-methyltransferase (COMT) inhibitors such as, but not limited to, tolcapone (TASMAR), entacapone (COMTAN), and tropolone, etc.

[0271] [

[0259] ]Combination therapies include combinations with immunomodulators such as, but not limited to, glatiramer acetate, dimethyl fumarate, fingolimod, roquinimex, lacanimod, rituximab, alemtuzumab, daclizumab, and natalizumab, etc.

[0272] In addition, combination therapies include combinations with interferons such as, but not limited to, interferon beta-1a and interferon beta-1b.

[0273]

[0261] Combination therapies also include combinations with neuroprotective agents such as, but not limited to, 2,3,4,9-tetrahydro-1H-carbazole-3-one oxime, desmoteplase, anatibant, astaxanthin, the neuropeptide NAP, neurostrol, perampenel, isopronicline, bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyl tartrate (also known as dactylorhizin B or DHB), hormobactin, xaliproden, lactacystin, dimebolin hydrochloride, disulfenton, arungenic acid, citicoline, edaravone, granulocyte colony-stimulating factor, ancrod, 17-β-hydroxyepiandrosterone, oligotrophin, pyridoxal 5'-phosphate, microplasmin, picotamide, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine, stilbazulenyl nitrone, and zonampanel.

[0274]

[0262] Combination therapies include combinations with trophic factors such as, but not limited to, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), neurotrophin-3, cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neoblastin, meteorin, and glial cell line-derived neurotrophic factor (GDNF), as well as agents that stimulate the production of trophic factors such as, but not limited to, prolyl endopeptidase and idebenone.

[0275]

[0263] The present disclosure also relates to a combination therapy for treating aging using a dietary supplement, i.e., a substance having physiological benefits or providing protection against chronic diseases, such as vitamins, e.g., prenatal vitamins, vitamin D3, or vitamin B12, Garcinia cambogia, raspberry ketone, green tea supplements, Echinacea, probiotics, omega-3 fatty acids, alpha-lipoic acid, etc., and NAD+ and NAD+ precursors, such as NMN, NR, and NA.

[0276]

[0264] As used herein, the term "another active agent" refers to any therapeutic agent other than a compound of formula I or a salt thereof that is useful in the treatment of a subject suffering from a disease or disorder. Examples of active agents include, but are not limited to, anti-rheumatoid arthritis drugs, such as NSAIDs, acetaminophen / paracetamol, disease-modifying anti-rheumatic drugs (DMARDs), steroids, methotrexate, anti-IL-6, Il-1 and anti-TNFα antibodies, JAK inhibitors, and the like.

[0277]

[0265] The present disclosure can follow the following appendices.

[0266] Appendix 1. Formula

[0278]

Chemical formula

[0279] of the compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, or Formula I *

[0280]

Chemical formula

[0281] of the compound or a pharmaceutically acceptable salt, ester, or prodrug thereof. (wherein, When the compound is of formula I, -X-Y-Z- is =CR 1 -CR 2 =CR 3 -, =N-CR 2 =CR 3 -, =CR 1 -N=CR 3 - or =CR 1 -CR 2 =N-; When the compound is of formula I * -, -X-Y-Z- is =CR 1 -CR 2 =C-, =N-CR 2 =C- or =CR 1 -N=C-; R 1 is selected from the group consisting of H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkoxy-; (C1-C6)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 2 is H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C6)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; Each R 4is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from the group consisting of (C1-C3)alkyl, perfluoro(C1-C3)alkyl, HO-(C2-C4)alkyl-, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3)alkyl, -CF3, (C1-C3)alkoxy, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3)alkyl; W is

[0282]

Chemical formula

[0283] and R 8 is H, -CH3, or -CF3; Het is the formula

[0284] [Chemical formula]

[0285] is a complex ring; Each R 9 is independently selected from H, halo, (C1-C6)alkyl, -CF3, (C1-C6)alkoxy, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O((C1-C3)alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )- and (R 11 )2N-(C=O)-; Each R 10 is independently selected from H, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, (R 11 )2N-, R 12 (O)(C=O)-, R 12 O-((C1-C3)alkyl)-(NR 11 )-, R 13 -(C=O)-(NR 11 )-, and (R 11 )2N-(C=O); Each R 11 is independently H or (C1-C3)alkyl; R 12 is H or (C1-C3)alkyl; R 13 is (C1-C3)alkyl)

[0267] Appendix 2. Het is formula i

[0286]

Chemical formula

[0287] is the ring of formula ii, the compound according to Appendix 1.

[0268] Appendix 3. Het is formula ii

[0288]

Chemical formula

[0289] The compound according to Appendix 1, which is a ring of

[0269] Appendix 4. Het is formula iii

[0290]

Chemical formula

[0291] The compound according to Appendix 1, which is a ring of

[0270] Appendix 5. Het is formula iv

[0292]

Chemical formula

[0293] The compound according to Appendix 1, which is a ring of

[0271] Appendix 6. Het is formula v

[0294]

Chemical formula

[0295] The compound according to Appendix 1, which is a ring of

[0272] Appendix 7. Het is formula vi

[0296]

Chemical formula

[0297] The compound according to Appendix 1, which is a ring of

[0273] Appendix 8. Het is formula vii

[0298]

Chemical formula

[0299] The compound according to Appendix 1, which is a ring of

[0274] Supplementary Note 9. Het is the ring of formula viii

[0300]

Chem.

[0301] The compound according to Supplementary Note 1, wherein Het is the ring of formula viii

[0275] Supplementary Note 10. Het is the ring of formula ix

[0302]

Chem.

[0303] The compound according to Supplementary Note 1, wherein Het is the ring of formula ix

[0276] Supplementary Note 11. W is the group of the compound of formula (a)

[0304]

Chem.

[0305] The compound according to any one of Supplementary Notes 1 to 10, wherein W is the group of the compound of formula (a)

[0277] Supplementary Note 12. W is the group of the compound of formula (b)

[0306]

Chem.

[0307] The compound according to any one of Supplementary Notes 1 to 10, wherein W is the group of the compound of formula (b)

[0278] Supplementary Note 13. W is the group of the compound of formula (c)

[0308]

Chem.

[0309] The compound according to any one of Supplementary Notes 1 to 10, wherein W is the group of the compound of formula (c)

[0279] Supplementary Note 14. W is the group of the compound of formula (d)

[0310] [Chemical formula]

[0311] A compound according to any one of Appendices 1 to 10, which is a group of the compound.

[0280] Appendix 15. W is formula (e)

[0312] [Chemical formula]

[0313] A compound according to any one of Appendices 1 to 10, which is a group of the compound.

[0281] Appendix 16. W is formula (f)

[0314] [Chemical formula]

[0315] A compound according to any one of Appendices 1 to 10, which is a group of the compound.

[0282] Appendix 17. R 1 is selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, (C1-C3) alkoxy, and perfluoro (C1-C3) alkoxy-, a compound according to any one of Appendices 1 to 16.

[0316]

[0283] Appendix 18. R 1 is selected from the group consisting of H, F, -CH3 and -OCH3, a compound according to any one of Appendices 1 to 17.

[0284] Appendix 19. R 1 is H, a compound according to any one of Appendices 1 to 18.

[0317]

[0285] Appendix 20. R 2 is H, (C1-C6) alkyl, (C1-C6) alkoxy-, and perfluoro (C1-C6) alkyl, perfluoro (C1-C6) alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl, R5 -(C(R 4 )2) n -O- or (R 6 )2N-, and is selected from the group consisting thereof; (C1-C6) alkyl, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, and aryl are each independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3, and -OCF3, and are optionally substituted with 1 to 3 substituents; each R 4 is independently H or (C1-C3) alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3, and -OCF3; R 5 is selected from (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, and aryl are each independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3, and -OCF3, and are optionally substituted with 1 to 3 substituents; R 6 is independently H or (C1-C3) alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3, and -OCF3, a compound according to any of Appendices 1 to 19.

[0318]

[0286] Appendix 21. R 2is H, (C1-C3)alkyl, (C1-C3)alkoxy-, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy-, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C3)alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; each R 4 is independently H, or (C1-C3)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from (C1-C3)alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, and 6- to 10-membered aryl; (C1-C3)alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, and 6- to 10-membered aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6is independently (C1-C3) alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; a compound according to any one of Appendices 1-20.

[0319]

[0287] Appendix 22.R 2 is methoxy-, cyclopropoxy- or R 5 -(C(R 4 ))2)-O-; each R 4 is H; R 5 is selected from C1-alkyl and tetrahydropyran, wherein the C1-alkyl is substituted with -OCH3; a compound according to any one of Appendices 1-21.

[0320]

[0288] Appendix 23.R 3 is H, halo, (C1-C3) alkyl, -CF3, -OCH3, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3) alkyl; a compound according to any one of Appendices 1-22.

[0321]

[0289] Appendix 24.R 3 is H, F, -CH3, -OCH3, or H2N-; a compound according to any one of Appendices 1-23.

[0290] Appendix 25.R 3 is H; a compound according to any one of Appendices 1-24.

[0322]

[0291] Appendix 26.R 9 is H, halo, (C1-C3) alkyl, -CF3, -OCH3, -OCF3, -CN, R 12 O((C1-C3) alkyl)-(NR 11 )-, -CO2R 12 and (R 11 )2N-(C=O)-; each R 11is independently selected from H and (C1-C3) alkyl; R 12 is a compound according to any one of Appendices 1 to 25, which is H or (C1-C3) alkyl.

[0323]

[0292] Appendix 27. A compound according to any one of Appendices 1 to 26, wherein at least one R 9 is selected from the group consisting of F, (C1-C3) alkyl, -CF3, -OCH3, -OCF3, -CN.

[0324]

[0293] Appendix 28. A compound according to any one of Appendices 1 to 27, wherein at least one R 9 is -CF3.

[0294] Appendix 29. A compound according to any one of Appendices 1, 4 or 11 to 28, wherein at least one R 10 is H.

[0325]

[0295] Appendix 30. A compound according to Appendix 29, wherein R 10 is H.

[0296] Appendix 31. Het is a ring of the formula

[0326]

Chemical formula

[0327] is a compound according to any one of Appendices 1 to 30. (wherein one R 9 is H, the other R 9 is -CF3, and R 10 is H)

[0297] Appendix 32. A compound according to any one of Appendices 1 to 31, wherein R 8 is H.

[0328]

[0298] Appendix 33. -X-Y-Z- is =CR 1 -CR 2 =CR 3 - or =N-CR 2 =CR 3 - is a compound according to any one of Appendices 1 to 32.

[0299] Supplementary Note 34. -X-Y-Z- is =CR 1 -CR 2 =CR 3 -, a compound described in any one of Supplementary Notes 1 to 33.

[0329]

[0300] Supplementary Note 35. The compound of formula I is a compound of formula IA

[0330] [Chemical Formula]

[0331] or a pharmaceutically acceptable salt, ester, or prodrug thereof, Formula I * of the compound is of formula I * A

[0332] [Chemical Formula]

[0333] or a pharmaceutically acceptable salt, ester, or prodrug thereof, a compound described in any one of Supplementary Notes 1, 4, or 11. (wherein, -X-Y-Z- of formula IA is =CR 1 -CR 2 =CR 3 - or =N-CR 2 =CR 3 -; Formula I * -X-Y-Z- of A is CR 1 -CR 2 =C or =N-CR 2 =C; R 1 is selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -OCH3, and -OCF3; R 2is H, (C1-C6)alkyl, (C1-C6)alkoxy-, and perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy-, cycloalkyl, cycloalkyl-O, heterocycloalkyl, aryl, R 5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C6)alkyl, cycloalkyl, cycloalkyl-O, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; Each R 4 is independently H or (C1-C3)alkyl; R 5 is selected from (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3)alkyl; (C1-C3)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3)alkyl; R8 is H, -CH3, or -CF3; R 9 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, R 12 O((C1-C3)alkyl)-(NR 11 )-, -CO2R 12 , and (R 11 )2N-(C=O)-selected from; -each R 11 is independently selected from H and (C1-C3)alkyl; R 12 is H or (C1-C3)alkyl)

[0301] Appendix 36. The compound of formula I is a compound of formula IB

[0334]

Chemical formula

[0335] or a pharmaceutically acceptable salt, ester, or prodrug thereof, and the compound of formula I * is a compound of formula I * B

[0336]

Chemical formula

[0337] or a pharmaceutically acceptable salt, ester, or prodrug thereof, a compound according to any of Appendices 1, 3, or 11. (wherein, for formula I * -X-Y-Z- of B is CH-CR 2 =C or =N-CR 2 =C; R 2 is H, (C1-C3)alkyl, (C1-C3)alkoxy-, and perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy-, cycloalkyl, heterocycloalkyl, aryl, R5 -(C(R 4 )2) n -O- or (R 6 )2N-; (C1-C3) alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; n is an integer from 1 to 3; Each R 4 is independently H or (C1-C3) alkyl; (C1-C3) alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 5 is selected from (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C1-C3) alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 6 is independently H or (C1-C3) alkyl; (C1-C3) alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3) alkyl, -NH2, (C1-C3) alkyl-(NH)-, ((C1-C3) alkyl)2N-, -CF3, -OCH3 and -OCF3; R 3 is H, halo, (C1-C3) alkyl, -CF3, -OCH3, -OCF3 or (R 7 )2N-; R 7 is H or (C1-C3) alkyl; R 8is H, -CH3, or -CF3; R 9 is H, halo, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, -(NR 10 )-((C1-C3)alkyl)-OR 11 , -CO2R 11 and -(C=O)-N(R 10 )2; R 10 is H or (C1-C3)alkyl; R 11 is (C1-C3)alkyl)

[0302] Appendix 37. The compound is 6-(1H-imidazol-1-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide; 6-(1H-imidazol-1-yl)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide; 2-(1H-imidazol-1-yl)-6-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide; 6-(1H-imidazol-1-yl)-4-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide; or 4-cyclopropoxy-6-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide; selected from the compounds described in Appendix 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0338]

[0303] Appendix 38. A pharmaceutical composition comprising a compound, salt, ester, or prodrug according to any of Appendices 1 to 37 and a pharmaceutically acceptable carrier.

[0304] Supplement 39. A method for treating a disease or disorder in a subject in which modulation of NAD+ levels or levels of related metabolites thereof is beneficial, the method comprising administering to the subject a compound according to any of Supplements 1 to 37 or a composition according to Supplement 38 in an amount effective to modulate NAD+ levels or levels of related metabolites thereof.

[0339]

[0305] Supplement 40. The method according to Supplement 39, wherein the disease or condition is non-alcoholic steatohepatitis.

[0306] Supplement 41. A compound or composition according to any of Supplements 1 to 38 for use in treating a disease or medical condition in a subject.

[0340]

[0307] Supplement 42. A compound or composition for use according to Supplement 41, wherein the disease or condition is one in which modulation of NAD+ levels or levels of related metabolites thereof is beneficial.

[0308] Supplement 43. A compound or composition for use according to Supplement 41 or 42, wherein the disease or condition benefits from inhibition of CD38.

[0341]

[0309] Supplement 44. A compound or composition for use according to any of Supplements 41 to 43, wherein the disease or condition is selected from aging (e.g., age-related chronic diseases), inflammation, cancer, such as PD-1 / PD-L1 resistant cancer, cardiovascular disorders, neuropathy, lung disorders, fibrotic diseases, metabolic disorders, 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, liver disorders, postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, skin diseases, radiation exposure-induced damage, periodontal disease, Leber hereditary cataract, sleep disorders, exercise intolerance, chronic diseases associated with cell death, and chemotherapy-associated neurodegeneration and peripheral neuropathy.

[0342]

[0310] Supplement 45. A compound or composition for use according to any of Supplements 41 to 44, wherein the disease or condition is an age-related disease or condition.

[0311] Supplementary Note 46. A compound or composition for use as described in any one of Supplementary Notes 41 - 45, wherein the disease or condition is selected from small cell lung cancer, 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, neuropathy, epilepsy, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity, sarcopenic obesity, 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, fatty liver, non-alcoholic steatohepatitis (NASH), postmenopausal osteoporosis, Hartnup disease, tuberculosis, leishmaniasis, muscular dystrophy, organ reperfusion injury, pellagra, cutaneous hyperpigmentation, UV skin damage, psoriasis, X-ray-induced DNA damage, periodontal disease, Leber hereditary cataract, sleep disorder, exercise intolerance, and chemotherapy-related neurodegeneration and peripheral neuropathy.

[0343]

[0312] Supplementary Note 47. A compound or composition for use as described in any one of Supplementary Notes 41 - 46, wherein the treatment is the treatment of multiple myeloma and is a combination treatment with an immuno-oncology drug.

[0313] Supplementary Note 48. A compound or composition for use as described in any one of Supplementary Notes 41 - 46, wherein the disease or condition is non-alcoholic steatohepatitis (NASH).

[0344]

[0314] Supplementary Note 49. A compound or composition for use as described in Supplementary Note 48, wherein the compound is 2-(1H-imidazol-1-yl)-6-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide.

[0345] Use of a compound according to any one of claims 1 to 37 for the treatment of a disease or disorder in a subject, wherein modulation of NAD+ levels or levels of related metabolites thereof is beneficial, the method comprising administering to the subject a therapeutically effective amount of the compound.

[0346]

[0316] Supplementary Note 51. A compound for use according to claim 50, wherein the disease or disorder is non-alcoholic steatohepatitis, aging, senescence, immunometabolism, inflammation, infection, sepsis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis vulgaris, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, cardiac fibrosis, cancer, multiple myeloma, neurodegeneration, infertility, loss of follicles, decrease in the quality and quantity of oocytes, 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 artery, obesity, type 2 diabetes, hepatotoxicity, digestive system, lung, heart, kidney, etc., or is related thereto.

[0347]

[0317] Supplementary Note 52. A compound for use according to claim 50, wherein the disease or disorder is related to aging.

[0318] Supplementary Note 53. A compound for use according to claim 52, wherein the disease or disorder is a chronic age-related disease or disorder or is related thereto.

[0348]

[0319] Supplementary Note 54. A compound for use according to claim 52, wherein the disease or disorder is senescence, immunometabolism, fibrosis, neurodegeneration, multiple myeloma, or sepsis, or is related thereto.

[0349]

[0320] Supplementary Note 55. A compound for use according to claim 54, wherein the disease or disorder is a fibrotic disease or disorder of the lung, heart, or kidney, or is related thereto.

[0350]

[0321] Supplementary Note 56. A compound for use according to claim 55, wherein the fibrotic disease is infection-induced pulmonary fibrosis or virus-induced pulmonary infection.

[0322] Supplementary Note 57. A compound for use according to claim 54, wherein the disease or disorder is multiple myeloma or is related thereto, and a method further comprising administering an immuno-oncology drug to a subject in need thereof.

[0351]

[0323] Supplementary Note 58. A compound for use according to claim 50, wherein the regulation is an increase in the level of NAD+ or its related metabolite.

[0324] Supplementary Note 59. A compound for use according to claim 50, wherein the regulation is a decrease in the level of NAD+ or its related metabolite.

[0352]

[0325] Supplementary Note 60. A compound for use according to claim 50, wherein the NAD+ or its related metabolite is selected from the group consisting of NAD+, NMN, ADPR, cADPR, NAM, NAAD, NAADP, NR, MNAM.

[0353]

[0326] Here, reference is made to specific examples for explaining the present disclosure. It should be understood that the examples are provided to illustrate exemplary embodiments and are not intended to limit the scope of the present disclosure.

Examples

[0354]

[0327] Several experimental examples are contemplated, but these examples are intended to be non-limiting. In the following non-limiting examples, "BOC", "Boc", or "boc" means N-tert-butoxycarbonyl, "DCM" (CH2Cl2) means methylene chloride, "DIPEA" or "DIEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMF" means N-N-dimethylformamide, "DMSO" means dimethyl sulfoxide, "DPPP" means 1,3-bis(diphenylphosphino)propane, "HOAc" means acetic acid, "IPA" means isopropyl alcohol, "MTBE" means methyl t-butyl ether, "NMP" means 1-methyl-2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" means ethyl acetate, "MgSO4" means magnesium sulfate, "NaSO4" means sodium sulfate, "MeOH" means methanol, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "POCl3" means phosphorus oxychloride, "DMSO" means dimethyl sulfoxide, "K2CO3" means potassium carbonate, "N" means normal, "M" means mole, "mL" means milliliter, "mmol" means millimole, "μmol" means micromole, "eq." means equivalent, "°C" means degree Celsius, and "Pa" means pascal.

[0355] Example 1 Synthesis of methyl 5-[6-(1H-imidazol-1-yl)pyridin-2-amide]pyridine-2-carboxylate (Compound 1)

[0356]

Chemical formula

[0357] Step-1: Ethyl 6-(1H-imidazol-1-yl)picolinate

[0358] [Chemistry]

[0359]

[0329] To a stirred solution of ethyl 6-bromopyridine-2-carboxylate (1 g, 4.35 mmol) in DMSO (10 mL) were added copper(I) iodide (0.276 g, 0.869 mmol), L-proline (0.20 g, 1.74 mmol), potassium carbonate (1.20 g, 8.69 mmol), and imidazole (0.444 g, 6.52 mmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature (RT), ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give ethyl 6-(1H-imidazol-1-yl)picolinate (1 g crude) as a brown solid. LCMS (ES) m / z = 218.1 [M+H] + . Step-2: 6-(1H-Imidazol-1-yl)picolinic acid

[0360] [Chemistry]

[0361]

[0330] To a stirred solution of ethyl 6-(1H-imidazol-1-yl)pyridine-2-carboxylate (1 g, 4.60 mmol) in THF (10 mL), MeOH (10 mL), and water (10 mL) was added lithium hydroxide monohydrate (0.29 g, 6.91 mmol). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The solvent was completely evaporated under reduced pressure and the mixture was extracted with ethyl acetate. The aqueous layer was acidified using 1N HCl and the pH was adjusted to about 2. The aqueous layer was completely evaporated under reduced pressure to give a crude material, which was triturated with acetonitrile and diethyl ether to give 6-(1H-imidazol-1-yl)pyridine-2-carboxylic acid (1.2 g crude) as a brown solid. LCMS (ES) m / z = 190.2 [M+H] + . Step-3: Methyl 5-(6-(1H-imidazol-1-yl)picolinamide) picolinate

[0362]

Chemical formula

[0363]

[0331] To a solution of 6-(1H-imidazol-1-yl)pyridine-2-carboxylic acid (1 g, 5.29 mmol) in DMF (5 mL), DIPEA (3.42 mL, 18.5 mmol), HATU (3.01 g, 9.73 mmol) and methyl 5-aminopyridine-2-carboxylate (0.96 g, 6.34 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain a crude product, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The compound eluted with 4% MeOH:DCM. The pure fractions were collected and evaporated to obtain pure methyl 5-[6-(1H-imidazol-1-yl)pyridine-2-amide]pyridine-2-carboxylate (0.5 g, yield 29%) as an off-white solid.

[0364]

[0332] The following Table 1 provides the characterization data of selected compounds of formula I prepared by the method shown in Example 1 above.

[0365]

Table 1-1

[0366]

Table 1-2

[0367]

Table 1-3

[0368]

Table 1-4

[0369]

Table 1-5

[0370]

Table 1-6

[0371]

Table 1-7

[0372]

Table 1-8

[0373]

Table 1-9

[0374]

Table 1-10

[0375] Example 2 Synthesis of Compound 29

[0376]

Chem.

[0377] Step-1: 4-(Benzyloxy)-6-bromopicolinic acid

[0378]

Chem.

[0379]

[0333] To a stirred suspension of sodium hydride (66.6 mg, 2.77 mmol) in THF, benzyl alcohol (150 mg, 1.39 mmol) was added at 0 °C. The reaction mixture was stirred at the same temperature for 15 minutes. 6-Bromo-4-nitropyridine-2-carboxylic acid (343 mg, 1.39 mmol) in THF was added thereto dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. TLC indicated consumption of the starting material. The reaction mixture was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 4-(benzyloxy)-6-bromopyridine-2-carboxylic acid (350 mg, crude) as an oily compound. The crude material was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 13.6 - 13.4 (bs, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.45 - 7.28 (m, 5H), 5.28 (s, 2H). LCMS (ES)m / z=310.2[M+H] + 。 Step - 2: 4-(Benzyloxy)-6-bromopicolinoyl chloride

[0380]

Chemical formula

[0381]

[0334] To a stirred solution of 4-(benzyloxy)-6-bromopyridine-2-carboxylic acid (350 mg, 1.14 mmol) in DCM (10 mL), 0.1 mL of DMF and oxalyl chloride (292 μL, 3.41 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by TLC. The reaction mixture was concentrated completely to give a yellow crude material, which was used in the next step without purification. Step 3: -(Benzyloxy)-6-bromo-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide

[0382]

Chemical formula

[0383]

[0335] To a stirred solution of crude 4-(benzyloxy)-6-bromopyridine-2-carbonyl chloride (350 mg, 1.07 mmol) in DCM, triethylamine (3.01 μL, 2.14 mmol) was added at 0 °C. To this solution, 2-(trifluoromethyl)pyridin-4-amine (174 mg, 1.07 mmol) in DCM was added dropwise. The reaction mixture was warmed gradually to room temperature and stirred for 16 h, at which point the reaction mixture was treated with water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give the crude material, which was purified by combiflash column chromatography using an ethyl acetate - hexane gradient. The required product eluted with approximately 30% ethyl acetate - hexane. The pure fractions were collected and evaporated to give pure 4-(benzyloxy)-6-bromo-N-[3-(trifluoromethyl)phenyl]pyridine-2-carboxamide (170 mg, 35.2%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.68 - 8.67 (m, 1H), 8.10 (s, 1H), 7.89 - 7.84 (m, 3H), 7.42 (s, 5H), 5.21 (s, 2H). LCMS (ES)m / z=452.0[M+H] + 。 Step - 4: 4-(Benzyloxy)-6-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide

[0384]

Chem.

[0385]

[0336] To a stirred solution of 4-(benzyloxy)-6-bromo-N-[2-(trifluoromethyl)pyridin-4-yl]pyridine-2-carboxamide (170 mg, 0.38 mmol) in DMF (2 mL) were added 1H-imidazole (38.4 mg, 0.57 mmol), copper(I) iodide (15 mg, 0.075 mmol), and cesium carbonate (245 mg, 0.75 mmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, the crude product was washed with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a crude product, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound eluted with approximately 5% MeOH-DCM. The pure fractions were collected and evaporated to give 4-(benzyloxy)-6-(1H-imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyridine-2-carboxamide (55.0 mg, 33%) as an off-white solid.

[0386]

[0337] Table 2 below shows the characterization data for additional compounds of formula I prepared as described above.

[0387]

Table 2-1

[0388]

Table 2-2

[0389]

Table 2-3

[0390] Example 3 Synthesis of Compound 35

[0391]

Chem.

[0392] Step - 1: 6 - Chloro - 4 - methoxy - N-(2-(trifluoromethyl)pyridin - 4 - yl)picolylamide

[0393]

Chem.

[0394]

[0338] A solution of methyl 6 - chloro - 4 - methoxypyridine - 2 - carboxylate (1.40 g, 6.94 mmol) dissolved in toluene was added with 2-(trifluoromethyl)pyridin - 4 - amine (901 mg, 5.56 mmol) and trimethylaluminum (10.4 mL, 20.8 mmol). The resulting mixture was stirred at 100 °C for 1 hour in a CEM (registered trademark) microwave (CEM Corporation, 3100 Smith Farm Road, Matthews, NC 28106). Then, the reaction mixture was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to obtain a crude product, which was purified by combiflash column chromatography using an ethyl acetate - hexane gradient. The required product eluted with approximately 30% ethyl acetate - hexane. The pure fractions were collected and evaporated to obtain 6 - chloro - 4 - methoxy - N-[2-(trifluoromethyl)pyridin - 4 - yl]pyridine - 2 - carboxamide (1.2 g, 52% yield) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6) δ 11.11 (s, 1H), 8.68 - 8.67 (m, 1H), 8.45 (s, 1H), 8.21 - 8.20 (m, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 3.96 (s, 3H). LCMS (ES) m / z = 332.2 [M + H] + 。 Step - 2: 6-(1H - Imidazol - 1 - yl)-4 - methoxy - N-(2-(trifluoromethyl)pyridin - 4 - yl)picolylamide

[0395] [Chemistry]

[0396]

[0339] To a solution of 6-chloro-4-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]pyridine-2-carboxamide (1.20 g, 3.62 mmol) in DMF (10.0 mL) were added copper(I) iodide (230 mg, 0.724 mmol), cesium carbonate (1.41 g, 4.34 mmol), and 1H-imidazole (369 mg, 5.43 mmol). The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The required product eluted with approximately 5% MeOH:DCM. The pure fractions were evaporated to give 6-(1H-imidazol-1-yl)-4-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]pyridine-2-carboxamide (0.95 g, 72% yield) as an off-white solid.

[0397]

[0340] Table 3 below shows the characterization data for additional compounds of formula I prepared by the method shown above.

[0398] [Table 3]

[0399] Example 4 Synthesis of Compound 37

[0400] [Chemistry]

[0401] Step-1: Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate

[0402] [Chemistry]

[0403]

[0341] Potassium carbonate (401 mg, 2.90 mmol) was added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (600 mg, 2.90 mmol) in methanol (12.0 mL), and the reaction mixture was stirred at room temperature for 16 h. The solvent was completely evaporated under reduced pressure, and water was added thereto. The crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain a crude substance, which was purified by combiflash column chromatography using an ethyl acetate-hexane gradient. The target compound was eluted with approximately 25% ethyl acetate-hexane. The pure fractions were collected and evaporated to give methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (0.5 g, 85% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H). LCMS (ES) m / z = 203.0 [M+H] + 。 Step - 2: 2-Chloro-6-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0404] [Chemistry]

[0405]

[0342] To a solution of methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (450 mg, 2.22 mmol) in toluene, 2-(trifluoromethyl)pyridin-4-amine (288 mg, 1.78 mmol) was added. The stirred solution was treated with a 2 M solution of trimethylaluminum in toluene (2.22 mL, 4.44 mmol). The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a crude product, which was purified by combiflash column chromatography using an ethyl acetate - hexane gradient. The target compound was eluted with approximately 20% ethyl acetate - hexane. The pure fractions were collected and evaporated to give 2-chloro-6-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.035 g, 47% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.70 - 8.68 (m, 1H), 8.43 (s, 1H), 8.20 - 8.19 (m, 1H), 7.50 (s, 1H), 4.02 (s, 3H). LCMS (ES)m / z=333.0[M+H] + 。 Step - 3: 2-(1H-Imidazol-1-yl)-6-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0406]

Chem.

[0407]

[0343] To a stirred solution of 2-chloro-6-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (300 mg, 0.902 mmol) in DMF (5 mL) were added copper(I) iodide (57.2 mg, 0.180 mmol), cesium carbonate (353 mg, 1.08 mmol), and 1H-imidazole (92.1 mg, 1.35 mmol), and the reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using a MeOH-DCM gradient. The product eluted with approximately 5% MeOH-DCM. The pure fractions were collected and evaporated to give 2-(1H-imidazol-1-yl)-6-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.11 g, 35% yield) as an off-white solid.

[0408]

[0344] Table 4 lists the characterization data of the compounds of formula I prepared by the method of Example 4.

[0409]

Table 4-1

[0410]

Table 4-2

[0411] Example 5 Synthesis of Compound 42

[0412]

Chem.

[0413] Step-1: 6-(1-Methyl-1H-imidazol-5-yl)-N-(pyridin-3-yl)picolinamide

[0414] [Chemistry]

[0415]

[0345] To a solution of 6-bromo-N-(pyridin-3-yl)picolinamide (0.15 g, 0.539 mmol) in DMF (5 mL) was added 1-methyl-5-(tributylstannyl)-1H-imidazole (0.2 mL, 0.647 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes. The reaction vial was sealed and heated at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and water was added. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, evaporated to give a crude product, which was purified by silica gel flash column chromatography. The compound was eluted with 4% MeOH:DCM. The pure fractions were collected and evaporated to give 6-(1-methyl-1H-imidazol-5-yl)-N-(pyridin-3-yl)pyridine-2-carboxamide (0.075 g, 50% yield) as an off-white solid.

[0416]

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.99 (s, 1H), 8.33 - 8.26 (m, 2H), 8.09 -8.05 (m, 1H), 7.99 -7.97 (m, 2H), 7.83 (s, 1H), 7.66 (s, 1H), 7.42 - 7.39 (m, 1H), 4.06 (s, 3H).

[0347] Table 5 provides the characterization data of the compounds of formula I prepared by the method shown in Example 5.

[0417] [Table 5-1]

[0418] [Table 5-2]

[0419]

Table 5-3

[0420] Example 6 Synthesis of Compound 49

[0421]

Chem.

[0422] Step-1: 2-Chloro-6-methyl-N-(pyridin-3-yl)pyrimidine-4-carboxamide

[0423]

Chem.

[0424]

[0348] A solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (250 mg, 1.34 mmol) in toluene was added to pyridin-3-amine (126 mg, 1.34 mmol) and a 2 M trimethylaluminum solution in toluene (1.34 mL, 2.68 mmol). The reaction mixture was stirred at 100 °C for 1 hour with a CEM microwave. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain the crude material, which was purified by combiflash column chromatography using an ethyl acetate - hexane gradient. The target compound was eluted with approximately 50% ethyl acetate - hexane. The pure fractions were collected and evaporated to give 2-chloro-6-methyl-N-(pyridin-3-yl)pyrimidine-4-carboxamide (0.20 g, 60% yield) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.0 (s, 1H), 8.36 - 8.35 (m, 1H), 8.25 - 8.23 (m, 1H), 8.04 (s, 1H), 7.43 - 7.36 (m, 1H), 2.61 (s, 3H). LCMS(ES) m / z=249.0[M+H] + 。 Step - 2: 2-(1H-Imidazol-1-yl)-6-methyl-N-(pyridin-3-yl)pyrimidine-4-carboxamide

[0425]

Chem.

[0426]

[0349] To a stirred solution of 2-chloro-6-methyl-N-(pyridin-3-yl)pyrimidine-4-carboxamide (200 mg, 0.804 mmol) in DMF (5.0 mL) were added copper(I) iodide (51.0 mg, 0.161 mmol), cesium carbonate (314 mg, 0.965 mmol), and 1H-imidazole (82.1 mg, 1.21 mmol). The reaction mixture was heated to 100 °C for 6 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude material, which was purified by combi-flash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 5% MeOH-DCM. The pure fractions were evaporated to give 6-(1H-imidazol-1-yl)-2-methyl-3-(pyridin-4-yl)-3H,4H-pyrido[3,2-d]pyrimidin-4-one (0.06 g, 27% yield) as an off-white solid.

[0427]

[0350] Table 6 provides the characterization data of the compounds of formula I prepared by the method shown in Example 6.

[0428]

Table 6

[0429] Example 7 Synthesis of Compound 52

[0430] [Chem.]

[0431] Step - 1: 6 - Chloro - 4 - methylpicolinic acid

[0432] [Chem.]

[0433]

[0351] To a stirred solution of methyl 6 - chloro - 4 - methylpyridine - 2 - carboxylate (2 g, 10.8 mmol) in THF (15 mL), MeOH (15 mL) and water (15 mL), lithium hydroxide monohydrate (0.96 g, 21.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure to give the crude material, which was treated with water and extracted with ethyl acetate. The aqueous layer was acidified using 1N HCl to pH ~ 2 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6 - chloro - 4 - methylpyridine - 2 - carboxylic acid (1.8 g, 97% yield) as an off - white solid. 1H NMR (400 MHz, DMSO - d6) δ 13.45 (bs, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 2.38 (s, 3H). LCMS (ES) m / z = 172.1[M + H] + . Step - 2: 6 - Chloro - 4 - methyl - N - (pyridin - 4 - yl) picolinamide

[0434] [Chem.]

[0435] To a stirred solution of 6-chloro-4-methylpyridine-2-carboxylic acid (300 mg, 1.75 mmol) in DMF, DIPEA (0.968 mL, 5.25 mmol), HATU (0.79 g, 2.10 mmol) and pyridin-4-amine (0.16 g, 1.75 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. Water was added to the reaction mixture and the substances were extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude material, which was purified by combiflash column chromatography using an ethyl acetate - hexane gradient. The target compound was eluted with approximately 30% ethyl acetate - hexane. The pure fractions were evaporated to give 6-chloro-4-methyl-N-(pyridin-4-yl)pyridine-2-carboxamide (0.35 g, 80% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.48 - 8.47 (m, 2H), 7.96 (s, 1H), 7.88 - 7.87 (m, 2H), 7.67 (s, 1H), 2.43 (s, 3H). LCMS (ES)m / z=248.1[M+H] + 。 Step - 3: 6-(1H-Imidazol-1-yl)-4-methyl-N-(pyridin-4-yl)picolinamide

[0436]

Chem.

[0437]

[0353] To a stirred solution of 6-chloro-4-methyl-N-(pyridin-4-yl)pyridine-2-carboxamide (100 mg, 0.41 mmol) in DMF (1.5 mL) were added copper(I) iodide (25.6 mg, 0.08 mmol), L-proline (18.6 mg, 0.16 mmol), potassium carbonate (112 mg, 0.81 mmol) and 1H-imidazole (41.2 mg, 0.61 mmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and quenched with water. The crude product was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and then evaporated under reduced pressure to give a crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 4% MeOH-DCM. The pure fractions were evaporated to give 6-(1H-imidazol-1-yl)-4-methyl-N-(pyridin-4-yl)pyridine-2-carboxamide (0.014 g, 12% yield) as an off-white solid.

[0438]

[0354] Table 7 provides the characterization data for the compounds of formula I prepared by the method shown in Example 7.

[0439]

Table 7

[0440] Example 8 Synthesis of Compound 54

[0441]

Chem.

[0442] Step 1: Methyl 5-(6-chloro-4-methylpicolinamide)picolinate

[0443]

Chem.

[0444] To a stirred solution of 6-chloro-4-methylpyridine-2-carboxylic acid (0.6 g, 3.5 mmol) in DMF (15 mL) was added methyl 5-aminopyridine-2-carboxylate (0.585 g, 3.85 mmol), HATU (1.6 g, 4.20 mmol), and DIPEA (1.83 mL, 10.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material, which was purified by combiflash column chromatography using an ethyl acetate-hexane gradient. The target compound was eluted with approximately 60% ethyl acetate-hexane. The solvent was evaporated to give methyl 5-(6-chloro-4-methylpicolinamido)picolinate (600 mg, 56%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.92 - 8.91 (m, 1H), 8.58 - 8.55 (m, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.38 (s, 1H), 4.01 (s, 3H), 2.39 (s, 3H). LC-MS (ES)m / z=306.1[M+H] + 。 Step 2: Methyl 5-(6-(1H-imidazol-1-yl)-4-methylpicolinamido)picolinate

[0445]

Chemical formula

[0446] To a stirred solution of methyl 5-(6-chloro-4-methylpyridine-2-carboxamido)pyridine-2-carboxylate (0.6 g, 1.96 mmol) in DMSO (10 mL) were added 1H-imidazole (0.2 g, 2.94 mmol), copper(I) iodide (0.075 g, 0.393 mmol), L-proline (0.0904 g, 0.785 mmol), and potassium carbonate (0.550 g, 3.93 mmol). The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound was eluted with ca. 5% MeOH-DCM. The fractions were evaporated to give methyl 5-(6-(1H-imidazol-1-yl)-4-methylpicolinamido)picolinate (0.15 g, 23%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.16 (s, 2H), 8.53 - 8.50 (m, 2H), 8.14 - 8.12 (m, 2H), 7.99 - 7.96 (m, 2H), 3.86 (s, 3H), 2.52 (s, 3H). LC-MS (ES)m / z=338.1[M+H] + 。 Step 3: N-(6-carbamoylpyridin-3-yl)-6-(1H-imidazol-1-yl)-4-methylpicolinamide

[0447]

Chem.

[0448]

[0357] A stirred solution of ethyl 4-[6-(1H-imidazol-1-yl)-4-methylpyridin-2-amido]pyridine-2-carboxylate (0.15 g, 0.445 mmol) in 37% aqueous ammonium hydroxide (8 mL) was heated at 65 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated under vacuum to give the crude material, which was purified by reverse phase HPLC (column: X-Bridge-C-18 (250 mm × 4.6 mm x 5 mic); mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile; flow rate: 2.0 mL / min). The pure fractions were evaporated to give N-(6-carbamoylpyridin-3-yl)-6-(1H-imidazol-1-yl)-4-methylpicolinamide (17 mg, 12%) as an off-white solid.

[0449]

[0358] Table 8 provides the characterization data of the compounds of formula I prepared by the method shown in Example 8.

[0450]

Table 8-1

[0451]

Table 8-2

[0452] Example 9 Synthesis of Compound 58

[0453]

Chem.

[0454] Step-1: 6-Bromo-5-methyl-N-(pyridin-3-yl)picolinamide

[0455]

Chem.

[0456] To a stirred solution of 6-bromo-5-methylpyridine-2-carboxylic acid (0.25 g, 1.16 mmol) in DMF (5 mL) were added DIPEA (0.64 mL, 3.47 mmol), HATU (0.528 g, 1.39 mmol), and pyridin-3-amine (0.120 g, 1.27 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 4% MeOH-DCM. The pure fractions were evaporated to give 6-bromo-5-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (0.23 g, 68% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.99 (s, 1H), 8.32 -8.31 (m, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.40 - 7.37 (m, 1H), 2.42 (s, 3H). LCMS (ES)m / z=293.9[M+2H] + 。 Step-2: 6-(1H-Imidazol-1-yl)-5-methyl-N-(pyridin-3-yl)picolylamide

[0457]

Chem.

[0458]

[0360] To a stirred solution of 6-bromo-5-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (0.15 g, 0.513 mmol) in DMSO (3 mL) were added copper(I) iodide (0.032 g, 0.103 mmol), L-proline (0.023 g, 0.205 mmol), potassium carbonate (0.142 g, 1.03 mmol), and imidazole (0.052 g, 0.770 mmol). The stirred reaction mixture was heated to 100 °C for 3 h, then cooled to room temperature and quenched with water. The crude mixture was extracted with ethyl acetate, dried over sodium sulfate, evaporated under reduced pressure to give the crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 4% MeOH-DCM. The pure fractions were evaporated to give 6-(1H-imidazol-1-yl)-5-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (0.08 g, 56% yield) as an off-white solid.

[0459]

[0361] Table 9 provides the characterization data for the compounds of formula I prepared by the method shown in Example 9.

[0460]

Table 9

[0461] Example 10 Synthesis of Compound 59

[0462]

Chem.

[0463] Step-1: 6-Bromo-3-methyl-N-(pyridin-3-yl)picolylamide

[0464]

Chem.

[0465] A solution of 6-bromo-3-methylpyridine-2-carboxylic acid (0.5 g, 2.31 mmol) in DMF (2 mL) was added to DIPEA (1.28 mL, 6.94 mmol), HATU (1.06 g, 2.78 mmol) and pyridin-3-amine (0.26 g, 2.78 mmol). The reaction mixture was stirred at room temperature for 16 h. The crude reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give the crude material, which was purified by combi-flash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 2% MeOH-DCM. The pure fractions were evaporated to give 6-bromo-3-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (1.3 g, 96% yield) as an off-white solid. LCMS (ES) m / z = 294.0 [M+2H] + . Step-2: 6-(1H-imidazol-1-yl)-3-methyl-N-(pyridin-3-yl)picolylamide

[0466] [Chemical formula]

[0467]

[0363] To a stirred solution of 6-bromo-3-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (0.1 g, 0.342 mmol) in DMSO (2 mL) were added copper(I) iodide (0.021 g, 0.0685 mmol), L-proline (0.015 g, 0.137 mmol), potassium carbonate (0.094 g, 0.685 mmol) and imidazole (0.035 g, 0.513 mmol). The stirred reaction mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature, treated with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a crude material, which was purified by combi-flash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 4% MeOH-DCM. The pure fractions were evaporated to give 6-(1H-imidazol-1-yl)-3-methyl-N-(pyridin-3-yl)pyridine-2-carboxamide (0.080 g, 84% yield) as an off-white solid.

[0468]

[0364] Table 10 provides the characterization data of the compounds of formula I prepared by the method shown in Example 10.

[0469]

Table 10-1

[0470]

Table 10-2

[0471] Example 11 Synthesis of Compound 64

[0472]

Chem.

[0473] Step-1: 3-Amino-6-bromo-N-(pyridin-4-yl)picolylamide

[0474]

Chem.

[0475]

[0365] To a stirred solution of methyl 3-amino-6-bromopyridine-2-carboxylate (500 mg, 2.16 mmol) in toluene was added pyridin-4-amine (204 mg, 2.16 mmol) in toluene and a toluene solution of 2M trimethylaluminum (5.41 mL, 10.8 mmol). The reaction mixture was stirred at 100 °C for 1 h with a CEM microwave. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude material, which was purified by combiflash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 3% MeOH-DCM. The pure fractions were evaporated to give 3-amino-6-bromo-N-(pyridin-4-yl)pyridine-2-carboxamide (0.5 g, 79% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.44 (d, J = 5.6 Hz, 2H), 7.81 (d, J = 5.6 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.08 (s, 2H). LCMS (ES) m / z=295.2[M+2H] + 。 Step - 2: 3-Amino-6-(1H-imidazol-1-yl)-N-(pyridin-4-yl)picolylamide

[0476]

Chem.

[0477]

[0366] To a stirred solution of 3-amino-6-bromo-N-(pyridin-4-yl)pyridine-2-carboxamide (220 mg, 0.751 mmol) in DMF (3 mL) were added copper(I) iodide (47.6 mg, 0.150 mmol), (2S)-pyrrolidine-2-carboxylic acid (34.6 mg, 0.300 mmol), potassium carbonate (207 mg, 1.50 mmol) and 1H-imidazole (76.6 mg, 1.13 mmol). The reaction mixture was heated at 100 °C for 16 h, then cooled to room temperature and treated with ice-cold water. The crude mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude material, which was purified by combi-flash column chromatography using a MeOH-DCM gradient. The target compound was eluted with approximately 4% MeOH-DCM. The pure fractions were evaporated to give 3-amino-6-(1H-imidazol-1-yl)-N-(pyridin-4-yl)pyridine-2-carboxamide (0.060 g, 28% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.68 (s, 1H), 8.48 - 8.46 (m, 2H), 8.08 (s, 1H), 7.86 - 7.85 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.08 - 7.04 (m, 3H). LCMS (ES)m / z=281.3[M+H] + 。

[0478]

[0367] Table 11 provides the characterization data for the compounds of formula I prepared by the method shown in Example 11.

[0479]

Table 11-1

[0480]

Table 11-2

[0481] Example 12 Synthesis of Compound 70

[0482]

Chem.

[0483]

[0368] Table 12 provides the characterization data of the compound of formula I prepared by the method shown in Example 12.

[0484]

Table 12

[0485] Example 13 Synthesis of Compound 71 Synthesis of Intermediate-1A

[0486]

Chem.

[0487]

[0369] To a solution of oxetan-3-one (1.0 g, 13.9 mmol) in tetrahydrofuran (10 mL) was added bromo(methyl)magnesium (9.25 mL, 27.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (50 mL) to give 3-methyloxetan-3-ol (0.7 g, yield 57.25%) as a pale yellow liquid. Synthesis of Compound 71

[0488]

Chem.

[0489] Step-1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0490]

Chem.

[0491]

[0370] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (0.4 g, 1.93 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (313 mg, 1.93 mmol) and trimethylaluminum (1.45 mL, 2.90 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to afford 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.5 g, yield 76.7%) as an off-white solid. Step-2: 6-Chloro-2-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0492]

Chem.

[0493] A solution of sodium hydride (60% in mineral oil) (0.136 g, 3.40 mmol) in tetrahydrofuran (5 mL) was added with 3-methyloxetan-3-ol (200 mg, 2.27 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 10 minutes, and 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.612 g, 1.82 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 6-chloro-2-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.15 g, yield 17%) and 2-chloro-6-[(3-methyloxetan-3-yl)oxy]-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.2 g, yield 22.6%) as off-white solids. Step - 3: 6-(1H-Imidazol-1-yl)-2-((3-methyloxetan-3-yl)oxy)-N-(2(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0494]

Chemical formula

[0495] A solution of sodium hydride (60% in mineral oil) (0.023 g, 0.386 mmol) in tetrahydrofuran (5 mL) was added to 1H-imidazole (39.4 mg, 0.579 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 10 minutes. 6-Chloro-2-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.15 g, 0.386 mmol) dissolved in tetrahydrofuran (5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 5% methanol in dichloromethane to obtain 6-(1H-imidazol-1-yl)-2-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.03 g, yield 18.5%) as an off-white solid.

[0496]

[0373] Table 13 provides the characterization data of the compounds of formula I prepared by the method shown in Example 13.

[0497]

Table 13

[0498] Example 14 Synthesis of Compound 72

[0499]

Chemical formula

[0500] Step - 1: 2,6 - Dichloro - N-(2-(trifluoromethyl)pyridin - 4 - yl)pyrimidine - 4 - carboxamide

[0501]

Chemical formula

[0502]

[0374] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour with a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to give 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.15 g, 70.62% yield) as an off-white solid. Step - 2: 2-Chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0503]

Chemical Structure

[0504] A solution of sodium hydride (60% in mineral oil) (0.059 g, 0.89 mmol) in tetrahydrofuran (5 mL) was added to (tetrahydro-2H-pyran-4-yl)methanol (69 mg, 0.59 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 10 minutes. 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.2 g, 0.59 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to give 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.13 g, 52.5% yield) and 6-chloro-2-[(oxan-4-yl)methoxy]-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.13 g, 52.5% yield) as off-white solids. Step - 3: 2-(1H-Imidazol-1-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0505]

Chemical Structure

[0506] A solution of 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.13 g, 0.312 mmol) in N,N-dimethylformamide (2 mL) was added with cesium carbonate (0.15 g, 0.468 mmol), copper(II) iodide (29.7 mg, 0.094 mmol) and 1H-imidazole (31.9 mg, 0.468 mmol). The resulting mixture was stirred at 100 °C for 5 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The crude residue was purified by gradient column chromatography using 0 - 10% methanol in dichloromethane to give 6-(1H-imidazol-1-yl)-2-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.044 g, yield 31.46%) as an off-white solid.

[0507]

[0377] Table 14 provides the characterization data of the compounds of formula I prepared by the method shown in Example 14.

[0508]

Table 14

[0509] Example 15 Synthesis of Compound 73

[0510]

Chem.

[0511] Step - 1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0512]

Chem.

[0513]

[0378] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.15 g, 70.62% yield) as an off-white solid. Step - 2: 2-Chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0514]

Chemical Structure

[0515] A solution of sodium hydride (60% in mineral oil) (0.237 g, 3.56 mmol) in tetrahydrofuran (10 mL) was added with (tetrahydro-2H-pyran-4-yl)methanol (0.26 mL, 2.37 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and then 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.8 g, 2.37 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.25 g, yield 25.27%) as an off-white solid. Step - 3: 2-(1-Methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0516] [Chemical Structure]

[0517]

[0380] A solution of 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.1 g, 0.24 mmol) in 1,4-dioxane (3 mL) was treated with 1-methyl-5-(tributylstannyl)-1H-imidazole (134 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (84 mg, 0.072 mmol). The resulting mixture was stirred at 100 °C for 2 h using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine solution. The crude residue was purified by gradient column chromatography using 0–10% methanol in dichloromethane and then by preparative TLC to give 2-(1-methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.017 g, 15.32% yield) as an off-white solid.

[0518]

[0381] Table 15 provides the characterization data for the compounds of formula I prepared by the method shown in Example 15.

[0519]

Table 15

[0520] Example 16 Synthesis of Compound 74

[0521]

Chemical Structure

[0522] Step-1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0523] [Chemical formula]

[0524]

[0382] To a solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) were added 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 h using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to give 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.15 g, 70.62% yield) as an off-white solid. Step - 2: 2-Chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0525] [Chemical formula]

[0526] A solution of sodium hydride (60% in mineral oil) (0.237 g, 3.56 mmol) in tetrahydrofuran (10 mL) was added to (tetrahydro-2H-pyran-4-yl)methanol (0.26 mL, 2.37 mmol) at 0 °C, and the reaction mixture was stirred for 10 minutes. 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.8 g, 2.37 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to give 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.25 g, yield 25.27%) as an off-white solid. Step - 3: 2-(1-Methyl-1H-imidazol-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0527]

Chemical formula

[0528]

[0384] A solution of 2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.13 g, 0.312 mmol) in 1,4-dioxane (10 mL) was treated with 1-methyl-2-(tributylstannyl)-1H-imidazole (174 mg, 0.468 mmol) and tetrakis(triphenylphosphine)palladium(0) (108 mg, 0.094 mmol). The resulting mixture was stirred at 100 °C for 2 h using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine solution. The crude residue was purified by gradient column chromatography using 0-10% methanol in dichloromethane and then by preparative TLC to give 2-(1-methyl-1H-imidazol-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.052 g, 36.05% yield) as an off-white solid.

[0529]

[0385] Table 16 provides the characterization data for the compounds of formula I prepared by the method shown in Example 16.

[0530]

Table 16

[0531] Example 17 Synthesis of Compound 75

[0532]

Chemical Formula

[0533] Step-1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0534]

Chem.

[0535]

[0386] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 h using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.2 g, 73.7% yield) as an off-white solid. Step - 2: 2-Chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0536]

Chem.

[0537] A solution of sodium hydride (60% in mineral oil) (0.208 g, 3.11 mmol) in tetrahydrofuran (10 mL) was added with 2-methoxyethan-1-ol (0.237 g, 3.11 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and then 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.05 g, 3.11 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.4 g, yield 34.09%) as an off-white solid. Step - 3: 6-(2-Methoxyethoxy)-2-(1-methyl-1H-imidazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0538]

Chemical Structure

[0539]

[0388] A solution of 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.1 g, 0.265 mmol) in 1,4-dioxane (5 mL) was added with 1-methyl-5-(tributylstannyl)-1H-imidazole (148 mg, 0.398 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol). The resulting mixture was stirred at 100 °C for 2 hours using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with a brine solution. The crude residue was purified by gradient column chromatography using 0 - 100% ethyl acetate in hexane and 0 - 10% methanol in dichloromethane, and then purified by preparative TLC to obtain 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.031 g, yield 36.05%) as an off-white solid.

[0540]

[0389] Table 17 provides the characterization data of the compound of formula I prepared by the method shown in Example 17.

[0541]

Table 17

[0542] Example 18 Synthesis of Compound 76

[0543]

Chemical formula

[0544] Step - 1: 2,6 - Dichloro - N-(2-(trifluoromethyl)pyridin - 4 - yl)pyrimidine - 4 - carboxamide

[0545] [Chemical formula]

[0546]

[0390] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.2 g, yield 73.7%) as an off-white solid. Step - 2: 2-Chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0547] [Chemical formula]

[0548] A solution of sodium hydride (60% in mineral oil) (0.208 g, 3.11 mmol) in tetrahydrofuran (10 mL) was added 2-methoxyethan-1-ol (0.237 g, 3.11 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.05 g, 3.11 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to give 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.4 g, 34.09% yield) as an off-white solid. Step - 3: 6-(2-Methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0549] [Chemical formula]

[0550]

[0392] A solution of 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.13 g, 0.345 mmol) in 1,4-dioxane (5 mL) was added to 1-methyl-2-(tributylstannyl)-1H-imidazole (192 mg, 0.518 mmol) and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.104 mmol). The resulting mixture was stirred at 100 °C for 2 hours using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine solution. The crude residue was purified by gradient column chromatography using 0-100% ethyl acetate in hexane and 0-10% methanol in dichloromethane, and then by preparative HPLC to obtain 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.042 g, yield 28.82%) as an off-white solid.

[0551]

[0393] Table 18 provides the characterization data of the compounds of formula I prepared by the method shown in Example 18.

[0552]

Table 18

[0553] Example 19 Synthesis of Compound 77

[0554]

Chemical formula

[0555] Step-1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0556] [Chemical formula]

[0557]

[0394] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (1.0 g, 4.83 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (783 mg, 4.83 mmol) and trimethylaluminum (3.62 mL, 7.25 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.2 g, yield 73.7%) as an off-white solid. Step - 2: 2-Chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0558] [Chemical formula]

[0559] A solution of sodium hydride (60% in mineral oil) (0.208 g, 3.11 mmol) in tetrahydrofuran (10 mL) was added 2-methoxyethan-1-ol (0.237 g, 3.11 mmol) at 0 °C, and the reaction mixture was stirred for 10 minutes. Then, 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (1.05 g, 3.11 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.4 g, yield 34.09%) as an off-white solid. Step - 3: 6-(2-Methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide

[0560]

Chemical formula

[0561]

[0396] A solution of 2-chloro-6-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.13 g, 0.345 mmol) in 1,4-dioxane (5 mL) was added with 1-methyl-2-(tributylstannyl)-1H-imidazole (192 mg, 0.518 mmol) and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.104 mmol). The resulting mixture was stirred at 100 °C for 2 hours with a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine solution. The crude residue was purified by gradient column chromatography using 0 - 100% ethyl acetate in hexane and 0 - 10% methanol in dichloromethane, and then purified by preparative HPLC to obtain 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrimidine-4-carboxamide (0.048 g, yield 32.93%) as an off-white solid.

[0562]

[0397] Table 19 provides the characterization data of the compound of formula I prepared by the method shown in Example 19.

[0563]

Table 19

[0564] Example 20 Synthesis of Compound 78

[0565]

Chemical formula

[0566] Step - 1: 2,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide 89879

[0567] [Chemistry]

[0568]

[0398] A solution of methyl 6-chloro-4-methoxypyridine-2-carboxylate (0.5 g, 2.42 mmol) in toluene (5 mL) was added with 2-(trifluoromethyl)pyridin-4-amine (392 mg, 2.42 mmol) and trimethylaluminum (1.8 mL, 3.62 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 1 hour using a CEM microwave. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), and extracted with ethyl acetate (50 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.6 g, yield 73.7%) as an off-white solid. Step - 2: 2-chloro-6-(2-hydroxy-2-methylpropoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide 90016

[0569] [Chemistry]

[0570] A solution of sodium hydride (60% in mineral oil) (0.1 g, 1.48 mmol) in tetrahydrofuran (10 mL) was added to 2-methylpropane-1,2-diol (0.134 g, 1.48 mmol) at 0 °C, and the reaction mixture was stirred for 10 minutes. Then, 2,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.5 g, 1.48 mmol) dissolved in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL). The crude residue was purified by gradient column chromatography using 0 - 30% ethyl acetate in hexane to obtain 2-chloro-6-(2-hydroxy-2-methylpropoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.25 g, yield 43.13%) as a thick solid. Step - 3: 6-(2-Hydroxy-2-methylpropoxy)-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide

[0571] [Chemical formula]

[0572] A solution of 2-chloro-6-(2-hydroxy-2-methylpropoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.2 g, 0.512 mmol) in N,N-dimethylformamide (5 mL) was treated with cesium carbonate (0.25 g, 0.768 mmol), copper(II) iodide (49.0 mg, 0.154 mmol) and 1H-imidazole (52.3 mg, 0.768 mmol). The resulting mixture was stirred at 100 °C for 8 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The crude residue was purified by gradient column chromatography using 0-10% methanol in dichloromethane and then by preparative HPLC to give 6-(2-hydroxy-2-methylpropoxy)-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (0.03 g, yield %) as an off-white solid.

[0573]

[0401] Preparative conditions · Column: Inertsil C18, (20 mm × 250 mm × 5 mic) · Mobile phase (A): 0.1% ammonia in water · Mobile phase (B): Acetonitrile · Flow rate: 19 mL / min · Gradient B: 0 / 8%, 9 - 14 / 55%, 15 - 20 / 90%, 22 - 25 / 10%.

[0574]

[0402] Table 20 provides the characterization data of the compound of formula I prepared by the method shown in Example 20.

[0575]

Table 20

[0576] Example 21 Synthesis of Compound 79

[0577] [Chemical formula]

[0578] Step - 1: 6-(Methylthio)-N-(pyridin-4-yl)pyrimido[5,4-d]pyrimidin-4-amine

[0579] [Chemical formula]

[0580]

[0403] To a stirred solution of 8-chloro-2-(methylsulfanyl)-[1,3]diazino[5,4-d]pyrimidine (300 mg, 1.41 mmol) in DMF, pyridin-4-amine (119 mg, 0.9 equivalent, 1.27 mmol) and cesium(1+) carbonate (689 mg, 1.5 equivalents, 2.12 mmol) were added. The reaction mixture was heated to 100 °C for 3 hours. The reaction mixture was cooled to room temperature and evaporated completely to give a crude compound, which was purified by silica gel flash column chromatography. The compound was eluted with 5% MeOH:DCM. The fractions were evaporated to give crude N-[6-(methylsulfanyl)-[1,3]diazino[5,4-d]pyrimidin-4-yl]pyridin-4-amine (200 mg, 740 μmol) as a yellow solid. LCMS (ES) m / z = 271.1 [M+H]+ Step - 2: N-{6-Methanesulfinyl-[1,3]diazino[5,4-d]pyrimidin-4-yl}pyridin-4-amine

[0581] [Chemical formula]

[0582]

[0404] To a stirred solution of N-[6-(methylsulfanyl)-[1,3]diazino[5,4-d]pyrimidin-4-yl]pyridin-4-amine (200 mg, 740 μmol) in DCM, 3-chlorobenzenecarboperoxy acid (255 mg, 2 equivalents, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give crude N-{6-methanesulfinyl-[1,3]diazino[5,4-d]pyrimidin-4-yl}pyridin-4-amine (180 mg, 629 μmol) as an oily compound. LCMS (ES) m / z = 287.1 [M+H]+ Step-4: 6-(1H-imidazol-1-yl)-N-(pyridin-4-yl)pyrimido[5,4-d]pyrimidin-4-amine

[0583]

Chemical formula

[0584]

[0405] To a stirred solution of N-{6-methanesulfinyl-[1,3]diazino[5,4-d]pyrimidin-4-yl}pyridin-4-amine (200 mg, 699 μmol) in NMP, ethylbis(propan-2-yl)amine (579 μL, 5 equivalents, 3.49 mmol) was added, followed by 6-(1H-imidazol-1-yl)-N-phenyl-[1,3]diazino[5,4-d]pyrimidin-4-amine (10.0 mg, 34.6 μmol). The reaction mixture was heated at 60 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give a crude product, which was purified by silica gel flash column chromatography. The compound was eluted as a mixture with 5% MeOH:DCM. The fractions were evaporated to give a crude product, which was repurified by preparative TLC. The silica gel band was collected and passed through a 4 g silica gel column. The fractions were evaporated to give the final compound as an off-white solid.

[0585]

[0406] What is provided in Table 21 are the characterization data of the compound of Formula I prepared by the method shown in Example 21.

[0586]

Table 21

[0587] Example 22 Heteroaryl amide derivative

[0407] What is provided in Table 22 are the characterization data of the compound of Formula I.

[0588]

Table 22-1

[0589]

Table 22-2

[0590] Example 23 Fluorescence-based NAD+ hydrolase activity assay (Assay 1) using the human T cell line NH7-dCas9 cells - Jurkat clone

[0408] The following protocol was modified from the following references: de Oliveira et al. (2018). Bio. Protoc. 8(14). doi:10.21769 / BioProtoc.2938; Matalonga et al. (2017) Cell Rep. 18(5), 1241-1255; doi:10.1016 / j.celrep.2017.01.007; Muller et al. (1983) Biochem J. 212(2), 459-464. doi:10.1042 / bj2120459; Schultzet et al. (2018). Meth. Mol. Bio. 1813, 77-90. doi:10.1007 / 978-1-4939-8588-3_6.

[0591]

[0409] For the modified assay, assay performance verification criteria as high-throughput screening (HTS): The Z-value (z-factor) within the plate was greater than 0.89 (optimal HTS z-value > 0.5), and the variation (CV) within the plate, between plates, and daily was less than 20%.

[0592]

[0410] The NAD+ hydrolase activity of human T cell lines treated with test compounds was measured using a fluorescence-based assay. NH7-dCas9 cells (Jurkat clone) were provided by the Weissman Lab (UCSF 1700 4th St., Byers Hall, Room 403B, San Francisco, CA 94158-2330). Briefly, the cells were centrifuged and resuspended in 44 μl of PBS / 10 6 cells and plated at a density of 1×10 6 per well in a 96-well black plate (CORNING).

[0593]

[0411] Each test compound was received in a powdered state and dissolved in DMSO as a 25 mM stock solution. To create a dose-response curve, each test compound was serially diluted. The dilution series of each test compound in DMSO was prepared at 50-fold the concentration to be assayed. To assay eight final concentrations in the range of 400 nM to 25.6 pM, each test compound was diluted to generate a 5-fold dilution series of eight concentrations from 20 μM to 0.256 nM. To each well of the plate containing 1×10 6 cells in PBS, 1 μl of the 50× concentration compound series was added.

[0594]

[0412] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 50 nM, and two wells containing PBS only (used as background values).

[0595]

[0413] Nicotinamide 1,N 6The reaction was initiated by adding etheno-adenine dinucleotide (Sigma Aldrich) to reach a final concentration of 80 μM. The samples were excited at 321–15 nm, and fluorescence emission was measured at 410–20 nm for 1 h at 37 °C per minute in a Clariostar® microplate reader (BMG LABTECH). NAD+ hydrolase activity was calculated as the slope of the linear part of the fluorescence time curve using MARS data analysis software (BMG LABTECH). The data were uploaded to Collaborative Drug Design (CDD) software, and the IC50 of each compound was calculated by the software. To establish the reproducibility of the results, each compound was tested in three independent experiments on three separate days. For each plate, the z-value was also calculated as the plate quality using CDD software.

[0596] Example 24 Fluorescence-based NAD+ cyclase activity assay using human recombinant CD38 protein (Assay 2)

[0414] This protocol was modified from de Oliveira et al., 2018 reference, supra.

[0597]

[0415] The NAD+ cyclase activity of 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 μl / well of sucrose-Tris buffer (sucrose 0.25 M, Tris pH 7.4 40 mM) and plated at a density of 125 ng / well in a 96-well black plate (CORNING).

[0598]

[0416] Each test compound was received in a powdered state and dissolved in DMSO as a 25 mM stock solution. To create a dose-response curve, each test compound was serially diluted. A dilution series of each test compound in DMSO was prepared at 50-fold the concentration to be assayed. To assay eight final concentrations in the range of 2 μM to 0.64 nM, each test compound was diluted to generate a 5-fold dilution series of eight concentrations from 100 μM to 32 nM. 1 μl of the 50× concentration compound series was added to each well of a plate containing 125 ng of protein in sucrose-Tris buffer.

[0599]

[0417] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 500 nM, and two wells containing sucrose-Tris buffer only (used as background values).

[0600]

[0418] The reaction was initiated by adding nicotinamide guanine dinucleotide (NGD+)(Sigma Aldrich) to reach a final concentration of 150 μM. The samples were excited at 337 - 15 nm, and fluorescence emission was measured at 442 - 20 nm for 1 hour at 37 °C per minute in a Clariostar microplate reader (BMG LABTECH). Using MARS data analysis software (BMG LABTECH), NAD+ cyclase activity was calculated as the slope of the linear portion of the fluorescence time curve. The data was uploaded to Collaborative Drug Design (CDD) software, and the IC50 of each compound was calculated by the software. For each plate, the z-value was also calculated as the quality of the plate using CDD software.

[0601] Example 25 Fluorescence-based NAD+ hydrolase activity assay using human recombinant CD38 protein (Assay 3)

[0419] 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, see above).

[0602]

[0420] For the modified assay, assay performance verification criteria as high-throughput screening (HTS): The Z-value (z-factor) within the plate was greater than 0.9 (optimal HTS z-value > 0.5), and the variation (CV) within the plate, between plates, and daily was less than 20%.

[0603]

[0421] The NAD+ hydrolase activity of 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 μl / well of sucrose-Tris buffer (0.25 M sucrose, 40 mM Tris pH 7.4) and plated at a density of 10 ng / well in a 96-well black plate (CORNING).

[0604]

[0422] Each test compound was received in powder form and dissolved in DMSO as a 25 mM stock solution. To create a dose-response curve, each test compound was serially diluted. The dilution series of each test compound in DMSO was prepared at 50× the concentration to be assayed. To assay eight final concentrations in the range of 400 nM to 25.6 pM, each test compound was diluted to generate a 5-fold dilution series of eight concentrations from 20 μM to 0.256 nM. 1 μl of the 50× concentration compound series was added to each well of the plate containing 10 ng of protein in sucrose-Tris buffer.

[0605]

[0423] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 50 nM, and two wells containing sucrose-Tris buffer only (used as background value).

[0606]

[0424] Nicotinamide 1,N 6 -etheno-adenine dinucleotide (Sigma Aldrich) was added to initiate the reaction, reaching a final concentration of 80 μM. Samples were excited at 321–15 nm, and fluorescence emission was measured at 410–20 nm for 1 h at 37 °C per minute 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 MARS data analysis software (BMG LABTECH). The data was uploaded to Collaborative Drug Design (CDD) software, and the IC50 of each compound was calculated by the software. To establish the reproducibility of the results, each compound was tested in three independent experiments on three separate days. For each plate, the z-value was also calculated as the plate quality using CDD software.

[0607] Example 26 Fluorescence-based NAD+ cyclase activity assay using mouse recombinant CD38 protein (Assay 4)

[0425] This protocol was modified from de Oliveira et al., (2018), supra.

[0608]

[0426] The NAD+ cyclase activity of human 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 μl / well of sucrose–Tris buffer (sucrose 0.25 M, Tris pH 7.4 40 mM) and plated at a density of 32 ng / well in a 96-well black plate (CORNING).

[0609]

[0427] Each test compound was received in a powdered state and dissolved in DMSO as a 25 mM stock solution. To create a dose-response curve, each test compound was serially diluted. A dilution series of each test compound in DMSO was prepared at 50-fold the concentration to be assayed. To assay eight final concentrations in the range of 2 μM to 0.64 nM, each test compound was diluted to generate a 5-fold dilution series of eight concentrations from 100 μM to 32 nM. 1 μl of the 50× concentration compound series was added to each well of a plate containing 125 ng of protein in sucrose-Tris buffer.

[0610]

[0428] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 500 nM, and two wells containing sucrose-Tris buffer only (used as background values).

[0611]

[0429] The reaction was initiated by adding nicotinamide guanine dinucleotide (NGD+)(Sigma Aldrich) to reach a final concentration of 150 μM. The samples were excited at 337 - 15 nm and fluorescence emission was measured at 442 - 20 nm for 1 hour at 37 °C per minute in a Clariostar® microplate reader (BMG LABTECH). Using MARS data analysis software (BMG LABTECH), NAD+ cyclase activity was calculated as the slope of the linear portion of the fluorescence time curve. The data was uploaded to Collaborative Drug Design (CDD) software and the IC50 of each compound was calculated by the software. To establish the reproducibility of the results, each compound was tested in three independent experiments on three separate days. For each plate, the z-value was also calculated as the plate quality using CDD software.

[0612] Example 27 Fluorescence-based NAD+ hydrolase activity assay using mouse recombinant CD38 protein (Assay 5)

[0430] 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), supra.

[0613]

[0431] The NAD+ hydrolase activity of recombinant mouse 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 μl / well of sucrose-Tris buffer (0.25 M sucrose, 40 mM Tris pH 7.4) and plated at a density of 2.5 ng / well in a 96-well black plate (CORNING).

[0614]

[0432] Each test compound was received in a powdered state and dissolved in DMSO as a 25 mM stock solution. To generate a dose-response curve, each test compound was serially diluted. A dilution series of each test compound in DMSO was prepared at 50-fold the concentration to be assayed. To assay eight final concentrations in the range of 400 nM to 25.6 pM, each test compound was diluted to generate a 5-fold dilution series of eight concentrations from 20 μM to 0.256 nM. 1 μl of the 50× concentration compound series was added to each well of the plate containing 2.5 ng of protein in sucrose-Tris buffer.

[0615]

[0433] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 50 nM, and two wells containing sucrose-Tris buffer only (used as background values).

[0616]

[0434] Nicotinamide 1,N 6-Etheno-adenine dinucleotide (Sigma Aldrich) was added to initiate the reaction, reaching a final concentration of 80 μM. The samples were excited at 321 - 15 nm, and fluorescence emission was measured at 410 - 20 nm for 1 hour at 37 °C per minute in a Clariostar® microplate reader (BMG LABTECH). Using MARS data analysis software (BMG LABTECH), NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence time curve. The data was uploaded to Collaborative Drug Design (CDD) software, and the IC50 of each compound was calculated by the software. To establish the reproducibility of the results, each compound was tested in three independent experiments on three separate days. For each plate, the z-value was also calculated as the plate quality using CDD software.

[0617] Example 28 Fluorescence-based NAD+ hydrolase activity assay using recombinant rat CD38 protein (Assay 6)

[0435] 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), supra.

[0618]

[0436] The NAD+ hydrolase activity of recombinant rat CD38 protein treated with test compounds was measured using a fluorescence-based assay. Briefly, recombinant rat CD38 protein (Sino Biological) was resuspended in 44 μl / well of sucrose-Tris buffer (sucrose 0.25 M, Tris pH 7.4 40 mM) and plated at a density of 2.5 ng / well in a 96-well black plate (CORNING).

[0619]

[0437] Each test compound was received in a powdered state and dissolved in DMSO as a 25 mM stock solution. To generate a dose-response curve, each test compound was serially diluted. The dilution series of each test compound in DMSO was prepared at 50-fold of the concentrations to be assayed. To assay eight final concentrations in the range of 400 nM to 25.6 pM, each test compound was diluted to generate a five-fold dilution series of eight concentrations from 20 μM to 0.256 nM. To each well of a plate containing 2.5 ng of protein in sucrose-Tris buffer, 1 μl of the 50× concentration compound series was added.

[0620]

[0438] Each plate had the following in-plate controls: three wells containing cells treated with vehicle only (DMSO), three wells of cells treated with the reference compound 78c at a final concentration of 50 nM, and two wells containing sucrose-Tris buffer only (used as background values).

[0621]

[0439] Nicotinamide 1,N 6 -etheno-adenine dinucleotide (Sigma Aldrich) was added to initiate the reaction to reach a final concentration of 80 μM. The samples were excited at 321 - 15 nm and the fluorescence emission was measured at 410 - 20 nm for 1 hour at 37 °C per minute in a Clariostar® microplate reader (BMG LABTECH). Using MARS data analysis software (BMG LABTECH), the NAD+ hydrolase activity was calculated as the slope of the linear part of the fluorescence time curve. The data was uploaded to Collaborative Drug Design (CDD) software and the IC50 of each compound was calculated by the software. To establish the reproducibility of the results, each compound was tested in three independent experiments on three separate days. For each plate, the z-value was also calculated as the quality of the plate using CDD software.

[0622]

[0440] The compounds according to the present disclosure are potent inhibitors of CD38 and are themselves active in the treatment of a number of disorders. The compounds according to the present disclosure that were tested had the following activities in the aforementioned assays (Assays 1-6). The results are shown in Table 23.

[0623]

Table 23-1

[0624]

Table 23-2

[0625]

Table 23-3

[0626] Example 29 In vitro functional potency of Compound 35 against CD38 hydrolase activity in primary human cells (immune cells and hepatocytes) (Assay 7)

[0441] The in vitro potency of Compound 35 against the human CD38 enzyme was determined using the NAD+ analog nicotinamide 1,N as a substrate. 6Determined by a fluorescence-based NAD+ hydrolase activity assay using ε-NAD+-etheno-adenine dinucleotide (εNAD+). Assays utilized: I) all primary human CD4+ T cells (from healthy donors) activated with anti-CD3 / CD28 antibodies and expressing human CD38; or II) all primary human macrophages (from healthy donors) stimulated with LPS to polarize into the inflammatory M1 state and expressing human CD38. Cells were incubated for 10 minutes in the presence of eight different concentrations of Compound 35, and the reaction was initiated by addition of the substrate εNAD+. Fluorescence emission was measured at 410 - 20 nm at 37 °C for 1 hour per minute. NAD+ hydrolase activity was calculated as the slope of the linear portion of the fluorescence time curve and used to calculate the IC50 value. The IC50 value of Compound 35 was 0.18 nM (0.065 ng / mL) in primary human CD4+ T cells (see Figure 1A) and 2.25 nM (0.817 ng / mL) in primary human M1 macrophages (see Figure 1B).

[0627]

[0442] To investigate the effect of the molecule on the pathophysiological phenotypes of NASH such as the release of inflammatory markers, the efficacy of Compound 35 was also determined in a NASH model (see InSphero Human 3D InSight™ Brunswick, ME). The microtissue model used was a co-culture of four different cell types of human hepatocytes (hepatocytes, Kupffer cells, endothelial, and stellate cells) cultured for 10 days in NASH-inducing medium containing FFA, LPS, and high levels of sugar. In the LEAN group, the microtissues were cultured in physiological medium for 10 days. The reference compound, the selective ASK1 inhibitor ceroncertib, was used as a downregulator of inflammatory markers. Release of cytokines and chemokines in the supernatant was measured on day 5 using the Magnetic Luminex® assay (R&D Systems). The results of the pharmacological inhibition of CD38 by Compound 35 show its efficacy in downregulating the release of NASH-inducing inflammatory markers such as IP-10 / CXCL-10 (Figure 2A), IL-8 (Figure 2B), MIP-1α / CCL3 (Figure 2C), and TNFα (Figure 2D).

[0628] Example 30 In Vivo Efficacy of Compound 35 Against CD38 in Aged Mice

[0443] The in vivo efficacy of compound 35 against human CD38 enzyme was tested in aged mice after oral administration, and determined by mass spectrometry of NAD+ metabolite levels in liver tissues. Two major CD38 substrates, NAD+ and NMN, and two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0629]

[0444] Briefly, aged mice (male C57BL6 / J, 22 months old) were fasted for 4 hours and compound 35 was force-fed orally at concentrations of 3 mg / kg and 10 mg / kg. Mice were humanely euthanized at 1, 3, and 6 hours after dosing to collect liver tissues. A vehicle control (DMSO:Solutol:SBE-CD, 2:5:93, v / v) was included to evaluate baseline NAD+ metabolite levels.

[0630]

[0445] The tissue sample preparation procedure and UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Briefly, frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol:10 mM HEPES aqueous solution, pH 7.1). Samples were vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Samples were then centrifuged at 16,000 xg at 4 °C for 10 minutes and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 xg at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0631]

[0446] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1x100mm, particle size 5μm, Thermo) column according to the method described by Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted Single Reaction Monitoring (t-SIM). For data processing, Thermo Xcalibur QualBrowser system software (version 4.2.47) and Freestyle (version 1.8.51.0) software were used. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue samples used, and calculated as fold changes relative to the 0-hour time point / vehicle group.

[0632]

[0447] Oral administration of a single 3 mg / kg dose of Compound 35 was able to increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figures 3A - 3B). Oral administration of a single 10 mg / kg dose of Compound 35 was able to increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figures 4A - 4B).

[0633] Example 31 In vitro efficacy of Compound 32 against CD38

[0448] The in vitro potency of compound 32 against human CD38 enzyme was determined by a fluorescence-based NAD+ hydrolase activity assay using the NAD+ analog nicotinamide 1,N6-etheno-adenine dinucleotide (εNAD+) as a substrate. In the assay, total primary human macrophages (derived from healthy donors) polarized to the inflammatory M1 state expressing human CD38 were utilized and stimulated with LPS. The cells were incubated for 10 minutes in the presence of eight different concentrations of compound 32, and the reaction was initiated by adding the substrate εNAD+. Fluorescence emission was measured at 410 - 20 nm at 37 °C for 1 hour per minute. The NAD+ hydrolase activity was calculated as the slope of the linear part of the fluorescence time curve and used to calculate the IC50 value. The IC50 value of compound 32 was 3.5 nM (1.36 ng / mL) in primary human M1 macrophages (see Figure 5).

[0634] Example 32 In Vivo Efficacy of Compound 32 against CD38 in Obese Mice

[0449] The in vivo efficacy of compound 32 against human CD38 enzyme was tested in obese mice after oral administration and determined by mass spectrometry (MS) of NAD+ metabolite levels in liver tissue. The two major CD38 substrates NAD+ and NMN, and the two major by-products of the CD38 enzyme reaction NAM and ADPR were measured.

[0635]

[0450] Obese mice (male DIO C57BL6 / J, 7.5 months old) were fasted for 4 hours and force-fed compound 32 at concentrations of 3 mg / kg and 10 mg / kg. The mice were humanely euthanized at 1, 3, and 6 hours after dosing to collect liver tissue. A vehicle control (DMSO:Solutol HS 15:80% Captisol (20% in water) (5:15:80 v / v)) was included to evaluate the baseline NAD+ metabolite levels.

[0636]

[0451] The procedure for tissue sample preparation and the UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol:10 mM aqueous HEPES, pH 7.1). The sample was vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the sample was centrifuged at 16,000 xg at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 xg at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0637]

[0452] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1x100 mm, particle size 5 μm, Thermo) column according to the method described by Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted single reaction monitoring (t-SIM). Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used for data processing. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue sample used, and calculated as the fold change relative to the 0-hour time point / vehicle group.

[0638]

[0453] Oral administration of a single dose of 3 mg / kg of Compound 32 was able to increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figs. 6B - 6E). Oral administration of a single dose of 10 mg / kg of Compound 32 was able to significantly increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver 1 hour after administration (Figs. 6B - 6E).

[0639] Example 33 In Vivo Efficacy of Compound 32 against CD38 in Obese Mice

[0454] The in vivo efficacy of Compound 32 against the human CD38 enzyme was tested in obese mice after oral administration, and determined by mass spectrometry (MS) of NAD+ metabolite levels in liver tissue. Two major CD38 substrates, NAD+ and NMN, and two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0640]

[0455] Obese mice (male DIO C57BL6 / J, 65 weeks old) were treated with Compound 32 by forced oral administration at a concentration of 10 mg / kg for 49 days. On day 49, the mice were humanely euthanized to collect liver tissue 4 hours after administration. A vehicle control (1% methylcellulose) was included to evaluate baseline NAD+ metabolite levels.

[0641]

[0456] The procedures for tissue sample preparation and the UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol: 10 mM aqueous HEPES solution, pH 7.1). The sample was vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the sample was centrifuged at 16,000 x g at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 x g at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0642]

[0457] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1 x 100 mm, particle size 5 μm, Thermo) column according to the method described in Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted single reaction monitoring (t-SIM). Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used for data processing. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue sample used, and calculated as fold change relative to the 0-hour time point / vehicle group.

[0643]

[0458] In obese mice, the levels of NAM and ADPR in the liver were significantly decreased by twice-daily administration of compound 32 at 10 mg / kg for a long term (Figs. 7A-7D).

[0644] Example 34 In vivo efficacy of compound 32 against CD38 in aged mice

[0459] The in vivo efficacy of compound 32 against human CD38 enzyme was tested in aged mice after oral administration, and determined by mass spectrometry (MS) of NAD+ metabolite levels in liver tissues. Two major CD38 substrates, NAD+ and NMN, and two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0645]

[0460] Aged mice (male DIO C57BL6 / J, 19-22 months old) were force-fed compound 32 at concentrations of 3 mg / kg and 10 mg / kg for 5 days. On the 5th day, the mice were humanely euthanized to collect liver tissues 3 hours after administration. A vehicle control (DMSO:Solutol HS 15:80% Captisol (20% in water) (5:15:80 v / v)) was included to evaluate the baseline NAD+ metabolite levels.

[0646]

[0461] The procedure for tissue sample preparation and the UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol: 10 mM aqueous HEPES, pH 7.1). The samples were vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the samples were centrifuged at 16,000 x g at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 x g at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0647]

[0462] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1 x 100 mm, particle size 5 μm, Thermo) column according to the method described in Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted Single Reaction Monitoring (t-SIM). For data processing, Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue samples used, and calculated as fold changes relative to the 0-hour time point / vehicle group.

[0648]

[0463] Long-term administration of compound 32 at 3 mg / kg and 10 mg / kg was able to significantly increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figs. 8A - 8D).

[0649] Example 35 In vitro efficacy of compound 39 against CD38

[0464] The in vitro potency of compound 39 against the human CD38 enzyme was determined by a fluorescence-based NAD+ hydrolase activity assay using the NAD+ analog nicotinamide 1,N6-etheno-adenine dinucleotide (εNAD+) as a substrate. In the assay, whole primary human macrophages (derived from healthy donors) stimulated with LPS to polarize into the inflammatory M1 state expressing human CD38 were utilized. The cells were incubated for 10 minutes in the presence of eight different concentrations of compound 39, and the reaction was initiated by adding the substrate εNAD+. Fluorescence emission was measured at 410 - 20 nm at 37 °C for 1 hour per minute. NAD+ hydrolase activity was calculated as the slope of the linear part of the fluorescence time curve and used to calculate the IC50 value. The IC50 value of compound 39 was 3.9 nM (1.6 ng / mL) in primary human M1 macrophages (see Fig. 9).

[0650] Example 36 In vivo efficacy of compound 39 against CD38 in obese mice

[0465] The in vivo efficacy of compound 39 against the human CD38 enzyme was tested in obese mice after oral administration and determined by mass spectrometry of NAD+ metabolite levels in liver tissue. The two major CD38 substrates, NAD+ and NMN, and the two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0651]

[0466] Obese mice (male DIO C57BL6 / J, 7.5 months old) were fasted for 4 hours, and compound 39 was administered orally by gavage at concentrations of 1 mg / kg and 10 mg / kg. The mice were humanely euthanized at 1, 3, and 6 hours after administration to collect liver tissue. To assess baseline NAD+ metabolite levels, a vehicle control (DMSO:Solutol HS 15:80% Captisol (20% in water) (5:15:80 v / v)) was included.

[0652]

[0467] The tissue sample preparation procedure and UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol:10 mM HEPES aqueous solution, pH 7.1). The samples were vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the samples were centrifuged at 16,000 xg at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 xg at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0653]

[0468] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1x100mm, particle size 5μm, Thermo) column according to the method described by Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted Single Reaction Monitoring (t-SIM). For data processing, Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue samples used, and calculated as fold changes relative to the 0-hour time point / vehicle group.

[0654]

[0469] Single oral administrations of 1 mg / kg and 10 mg / kg doses of Compound 39 were able to increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figures 10A - 10D).

[0655] Example 37 In Vivo Efficacy of Compound 39 Against CD38 in Obese Mice

[0470] The in vivo efficacy of Compound 39 against the human CD38 enzyme was tested in obese mice after oral administration and determined by mass spectrometry of NAD+ metabolite levels in liver tissue. Two major CD38 substrates, NAD+ and NMN, and two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0656]

[0471] Obese mice (male DIO C57BL6 / J, 65 weeks old) were treated by gavage with compound 39 at a concentration of 10 mg / kg for 49 days. On day 49, the mice were humanely euthanized 4 hours after dosing to collect liver tissue. A vehicle control (1% methylcellulose) was included to evaluate baseline NAD+ metabolite levels.

[0657]

[0472] The tissue sample preparation procedure and UPLC-MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol: 10 mM aqueous HEPES, pH 7.1). The samples were vortexed, sonicated briefly in a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the samples were centrifuged at 16,000 x g at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 x g at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0658]

[0473] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was carried out on a Hypercarb (2.1x100mm, particle size 5μm, Thermo) column according to the method described by Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted Single Reaction Monitoring (t-SIM). For data processing, Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used. For relative fold changes, peak areas were normalized to their respective internal standards and to the weight of the tissue samples used, and calculated as fold changes relative to the 0-hour time point / vehicle group.

[0659]

[0474] Long-term administration of 10 mg / kg of Compound 39 in obese mice was able to significantly increase NAD+ and NMN levels and decrease NAM and ADPR levels in the liver (Figures 11A - 11D).

[0660] Example 38 In Vivo Efficacy of Compound 39 against CD38 in Aged Mice

[0475] The in vivo efficacy of Compound 39 against the human CD38 enzyme was tested in aged mice after oral administration and determined by mass spectrometry of NAD+ metabolite levels in liver tissue. Two major CD38 substrates, NAD+ and NMN, and two major by-products of the CD38 enzyme reaction, NAM and ADPR, were measured.

[0661]

[0476] Aged male DIO C57BL6 / J mice (19 - 22 months old) were orally administered compound 39 at a concentration of 10 mg / kg for 5 days. On the 5th day, the mice were humanely euthanized 3 hours after administration to collect liver tissue. A vehicle control (DMSO:Solutol HS 15:80% Captisol (20% in water) (5:15:80 v / v)) was included to evaluate the baseline NAD+ metabolite levels.

[0662]

[0477] The tissue sample preparation procedure and UPLC - MS / MS method were adapted from Trammell et al. (2013) Compu. Struct. Biotechnol. J. 20:4 (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3962138 / ). Frozen liver tissue was pulverized and resuspended in extraction buffer (3:1 ethanol:10 mM HEPES aqueous solution, pH 7.1). The sample was vortexed, sonicated briefly with a bath sonicator, and shaken at 55 °C at 1,200 rpm for 3 minutes. Next, the sample was centrifuged at 16,000 xg at 4 °C for 10 minutes, and the supernatant was dried by speedvac. The dried pellet was resuspended in 97% 10 mM ammonium acetate / 3% acetonitrile, centrifuged at 16,000 xg at 4 °C for 10 minutes, and 2 μL was injected for LCMS analysis.

[0663]

[0478] UPLC-MS / MS analysis for measuring NAD+ metabolites was performed using both a Vanquish UHPLC system equipped with an H-ESI ion source from Thermo Scientific and a Q Exactive Orbitrap mass spectrometer. UPLC separation was performed on a Hypercarb (2.1x100 mm, particle size 5 μm, Thermo) column according to the method described by Trammell et al. (2013). Acquisition was performed in positive ion, parallel reaction monitoring (PRM) mode, and targeted Single Reaction Monitoring (t-SIM). For data processing, Thermo Xcalibur QualBrowser system (version 4.2.47) and Freestyle (version 1.8.51.0) software were used. For relative fold changes, peak areas were normalized to their respective internal standards, normalized to the weight of the tissue samples used, and calculated as fold changes relative to the 0-hour time point / vehicle group.

[0664]

[0479] Long-term administration of 10 mg / kg of Compound 39 was able to increase NAD+ levels and decrease NAM and ADPR levels in the liver (Figures 12A - 12D).

[0665] Example 39 In vivo efficacy of Compound 39 against CD38 in mice after LPS-induced inflammation

[0480] The in vivo efficacy of Compound 39 against the human CD38 enzyme was evaluated after LPS challenge. The effects of Compound 39 (10 mg / kg and 30 mg / kg) on inflammatory cytokines, inflammatory markers, and NAD+ levels were evaluated at 4 and 8 hours after LPS-induced inflammation in 12-week-old male C57BL / 6J mice.

[0666]

[0481] In this study, (1) the animals showed normal behavior (appearance, behavior, posture, respiratory rate and pattern), normal urination and defecation throughout the study and showed no signs of distress; (2) no changes in feces and / or urine were observed; and (3) there were normal signs of distress observed by gentle handling during the forced oral administration procedure. The animals were euthanized by terminal CO2 immediately followed by terminal cardiac puncture 4 and 8 hours after LPS administration. At necropsy, tissues (liver, plasma, spleen, kidney, lung, heart, visceral adipose tissue, muscle - gastrocnemius) were collected and snap - frozen in liquid nitrogen. Blood was collected into BD Microtainer® tubes with K2EDTA additive, centrifuged at 1000 g for 10 minutes at 4 °C, and plasma was stored at - 80 °C). Quantification of cytokines in plasma

[0482] Cytokines in plasma were quantified: (1) a statistically significant decrease in plasma IL - 6, TNFα, and IP - 10 8 hours after LPS challenge in two compound 39 treatment groups (10 mg / kg and 30 mg / kg); (2) a statistically significant decrease in plasma IP - 10 4 hours after LPS challenge in two compound 39 treatment groups (10 mg / kg and 30 mg / kg) and the control group (dexamethasone 1 mg / kg); (3) a 43% and 75% decrease in plasma IL - 6 respectively 4 hours after LPS challenge with compound 39 at 10 mg / kg and 30 mg / kg; (4) a 22% and 58% decrease in plasma TNFα respectively 4 hours after LPS challenge with compound 39 at 10 mg / kg and 30 mg / kg; and (5) a statistically significant decrease in plasma IL - 6, TNFα and IP - 10 4 hours after LPS challenge in the control group (dexamethasone 1 mg / kg) (Figures 13A - 13C). MS analysis of NAD+ metabolism

[0483] NAD+ metabolism in the spleen was evaluated using mass spectrometry (MS): an increase in NAD+ levels (2.3 - fold) and a statistically significant decrease in ADPR levels (40% decrease) were o...

Claims

1. The compound of formula I 【Chemical 1】 or a pharmaceutically acceptable salt thereof, or Formula I ＊ ​ the compound of formula (wherein, When the compound is of formula I, -X-Y-Z- is =CR １ -CR ２ =CR ３ -, =N-CR ２ =CR ３ -, =CR １ -N=CR ３ - or =CR １ -CR ２ =N; when the compound is of formula I ＊ of, -X-Y-Z- is CR １ -CR ２ =C, N-CR ２ =C, or CR １ -N=C; R １ is selected from the group consisting of H, halo, -CN, (C １ ~C ６ alkyl, (C １ ~C ６ alkoxy, and perfluoro(C １ ~C ６ alkoxy-; (C １ ~C ６ alkyl is independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ alkyl, -NH ２ , (C １ ~C ３ alkyl-(NH)-, ((C １ ~C ３ alkyl)) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ２ is H, halo, -CN, (C １ ~C ６ alkyl, (C １ ~C ６ alkoxy, and perfluoro(C １ ~C ６ alkyl, perfluoro(C １ ~C ６ alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R ５ -(C(R ４ )) ２ )) ｎ -O- or (R ６ )) ２ N-; (C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, and aryl are each H, halo, -CN, (C １ ~C ３ alkyl, -NH ２ , (C １ ~C ３ alkyl-(NH)-, ((C １ ~C ３ alkyl)) ２ N-, -CF ３ , -OCH ３ and -OCF ３ may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ３ is H, halo, (C １ ~C ３ )alkyl, -CF ３ , (C １ ~C ３ )alkoxy, -OCF ３ or (R ７ ) ２ N-, and R ７ is H or (C １ ~C ３ )alkyl; n is an integer from 1 to 3; Each R ４ is independently H or (C １ ~C ３ )alkyl; (C １ ~C ３ )alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; R ５ is selected from the group consisting of (C １ to C ３ )alkyl, perfluoro(C １ to C ３ )alkyl, HO-(C ２ to C ４ )alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C １ to C ３ )alkyl, cycloalkyl, heterocycloalkyl, and aryl are each independently substituted with 1 to 3 substituents selected from the group consisting of H, halo, -CN, (C １ to C ３ )alkyl, -NH ２ , (C １ to C ３ )alkyl-(NH)-, ((C １ to C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; and may be optionally substituted; R ６ is independently H or (C １ ~C ３ )-alkyl; (C １ ~C ３ )-alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )-alkyl, -NH ２ , (C １ ~C ３ )-alkyl-(NH)-, ((C １ ~C ３ )-alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; W is [Chemical Formula 3] and R ８ is H, -CH ３ or -CF ３ ; Het is a heterocyclic ring of formula [Chemical Formula 4] ; Each R ９ is independently selected from H, halo, (C １ ~C ６ )alkyl, -CF ３ , (C １ ~C ６ )alkoxy, -OCF ３ , -CN, (R １１ ) ２ N-, R １２ (O)(C=O)-, R １２ O((C １ ~C ３ )alkyl)-(NR １１ ), R １３ -(C=O)-(NR １１ )-and (R １１ ) ２ N-(C=O)-; Each R １０ is independently selected from H, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ , -CN, (R １１ ) ２ N-, R １２ (O)(C=O)-, R １２ O-((C １ ~C ３ )alkyl)-(NR １１ ), R １３ -(C=O)-(NR １１ ), and (R １１ ) ２ N-(C=O); R １１ is independently H or (C １ ~C ３ ) alkyl; R １２ is H or (C １ ~C ３ ) alkyl; R １３ is (C １ to C ３ ) alkyl)

2. The compound according to claim 1, wherein Het is the ring of the said formula i 【Chemical Formula 5】 .

3. The compound according to claim 1, wherein Het is the ring of the said formula ii 【Chemical Formula 6】 .

4. The compound according to claim 1, wherein Het is the ring of the said formula iii 【Chemical Formula 7】 .

5. The compound according to claim 1, wherein Het is the ring of the said formula iv 【Chemical Formula 8】 .

6. The compound according to claim 1, wherein Het is the ring of the said formula v 【Chemical Formula 9】 .

7. The compound according to claim 1, wherein Het is the ring of the said formula vi 【Chemical Formula 10】 .

8. The compound according to claim 1, wherein Het is the ring of the said formula vii 【Chemical 11】 .

9. The compound according to claim 1, wherein Het is the ring of the said formula viii 【Chemical 12】 .

10. The compound according to claim 1, wherein Het is the ring of the said formula ix 【Chemical 13】 .

11. Compound of formula I or II ＊ In the compounds of ８ wherein R ３ is -CH ３ or -CF and W is of formula (a) 【Chemical Formula 14】 The compound according to any one of claims 1 to 10, which is the said compound of

12. Compound of formula I or II ＊ In the compound of ８ R is -CH ３ or -CF ３ and W is of formula (b) 【Chemical Formula 15】 The compound according to any one of claims 1 to 10, which is the said compound of

13. Compound of formula I or II ＊ In the compound of, R ８ is -CH ３ or -CF ３ and W is of formula (c) 【Chemical Formula 16】 The compound according to any one of claims 1 to 10, which is the said compound of

14. Compound of formula I or II ＊ In the compound of, R ８ is -CH ３ or -CF ３ and W is of formula (d) 【Chemical 17】 The compound according to any one of claims 1 to 10, which is the said compound of

15. Compound of formula I or II ＊ in which R ８ is -CH ３ or -CF ３ and; The compound according to any one of claims 1 to 10, wherein W is the said compound of formula (e) 【Chemical Formula 18】 .

16. Compound of formula I or II ＊ in which R ８ is -CH ３ or -CF ３ and; The compound according to any one of claims 1 to 10, wherein W is the said compound of formula (f) 【Chemical Formula 19】 .

17. R １ is selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -OCH ３ , and -OCF ３ The compound according to any one of claims 1 to 16

18. R ２ is selected from the group consisting of H, (C １ ~C ６ )alkyl, (C １ ~C ６ )alkoxy, and perfluoro(C １ ~C ６ )alkyl, perfluoro(C １ ~C ６ )alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl, R ５ -(C(R ４ )) ２ ) ｎ -O- or (R ６ )) ２ N-; (C １ ~C ６ )alkyl, cycloalkyl, heterocycloalkyl, and aryl are independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group; Each R ４ is independently H, or H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C １ ~C ３ )alkyl; R ５ is selected from the group consisting of (C １ -C ３ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C １ -C ６ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl are H, halo, -CN, (C １ -C ３ ) alkyl, -NH ２ , (C １ -C ３ ) alkyl-(NH)-, ((C １ -C ３ ) alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ６ is independently H, or is substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and is optionally (C １ ~C ３ )alkyl as defined in any of claims 1 to 17.

19. R ３ is selected from the group consisting of H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ and (R ７ ) ２ N-; R ７ is H or (C １ ~C ３ )alkyl, the compound according to any one of claims 1 to 18.

20. R １ is H, F, -CH ３ and -OCH ３ A compound according to any one of claims 1 to 19, selected from the group consisting of.

21. R １ The compound according to any one of claims 1 to 20, wherein R is H.

22. R ２ is selected from the group consisting of H, (C １ ~C ３ alkyl), (C １ ~C ３ alkoxy)-, perfluoro(C １ ~C ３ alkyl), perfluoro(C １ ~C ３ alkoxy)-, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, R ５ -(C(R ４ )) ２ )) ｎ -O- or (R ６ )) ２ N-; (C １ ~C ３ alkyl), 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O-, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl are each independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ alkyl), -NH ２ , (C １ ~C ３ alkyl)-(NH)-, ((C １ ~C ３ alkyl)) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group; Each R ４ is independently H, or H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of (C １ ~C ３ )alkyl; R ５ is (C １ -C ３ ) alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclo selected from alkyl and 6- to 10-membered aryl; (C １ -C ３ ), alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, and 6- to 10-membered aryl are each independently selected from the group consisting of H, halo, -CN, (C １ -C ３ ), alkyl, -NH ２ , (C １ -C ３ ), alkyl-(NH)-, ((C １ -C ３ ), alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ６ is independently H, or H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C １ ~C ３ )alkyl, a compound according to any of claims 1 to 21.

23. R ２ is selected from the group consisting of methoxy-, cyclopropoxy- or R ５ -(C(R ４ ))-O-; ２ ​ Each R ４ is H; R ５ is selected from C １ -alkyl and tetrahydropyran, and the C １ -alkyl is substituted with -OCH ３ The compound according to any one of claims 1 to 22

24. R ３ is H, F, -CH ３ , -OCH ３ , and H ２ N- and is a compound according to any one of claims 1 to 23

25. R ３ The compound according to any one of claims 1 to 24, wherein R is H.

26. R ９ is selected from the group consisting of H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ , -CN, R １２ O((C １ -C ３ )alkyl)-(NR １１ ), -CO ２ R １２ , and (R １１ ) ２ N-(C=O)-; Each R １１ is independently selected from the group consisting of H, (C １ ~C ３ )alkyl; R １２ is H or (C １ ~C ３ )alkyl, the compound according to any one of claims 1 to 25.

27. At least one R ９ is selected from the group consisting of F, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ , and -CN, a compound according to any one of claims 1 to 26.

28. At least one R ９ is —CF ３ The compound according to any one of claims 1 to 27, wherein R is —CF

29. At least one R １０ The compound according to any one of claims 1 to 28, wherein R is H.

30. In the compound of formula I, R １０ The compound according to claim 29, wherein １０ is H.

31. The compound according to claim 1, wherein Het is the ring of the said formula 【Chemical 20】 . (wherein, One R ９ is H, and the other R ９ is -CF ３ and R １０ is H)

32. R ８ The compound according to any one of claims 1 to 31, wherein R is H.

33. -X-Y-Z- is =CR １ -CR ２ =CR ３ - or =N-CR ２ =CR ３ - being the compound according to any one of claims 1 to 32.

34. -X-Y-Z- is =CR １ -CR ２ =CR ３ The compound according to claim 33, wherein -X-Y-Z- is =CR-

35. The said compound of formula I is the compound of formula IA 【Chemical 21】 or a pharmaceutically acceptable salt thereof, Formula I ＊ wherein said compound is of formula I ＊ A 【Chemical 22】 and the compound according to claim 1, which is the compound of (wherein, -X-Y-Z- of the formula IA is =CR １ -CR ２ =CR ３ - or =N-CR ２ =CR ３ -; Said formula I ＊ A's -X-Y-Z- is CR １ -CR ２ =C or =N-CR ２ =C; R １ is selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -OCH ３ , and -OCF ３ ; R ２ is H, (C １ ~C ６ )-alkyl, (C １ ~C ６ )-alkoxy, and perfluoro(C １ ~C ６ )-alkyl, perfluoro(C １ ~C ６ )-alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl, R ５ -(C(R ４ ) ２ ) ｎ -O- or (R ６ ) ２ N-; and (C １ ~C ６ )-alkyl, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, and aryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )-alkyl, -NH ２ , (C １ ~C ３ )-alkyl-(NH)-, ((C １ ~C ３ )-alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; n is an integer from 1 to 3; Each R ４ is independently H or (C １ to C ３ ) alkyl; R ５ is selected from the group consisting of (C １ to C ３ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C １ to C ３ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl are H, halo, -CN, (C １ to C ３ ) alkyl, -NH ２ , (C １ to C ３ ) alkyl-(NH)-, ((C １ to C ３ ) alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ６ is independently H or (C １ ~C ３ )alkyl, and (C １ ~C ３ )alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; R ３ is H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ or (R ７ ) ２ N-; R ７ is H or (C １ ~C ３ ) alkyl; R ８ is H, -CH ３ , or -CF ３ ; R ９ is selected from H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ , -CN, R １２ O((C １ -C ３ ))alkyl)-(NR １１ ), -CO ２ R １２ , and (R １１ ) ２ N-(C=O)-; Each R １１ is independently selected from the group consisting of H and (C １ ~C ３ ) alkyl; R １２ is H or (C １ ~C ３ ) alkyl)

36. The said compound of formula I is the compound of formula IB 【Chemical 23】 or a pharmaceutically acceptable salt thereof, Formula I ＊ wherein said compound of Formula I ＊ B 【Chemical Formula 24】 and the compound according to claim 1, which is the compound of (wherein, Formula I ＊ -X-Y-Z- of B is CH-CR ２ =C or =N-CR ２ =C; R ２ is H, (C １ ~C ３ )-alkyl, (C １ ~C ３ )-alkoxy, and perfluoro(C １ ~C ３ )-alkyl, perfluoro(C １ ~C ３ )-alkoxy-, cycloalkyl, heterocycloalkyl, aryl, R ５ -(C(R ４ )) ２ ) ｎ -O- or (R ６ )) ２ N-; (C １ ~C ３ )-alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )-alkyl, -NH ２ , (C １ ~C ３ )-alkyl-(NH)-, ((C １ ~C ３ )-alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; n is an integer from 1 to 3; Each R ４ is independently H or (C １ ~C ３ )alkyl; (C １ ~C ３ )alkyl is , H, halo, -CN, (C １ ~C ３ )alkyl, -NH ２ , (C １ ~C ３ )alkyl-(NH)-, ((C １ ~C ３ )alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ５ is selected from the group consisting of (C １ ~C ３ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl; (C １ ~C ３ ) alkyl, cycloalkyl, heterocycloalkyl, and aryl are H, halo, -CN, (C １ ~C ３ ) alkyl, -NH ２ , (C １ ~C ３ ) alkyl-(NH)-, ((C １ ~C ３ ) alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ and may be substituted with 1 to 3 substituents independently selected from the group consisting of; R ６ is independently H or (C １ ~C ３ )-alkyl; (C １ ~C ３ )-alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of H, halo, -CN, (C １ ~C ３ )-alkyl, -NH ２ , (C １ ~C ３ )-alkyl-(NH)-, ((C １ ~C ３ )-alkyl) ２ N-, -CF ３ , -OCH ３ and -OCF ３ ; R ３ is H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ or (R ７ ) ２ N-; R ７ is H or (C １ ~C ３ )alkyl; R ８ is H, -CH ３ or -CF ３ ; R ９ is selected from the group consisting of H, halo, (C １ ~C ３ )alkyl, -CF ３ , -OCH ３ , -OCF ３ , -CN, -(NR １０ )( (C １ ~C ３ )alkyl)-OR １１ , -CO ２ R １１ and -(C=O)-N(R １０ ) ２ ; R １０ is H or (C １ ~C ３ )alkyl; R １１ is (C １ ~C ３ )alkyl)

37. 6-(1H-Imidazol-1-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 6-(1H-Imidazol-1-yl)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 2-(1H-Imidazol-1-yl)-6-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-Imidazol-1-yl)-4-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 4-cyclopropoxy-6-(1H-Imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 6-(1H-Imidazol-1-yl)-N-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine, 6-(1H-Imidazol-1-yl)-N-(pyridin-4-yl)pyrimid[5,4-d] pyrimidin-4-amine, 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(1H-imidazol-1-yl)-4-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)picolylamide, 2-(3-methyl-4H-3l4-imidazol-4-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((3-methyloxetan-3-yl)oxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 2-(1-methyl-1H-imidazol-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-methoxyethoxy)-2-(1-methyl-1H-imidazol-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, 6-(2-hyd, The compound according to claim 1, selected from the group consisting of roxy-2-methylpropoxy)-2-(1H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, and pharmaceutically acceptable salts thereof.

38. The compound of formula I or I according to any one of claims 1 to 37, ＊ or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier A pharmaceutical composition comprising.

39. The pharmaceutical composition according to claim 38, for treating a disease or disorder in a subject, wherein modulation of NAD+ (nicotinamide adenine dinucleotide) levels or levels of its related metabolites is beneficial, wherein the NAD+ or its related metabolite is selected from the group consisting of NAD+, NMN (nicotinamide mononucleotide), ADP-Rib (adenosine diphosphate ribose), cADPR (cyclic adenosine diphosphate ribose), NAM (nicotinamide), NAAD (nicotinic acid adenine dinucleotide), NAADP (nicotinic acid adenine dinucleotide phosphate), NR (nicotinamide riboside), MNAm (N1-methylnicotinamide), and wherein the disease or disorder is non-alcoholic steatohepatitis, inflammation, infection, sepsis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis vulgaris, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, fibrosis, liver fibrosis, kidney fibrosis, lung fibrosis, heart fibrosis, cancer, multiple myeloma, neurodegeneration, infertility, follicle loss, reduction in the quality and quantity of oocytes, ischemia-reperfusion injury, bipolar disorder, Alzheimer's disease, neuropathic pain, Parkinson's disease, obesity, type 2 diabetes, or hepatotoxicity.

40. The pharmaceutical composition according to claim 39, wherein the disease or disorder is multiple myeloma or sepsis.

41. The pharmaceutical composition according to claim 39, wherein the disease or disorder is a fibrotic disease or disorder of the lung, heart, or kidney.

42. The pharmaceutical composition according to claim 41, wherein the fibrotic disease is infection-induced pulmonary fibrosis or virus-induced pulmonary infection.

43. The pharmaceutical composition according to claim 39, wherein the disease or disorder is multiple myeloma, and the treatment further comprises administering an immuno-oncology drug to the subject.

44. The pharmaceutical composition according to claim 39, wherein the modulation is an increase in the level of NAD+ or its related metabolite.

45. The pharmaceutical composition according to claim 39, wherein the modulation is a decrease in the level of NAD+ or a related metabolite thereof.

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