Inhibitors of cyclic ADP-ribose hydrolase and methods of use thereof

Abstract

The present disclosure provides compounds, in part, compounds of Formula I, Formula II, or Formula III, and their use in treating medical diseases or disorders, such as neurodegenerative diseases, e.g., Parkinson's disease. Pharmaceutical compositions and methods of making the disclosed compounds are provided. It is contemplated that the compounds are modulators, e.g., inhibitors, of cyclic ADP-ribose hydrolase (CD38). The present disclosure is directed, at least in part, to compounds that modulate (e.g., inhibit) the expression and / or activity of CD38. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable excipient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 424,443, filed November 10, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The glycoprotein CD38 (cluster of differentiation 38), also known as cyclic ADP-ribose hydrolase, is a multifunctional enzyme that catalyzes the degradation of, for example, nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose (ADP-ribose or ADPR). CD38 can also function as a cyclase, converting NAD+ to cyclic ADP-ribose (cADPR). Its NADase activity predominates over its function as an ADP-ribosyl cyclase, and the cyclization of NAD+ to cADPR is 100-fold less efficient than the hydrolysis of NAD+ to ADP-ribose. CD38 can also hydrolyze nicotinamide adenine dinucleotide phosphate (NADP) to nicotinic acid adenine dinucleotide phosphate (NAADP), both of which are derived from NAD+. Therefore, CD38 is considered an important consumer of NAD+ and a regulator of NAD+ levels.

[0003] Dysregulation of NAD+ levels is associated with various pathologies.For example, disease states associated with NAD+ depletion and dysregulation of NAD+-related metabolites include, but are not limited to, obesity, diabetes, cancer, heart disease, asthma and inflammation.Therefore, in pathologies that consume large amounts of NAD+, restoring NAD+ to its normal level can provide therapeutic benefits.

[0004] For example, a decrease in NAD+ levels is associated with aging, and this age-related dysfunction may contribute to increased neurogenesis and the development of neurodegenerative disorders. The expression of CD38, an enzyme responsible for NAD+ degradation, increases as a result of aging, thus providing a reasonable rationale for the decrease in NAD+ levels as a result of aging. Therefore, one approach to regulating cellular NAD+ levels may be to inhibit NAD+-consuming enzymes, such as CD38. Summary of the Invention [Problem to be solved by the invention]

[0005] Inhibition of CD38 enzymatic activity, which consequently regulates NAD+ tissue levels, presents a useful approach for treating diseases associated with increased CD38 expression and / or decreased cellular NAD+ levels. Thus, there is a continuing need for small molecule inhibitors of CD38 in the treatment of diseases or conditions that respond to modulation (e.g., inhibition) of cellular levels of NAD+. [Means for solving the problem]

[0006] The present disclosure is directed, at least in part, to compounds that modulate (e.g., inhibit) the expression and / or activity of CD38. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable excipient.

[0007] For example, as used herein, Formula I: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R 1 is R 11 and optionally substituted by one or more substituents each independently selected from R 2is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R 2 is R 22 and optionally substituted by one or more substituents each independently selected from R 3 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 selected from the group consisting of alkynyl and halogen; 1~6 Alkyl, -C 2~6 Alkenyl and -C 2~6 The alkynyl may be optionally substituted with one or more halogens. R 4 is —C optionally substituted with hydrogen and one or more halogens 1~3 is selected from the group consisting of alkyl, R 5 and R 6 is independently hydrogen, halogen, deuterium, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -CN, -NR a R b , -C(O)-NR a R b and -NR a -C(O)-R b is selected from the group consisting of R 11 , R 22 and R 33 is independently at each occurrence a halogen, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -C 3~6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b and deuterium, -C 1~6 Alkyl and -C 1~6 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3may be optionally substituted by one or more substituents each independently selected from alkoxy, and R a and R b represents, independently at each occurrence, —C optionally substituted by hydrogen and one or more halogens; 1~3 alkyl.

[0008] As used herein, Formula II: [ka] Also disclosed is a compound represented by the formula: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered heteroaryl containing at least one ring nitrogen, and R 1 is halogen, hydroxyl, -NH2, -C 1~3 Alkyl, -C 1~3 Alkyl-OH and -C 1~3 may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of alkoxy, and R 2 is halogen, hydroxyl or -C 1~3 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl optionally substituted by alkyl, 1~3 Alkyl and -C 1~3 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3 It may be optionally substituted by one or more groups selected from alkoxy.

[0009] As used herein, the compounds of formula III: [ka] Further disclosed is a compound of the formula: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: X and Y are each independently selected from N and CH, and at least one of X and Y is N; R 1is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R 1 is R 11 and optionally substituted by one or more substituents each independently selected from R 2 is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R 2 is R 22 and optionally substituted by one or more substituents each independently selected from R 3 is —C optionally substituted with hydrogen and one or more halogens 1~3 is selected from the group consisting of alkyl, R 4 and R 5 are independently hydrogen, halogen, deuterium, hydroxyl, -CF3, -C 1~6 Alkyl, -C 1~6 Alkoxy, -CN, -NR a R b , -C(O)-NR a R b and -NR a -C(O)-R b is selected from the group consisting of R 11 and R 22 is independently at each occurrence a halogen, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -C 3~6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b and deuterium, -C 1~6 Alkyl and -C 1~6 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3 may be optionally substituted by one or more substituents each independently selected from alkoxy, and R a and R brepresents, independently at each occurrence, —C optionally substituted by hydrogen and one or more halogens; 1~3 alkyl.

[0010] Also disclosed herein are methods of treating a disease (e.g., a neurodegenerative disease) that would benefit from CD38 inhibition and / or NAD+ increase in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed CD38 inhibitor. In some embodiments, the neurodegenerative disease is, for example, Parkinson's disease, Alzheimer's disease, or Huntington's disease. DETAILED DESCRIPTION OF THE INVENTION

[0011] The features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, certain terms used in the specification, examples and appended claims are summarized here. These definitions should be read in light of the remainder of the disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0012] definition As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched chain hydrocarbons of 1 to 6, 1 to 4, or 1 to 3 carbon atoms, each of which is referred to herein as C. 1~6 Alkyl, C 1~4 Alkyl and C 1~3Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0013] As used herein, the term "alkenyl" refers to an unsaturated, straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups of 2 to 6 or 3 to 4 carbon atoms, referred to herein as C1-C5 alkenyl, C2-C6 alkenyl, and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0014] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched chain groups of 2 to 6 or 3 to 6 carbon atoms, respectively, as used herein. 2~6 Alkynyl and C 3~6 Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0015] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1 to 6 or 2 to 6 carbon atoms, referred to herein as C1-C5 alkoxy, C1-C6 alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0016] The term "aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and no heteroatoms present in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the group or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Representative examples of substituted aryl groups include: [ka] In the formula, R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocycle, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59, S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl, or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 are each independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0017] As used herein, the term "carbonyl" refers to the group --C(O)--.

[0018] As used herein, the term "cyano" refers to the group --CN.

[0019] As used herein, the term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3 to 6 or 4 to 6 carbons, and is defined herein as C3 to C6, respectively. 10 Cycloalkyl, C 3~6 Cycloalkyl or C 4~6 Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0020] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0021] As used herein, the term "haloalkyl" refers to an alkyl group wherein the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched chain hydrocarbons of 1 to 6, 1 to 4, or 1 to 3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), each of which is referred to herein as C. 1~6 Haloalkyl, C 1~4 Haloalkyl and C 1~3 Also called haloalkyl.

[0022] The term "hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), and cycloalkenyl (e.g., cycloheteroalkenyl), having 1 to 5, especially 1 to 3, heteroatoms.

[0023] As used herein, the term "heteroaryl" or "heteroaromatic group" refers to an aromatic 5- to 10-membered ring system containing one or more heteroatoms, e.g., 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5- to 7-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Where possible, the heteroaryl ring may also be attached to an adjacent group through a carbon or nitrogen atom. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzimidazole, imidazopyridine, pyrazole, triazole, pyridine, pyrimidine, and the like.

[0024] The terms "heterocyclyl," "heterocycle," or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 4- to 10-membered ring structures whose ring structures contain one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings can be attached to adjacent groups through carbon or nitrogen. The term can also be used to refer to bridged, fused, or spirocyclic ring structures whose ring structures contain one to three heteroatoms, such as nitrogen, oxygen, and sulfur, and whose 4- to 10-membered saturated or partially unsaturated ring structures are bridged, fused, or spirocyclic ring structures. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, and the like. In some embodiments, the heterocycle is a spiroheterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7-methanoisoindole). "Spiroheterocyclyl" or "spiroheterocycle" refers to a polycyclic heterocyclyl having rings joined through one common atom (called a spiroatom), and the rings are selected from N, O, and S(O). m (wherein m is an integer of 0 to 2) as ring atoms.

[0025] As used herein, the terms "hydroxy" and "hydroxyl" refer to an --OH group.

[0026] As used herein, the term "oxo" refers to the group ═O.

[0027] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0028] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0029] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present compositions that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present compositions that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0031] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. The term "stereoisomer," as used herein, consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)," "(-)," "R," or "S," depending on the arrangement of substituents around the stereogenic carbon atom, although those of skill in the art will recognize that the structure may implicitly represent a chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the nomenclature "(±)," although those of skill in the art will recognize that the structure may implicitly represent a chiral center.

[0032] The compounds of the present disclosure may contain one or more double bonds and, therefore, may exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. [ka] indicates a bond, which may be a single bond, double bond, or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be designated as "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond.

[0033] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers due to the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans", with the term "cis" referring to substituents on the same side of the plane of the ring and the term "trans" referring to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is designated "cis / trans".

[0034] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the enantiomeric mixture to a chiral auxiliary, recrystallization or chromatography of the resulting diastereomeric mixture, and separation by liberation of the optically pure product from the auxiliary; (2) salt formation using an optically active resolving agent; (3) direct separation of the enantiomeric mixture on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, i.e., chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the generation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0035] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0036] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those described herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0037] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 isotopes (i.e. 14 C) is particularly preferred due to its ease of preparation and detection. 2Substitution with heavier isotopes, such as H, may afford certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and, therefore, may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures similar to those disclosed in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0038] The term "prodrug" refers to a compound that is converted in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The conversion can occur at various locations (e.g., in the intestinal lumen or during passage through the intestine, blood, or liver) and by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative and / or reductive metabolism). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug can be prepared by replacing a hydrogen atom of the acid group with a carboxylic acid functional group such as (C 1~8 ) alkyl, (C 2~12 ) alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C 1~2 ) Alkylamino(C 2~3 ) alkyl (e.g., β-dimethylaminoethyl), carbamoyl-(C 1~2) alkyl, N,N-di(C 1~2 ) alkylcarbamoyl-(C 1~2 ) alkyl and piperidino-, pyrrolidino- or morpholino (C 2~3 ) alkyl.

[0039] Similarly, if a compound of the present disclosure contains an alcohol functional group, the prodrug may be a compound that converts a hydrogen atom of the alcohol group to a hydroxyl group such as (C 1~6 ) alkylcarbonyloxymethyl, 1-((C 1~6 ) alkylcarbonyloxy) ethyl, 1-methyl-1-((C 1~6 ) alkylcarbonyloxy) ethyl, (C 1~6 )alkoxycarbonyloxymethyl, N-(C 1~6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) alkylcarbonyl, α-amino (C 1~4 ) alkylcarbonyl, arylalkylcarbonyl, and α-aminoalkylcarbonyl or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl groups, each of which is a group selected from the group consisting of the naturally occurring L-amino acids, P(O)(OH), -P(O)(O(C 1~6 ) alkyl) 2 or glycosyl (a group formed by removing the hydroxyl group of a hemiacetal form of a carbohydrate).

[0040] When an amine function is incorporated into a compound of the present disclosure, a prodrug can be formed, for example, by the formation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, an imine, or an enamine. Furthermore, a secondary amine can be metabolically cleaved to generate a biologically active primary amine, or a tertiary amine can be metabolically cleaved to generate a biologically active primary or secondary amine. See, for example, Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0041] The term "treatment" or "treating" refers to the medical management of a patient with the intent to reverse, improve, stabilize (i.e., not worsen), prevent, or cure a disease, pathological condition, or disorder. "Treatment" includes active treatment (treatment directed at reversing the disease, pathological condition, or disorder), causal treatment (treatment directed at the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed to relieve symptoms), preventive treatment (treatment directed at minimizing or partially or completely preventing the occurrence of the associated disease, pathological condition, or disorder), and supportive treatment (treatment used to complement another therapy). Treatment also includes reducing the extent of the disease or condition, whether detectable or undetectable, preventing the spread of the disease or condition, delaying or slowing the progression of the disease or condition, ameliorating or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition. To "ameliorate" or "alleviate" a disease or condition means to lessen the severity and / or undesirable clinical symptoms of the disease, disorder or condition and / or slow or prolong its progression over time compared to the severity or course of time that would occur in the absence of treatment. "Treatment" also includes prolonging survival as compared to expected survival in the absence of treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in whom the condition or disorder is to be prevented.

[0042] The terms "effective amount," "therapeutically effective amount," or "sufficient amount" refer to an amount sufficient to, when administered to a patient (e.g., a mammal such as a human patient), effect a treatment (e.g., produce a beneficial or desired result), including an effect at a cellular, tissue, or clinical level. Thus, the term depends on the context in which it is applied. For example, in the context of treating a disclosed neurodegenerative disease, it would be an amount of a disclosed CD38 inhibitor sufficient to achieve a response compared to the response obtained without administration of the CD38 inhibitor. The amount of a given composition described herein that corresponds to such an amount will vary depending on various factors, such as the given CD38 inhibitor, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the patient's identity (e.g., age, sex, weight), or the host being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. In some embodiments, a "therapeutically effective amount" of a composition of the present disclosure is an amount that produces a beneficial or desired result in a patient (e.g., compared to a control). A therapeutically effective amount of a composition of the present disclosure can be readily determined by one of ordinary skill in the art using routine methods known in the art. Dosage regimens can be adjusted to provide an optimal therapeutic response.

[0043] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human. The compounds of the present disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0044] In some embodiments, the patient is a human. In some embodiments, the patient is an adult patient. In some embodiments, the subject is 30 years of age or older, e.g., at least 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 years of age.

[0045] I. Compound The present disclosure is directed, in part, to compounds that are contemplated to be modulators, eg, inhibitors, of CD38.

[0046] For example, as used herein, Formula I: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R 1 is R 11 and optionally substituted by one or more substituents each independently selected from R 2 is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R 2 is R 22 and optionally substituted by one or more substituents each independently selected from R 3 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 selected from the group consisting of alkynyl and halogen; 1~6 Alkyl, -C 2~6 Alkenyl and -C 2~6 The alkynyl may be optionally substituted with one or more halogens. R 4 is —C optionally substituted with hydrogen and one or more halogens 1~3 is selected from the group consisting of alkyl, R 5 and R 6 is independently hydrogen, halogen, deuterium, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -CN, -NR a R b , -C(O)-NR a R b and -NR a -C(O)-R bis selected from the group consisting of R 11 , R 22 and R 33 is independently at each occurrence a halogen, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -C 3~6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b and deuterium, -C 1~6 Alkyl and -C 1~6 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3 may be optionally substituted by one or more substituents each independently selected from alkoxy, and R a and R b represents, independently at each occurrence, —C optionally substituted by hydrogen and one or more halogens; 1~3 alkyl.

[0047] In some embodiments, R 5 and R6 is absent. For example, in some embodiments, the compounds disclosed herein are [ka] It can be represented by:

[0048] In some embodiments, R 1 is a 5-6 membered heteroaryl containing at least one ring nitrogen, and R 1 is R 11 and optionally substituted with one or two substituents each independently selected from:

[0049] For example, in certain embodiments, R 1 is selected from the group consisting of imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridyl; R1 may be optionally substituted with one or two substituents each independently selected from the group consisting of -CH2OH, -OH, and -NH2.

[0050] In a further embodiment, R 1 teeth, [ka] is selected from the group consisting of:

[0051] In other embodiments, R 1 For example, [ka] is selected from the group consisting of:

[0052] In some embodiments, R 2 is a 5-membered heteroaryl, and R 2 is hydroxyl or -C 1~3 optionally substituted by alkyl, -C 1~3 Alkyl is hydroxyl or -C 1~3 It may be optionally substituted with alkyl.

[0053] For example, in certain embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0054] In yet other embodiments, R 2 is a 5- to 6-membered heterocyclyl, and R 2 is hydroxyl or -C 1~3 optionally substituted by alkyl, -C 1~3 Alkyl is hydroxyl or -C 1~3 It may be optionally substituted by alkoxy.

[0055] For example, in certain embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0056] In some embodiments, R 3 is —C optionally substituted with one, two or three fluoro groups; 1~3 In another embodiment, R 3 is, for example, -CF3.

[0057] In other embodiments, the compounds of the present disclosure are [ka] It can be represented by:

[0058] In certain embodiments, R 4 is, for example, hydrogen.

[0059] As used herein, Formula II: [ka] Also disclosed is a compound represented by the formula: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered heteroaryl containing at least one ring nitrogen, and R 1 is halogen, hydroxyl, -NH2, -C 1~3 Alkyl, -C 1~3 Alkyl-OH and -C 1~3 may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of alkoxy, and R 2 is halogen, hydroxyl or -C 1~3 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl optionally substituted by alkyl, 1~3 Alkyl and -C 1~3 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3It may be optionally substituted by one or more groups selected from alkoxy.

[0060] In some embodiments, R 1 For example, [ka] is selected from the group consisting of:

[0061] For example, in certain embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0062] In other embodiments, R 2 For example, [ka] is selected from the group consisting of:

[0063] As used herein, the compounds of formula III: [ka] Further disclosed is a compound represented by the formula: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: X and Y are each independently selected from N and CH, and at least one of X and Y is N; R 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R 1 is R 11 and optionally substituted by one or more substituents each independently selected from R 2 is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R 2 is R 22 and optionally substituted by one or more substituents each independently selected from R3 is —C optionally substituted with hydrogen and one or more halogens 1~3 is selected from the group consisting of alkyl, R 4 and R 5 are independently hydrogen, halogen, deuterium, hydroxyl, -CF3, -C 1~6 Alkyl, -C 1~6 Alkoxy, -CN, -NR a R b , -C(O)-NR a R b and -NR a -C(O)-R b is selected from the group consisting of R 11 and R 22 is independently at each occurrence a halogen, hydroxyl, -C 1~6 Alkyl, -C 1~6 Alkoxy, -C 3~6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b and deuterium, 1~6 Alkyl and -C 1~6 Alkoxy is a group consisting of hydroxyl, halogen and -C 1~3 may be optionally substituted by one or more substituents each independently selected from alkoxy, and R a and R b represents, independently at each occurrence, —C optionally substituted by hydrogen and one or more halogens; 1~3 alkyl.

[0064] In some embodiments, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0065] [Table 1]

[0066] The following examples provide procedures for making the compounds described herein. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio, and carboxyl groups) to prevent them from participating in the reaction in an undesired manner. The incorporation of such groups and the methods required for their introduction and removal are known to those skilled in the art (see, for example, Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis, and removal of the protecting group yields the compounds disclosed herein. The starting materials used in the following schemes may be purchased or may be prepared using methods known to those skilled in the art, such as those described in the chemical literature or modifications thereof. The order in which the steps are performed may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0067] The compounds disclosed herein or any of the intermediates described in the schemes above can be further derivatized using one or more standard synthetic methods known to those skilled in the art. Such methods can include substitution, oxidation, or reduction reactions. These methods can be used to modify, introduce, or remove appropriate functional groups to obtain or alter the disclosed compounds or preceding intermediates.

[0068] If it is desired to obtain a specific enantiomer of a disclosed compound, it can be produced from the corresponding mixture of enantiomers by using any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reacting a mixture of enantiomers (such as a racemate) of a disclosed compound with an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means, such as crystallization or chromatography, and the desired enantiomer can be recovered (e.g., by treatment with acid if the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0069] In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate of the disclosed compound. Alternatively, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the above processes. Chromatography, recrystallization and other conventional separation procedures can also be used with intermediates or final products of the present disclosure that are desired to obtain a specific geometric isomer.

[0070] In alternative embodiments, the disclosed compounds may also contain one or more isotopic substitutions. For example, hydrogen may be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, and the nitrogen can be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O or 15N) can account for at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site on the compound.

[0071] II. Method The compounds of the present disclosure are intended to inhibit the activity of CD38. For example, provided herein are methods for inhibiting the activity or function of CD38 in a cell or patient in need thereof, comprising administering to the cell or patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. Also disclosed herein are methods for treating a disease in a patient in need thereof that would benefit from CD38 inhibition, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, thereby treating the disease in the patient.

[0072] The compounds of the present disclosure are intended to increase NAD+ levels. For example, provided herein is a method for increasing NAD+ levels in a sample or a patient in need thereof, comprising contacting the sample with or administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II, wherein the increase in NAD+ level is compared to the NAD+ level prior to contact or administration. Further disclosed herein is a method for treating a disease in a patient in need thereof that would benefit from increased NAD+, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the disease in the patient.

[0073] The compounds of the present disclosure may be useful in treating diseases associated with aberrant expression or activity of CD38. For example, the present disclosure provides a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the cancer in the patient. In some embodiments, the cancer is characterized as having aberrant expression or activity, e.g., elevated expression or activity, of CD38 compared to normal cells. In other embodiments, the cancer may be selected from the group consisting of, for example, breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer, urinary tract cancer, and colon cancer. In some embodiments, the cancer is lung cancer. In other embodiments, the cancer is melanoma, and in certain embodiments, the cancer is colon cancer. In still other embodiments, the cancer may be leukemia or lymphoma. Examples of lymphomas contemplated herein include, but are not limited to, Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Examples of leukemias contemplated herein include, but are not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). In further embodiments, the cancer may be selected from the group consisting of, for example, a cancer treated with checkpoint therapy, a resistant cancer treated with checkpoint therapy, an adenosine-dependent tumor, a Treg-infiltrated tumor, and an MDSC-infiltrated tumor.

[0074] For example, cancers contemplated by the present disclosure that are treatable by administration of the compounds described herein may be selected from the group consisting of bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, glioma, head and neck cancer (upper gastrointestinal cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. In some embodiments, cancers contemplated by the present disclosure that are treatable by administration of the compounds described herein may be selected from the group consisting of multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper gastrointestinal cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0075] Also provided herein are methods of treating a condition or disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. In some embodiments, the disease or condition is selected from the group consisting of HIV / AIDS, acute lung injury, acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis, ataxia-telangiectasia, sleep disorders, epilepsy, exercise intolerance, hypertension, hypoxic pulmonary vasoconstriction, leprosy, tuberculosis, leishmaniasis, cardiac hypertrophy, congestive heart failure (CHF), muscular dystrophy, stroke, organ reperfusion injury, idiopathic pulmonary fibrosis, pancreatitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), irritable bowel syndrome (IBS), colitis, gout, obesity, sarcopenia, and the like. The condition is selected from the group consisting of obesity, end-stage renal disease, dyslipidemia, hearing loss, liver disease, fatty liver, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, multiple sclerosis, neurocognitive impairment, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnup disease, skin pigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontal disease, chronic lymphocytic leukemia, myelotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Leber's hereditary amaurosis, insulin resistance, type 1 diabetes, and type 2 diabetes.

[0076] The compounds described herein are contemplated to have therapeutic utility in CD38-associated diseases, e.g., in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, which diseases are characterized by overexpression or increased activity of CD38.

[0077] Another aspect of the present disclosure provides a method of treating a patient suffering from a neurodegenerative disease or disorder, such as Parkinson's disease. As used herein, the term "neurodegenerative disease" or "neurodegenerative disorder" encompasses diseases, disorders, or conditions in which cells of the central nervous system fail or die. Neurodegenerative diseases usually worsen over time and have no cure. Such diseases can be genetic or caused by tumors or stroke. Neurodegenerative diseases also occur in people who consume large amounts of alcohol or are exposed to certain viruses or toxins. Non-limiting examples of neurodegenerative disorders include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), prion diseases, spinocerebellar ataxia (SCA), vascular dementia, frontotemporal dementia (FTD), mixed dementia, and dementia with Lewy bodies (LBD). In some embodiments, the neurodegenerative disease is a late-onset disease. In other embodiments, the present disclosure provides methods of treating a patient suffering from neuroinflammation.

[0078] In some embodiments, the neurodegenerative disease affects the basal ganglia, thalamus, red nucleus, locus coeruleus, parahippocampal gyrus, or a combination thereof, hi some embodiments, the neurodegenerative disease affects the basal ganglia and / or thalamus.

[0079] In some embodiments, the neurodegenerative disease is ALS, HD, PD, or SCA. In certain embodiments, the neurodegenerative disease is PD. In certain embodiments, the PD is familial Parkinson's disease.

[0080] Patients treated according to the methods described herein may be those diagnosed with a neurodegenerative disease (e.g., PD) or those at risk for developing such a disease. Diagnosis of a neurodegenerative disease or risk for developing a neurodegenerative disease may be performed by a skilled medical professional using any suitable method or technique known in the art. One of skill in the art will understand that patients for treatment according to the present disclosure may have undergone standard testing or may be identified as at risk without testing because of the presence of one or more risk factors associated with the disease or condition.

[0081] In some embodiments, the patient has a neurodegenerative disease (e.g., PD). In some embodiments, the patient has been diagnosed with a neurodegenerative disease (e.g., PD). In other embodiments, the patient is at risk for developing a neurodegenerative disease (e.g., PD). In some embodiments, the patient has or is at risk for developing PD.

[0082] For example, the disclosure provides a method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the neurodegenerative disease in the patient. In some embodiments, the neurodegenerative disease is, for example, Parkinson's disease, Alzheimer's disease, or Huntington's disease.

[0083] Also disclosed herein is a method of slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or any of the compounds described herein, and a pharmaceutically acceptable excipient carrier.

[0084] Also contemplated are neurodegenerative diseases that are ophthalmic diseases or disorders, comprising administering an effective amount of a disclosed CD38 inhibitor, e.g., a compound of Formula I or Formula II. For example, provided herein are methods of treating one or more of the following ophthalmic diseases: macular degeneration (e.g., age-related macular degeneration (AMD) or dry macular degeneration), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP), Stargardt's disease, myopic macular degeneration (MMD), submacular hemorrhage, diabetic macular edema (DME), or uveitis.

[0085] Another aspect of the present disclosure provides a method for treating patients suffering from fatty liver disease or disorder, such as NAFLD or NASH.As used herein, the term "fatty liver disease" includes the disease, disorder or condition caused by the accumulation of excess fat in the liver.Alcoholic fatty liver is the accumulation of fat in the liver as a result of heavy alcohol consumption.Non-alcoholic fatty liver disease (NAFLD) occurs in people who do not consume heavy alcohol.

[0086] In some embodiments, the fatty liver disease is NAFLD. NAFLD is a range of liver diseases in which fatty liver, the accumulation of large vesicles of triglycerides in hepatocytes, occurs in the absence of secondary causes (e.g., drug therapy, excessive alcohol consumption, or certain genetic conditions). In some embodiments, the NAFLD is simple fatty liver (NAFL). In certain embodiments, the NAFLD is nonalcoholic fatty liver (NASH). NASH is an inflammatory subtype of NAFLD, with evidence of fatty liver and hepatocellular injury (ballooning) and inflammation (with or without fibrosis).

[0087] Patients treated according to the methods described herein may be those diagnosed with fatty liver disease (e.g., NAFLD) or those at risk for developing such a disease. Diagnosis of fatty liver disease or the risk of developing fatty liver disease can be performed by a skilled medical professional using any suitable method or technique known in the art. Those skilled in the art will understand that subjects for treatment according to the present disclosure may have undergone standard tests or may be identified as at risk without testing due to the presence of one or more risk factors associated with the disease or condition.

[0088] In some embodiments, the patient has fatty liver disease (e.g., NAFLD, such as NASH). In some embodiments, the patient has been diagnosed with fatty liver disease (e.g., NAFLD, such as NASH). In other embodiments, the patient is at risk of developing fatty liver disease (e.g., NAFLD, such as NASH). In some embodiments, the patient has or is at risk of developing NAFLD. In some embodiments, the patient has or is at risk of developing NASH.

[0089] In some embodiments, the patient has NAFLD (e.g., NASH). In some embodiments, the patient also has hypertriglyceridemia, obesity, dyslipidemia, metabolic syndrome, hypertension, or type 2 diabetes, or a combination thereof.

[0090] For example, the disclosure provides a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the metabolic disease in the patient. In some embodiments, the metabolic disease is, for example, selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and diabetes (type I or type II).

[0091] In another embodiment, the present disclosure provides a method of inhibiting or slowing the progression of fatty liver disease, such as NAFLD (e.g., NASH), in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II, thereby inhibiting or slowing the progression of fatty liver disease in the patient.

[0092] In certain embodiments, the present disclosure provides a method of treating the medical indications described below, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0093] Also disclosed are methods of treating, for example, a neurodegenerative disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or any of the compounds described herein, and a pharmaceutically acceptable excipient carrier. In some embodiments, the neurodegenerative disease is Parkinson's disease.

[0094] Also disclosed herein is a method of treating neuroinflammation in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or any of the compounds described herein, and a pharmaceutically acceptable excipient carrier.

[0095] Further disclosed herein is a method for treating fatty liver disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of any of the compounds described herein, for example, a compound of Formula I or Formula II, or any of the compounds described herein, and a pharmaceutically acceptable excipient carrier. In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD). In other embodiments, the fatty liver disease is non-alcoholic steatohepatitis (NASH). In further embodiments, the fatty liver disease is simple steatosis. In certain embodiments, treating fatty liver disease comprises delaying the progression of fatty liver disease.

[0096] Also disclosed herein is a method of treating fibrosis in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or any of the compounds described herein, and a pharmaceutically acceptable excipient carrier. In some embodiments, the fibrosis is multiorgan fibrosis. In other embodiments, the fibrosis is associated with systemic sclerosis. For example, a patient suffering from fibrosis also suffers from systemic sclerosis. In yet other embodiments, the fibrosis is selected from the group consisting of dermal fibrosis, pulmonary fibrosis, and peritoneal fibrosis.

[0097] In certain embodiments, the methods described herein further comprise administering to the patient an additional therapeutic agent that treats a disclosed disease or disorder, or that treats a disclosed disease or disorder that is affected by, is associated with, or would benefit from selective modulation (e.g., inhibition) of CD38.

[0098] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein. For clarity, both fixed compositions comprising a disclosed compound and another therapeutic agent as disclosed herein, as well as methods of administering the disclosed compound and the disclosed therapeutic agent separately, are contemplated herein. For example, the present disclosure provides pharmaceutical compositions comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent are administered. In some embodiments, a disclosed compound defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, the disclosed compound and the additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. Two or more agents in combination therapy can be, but need not be, administered simultaneously. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, two or more agents can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks of each other. In some cases, even longer intervals are possible. While it is often desirable for two or more agents used in combination therapy to be present in the patient's body at the same time, this is not necessarily the case.

[0099] Combination therapy can also include administering one or more of the agents used in the combination more than once, using a different sequence of the component agents. For example, when agent X and agent Y are used in combination, they can be administered one or more times in any combination, e.g., one or more times sequentially in any combination in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0100] In particular, in certain embodiments, the present disclosure provides a method of treating the above medical indications, comprising administering to a patient in need thereof an effective amount of a compound described herein, e.g., a compound of Formula I or Formula II.

[0101] III. Pharmaceutical Compositions and Kits Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most appropriate administration form in a given case will depend on the degree and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions can be formulated as a unit dose and / or can be formulated for oral or subcutaneous administration.

[0102] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, containing one or more of the compounds of the present disclosure as an active ingredient, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient can be compounded with conventional non-toxic pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0103] When preparing solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0104] In solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbents, such as sorbitol, ... (5) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) solution retarders such as paraffin; (7) absorption accelerators such as quaternary ammonium compounds; (8) wetting agents such as acetyl alcohol and glycerol monostearate; (9) absorbents such as kaolin and bentonite clay; (10) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0105] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0106] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0107] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0108] Formulations for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and will therefore melt in the body cavity, releasing the active agent.

[0109] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0110] The ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0111] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example, butane and propane.

[0112] Alternatively, the compositions and compounds of the present disclosure may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can be used to minimize drug exposure to shear, which can lead to degradation of the compound contained in the subject composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween®, Pluronic®, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0113] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include a combination of the subject composition with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted immediately before use into a sterile injectable solution or dispersion, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the subject's blood or suspending or thickening agents.

[0114] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0115] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric material and a pharmaceutically acceptable carrier or excipient thereof. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluids at a specific pH. The small intestine is the portion of the digestive tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Thus, the enteric material does not dissolve until the pH is, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal collofolium, and some commercially available enteric dispersions (e.g., Eudragit Examples of suitable solubility materials include Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily measured in vitro.While the above is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that this is not exhaustive and that other enteric materials exist that would also satisfy the objectives of this disclosure.

[0116] Advantageously, the present disclosure also provides kits for use by consumers in need of treatment, for example, of the diseases or disorders described herein. Such kits include a suitable dosage form, such as those described above, and instructions describing how to use such dosage form to alleviate, reduce, or prevent inflammation. The instructions would instruct the consumer or medical professional to administer the dosage form according to modes of administration known to those skilled in the art. Such kits can advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a 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.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil with the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying manual pressure to the recesses, which forms openings in the sheet at the locations of the recesses, through which the tablets or capsules can then be removed.

[0117] It may be desirable to provide a memory aid in the kit, such as by marking next to the tablets or capsules numbers corresponding to the days of the regimen when the designated tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, indicating, for example, "Week 1, Monday, Tuesday, etc. ... Week 2, Monday, Tuesday, etc." Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or multiple pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule, while a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this. [Example]

[0118] The compounds described herein, for example, compounds of Formula I or Formula II, can be prepared in many ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, unless otherwise indicated, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup procedures, can be selected to be standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods will be shown accordingly. Starting materials for the examples are commercially available or easily prepared from known materials by standard methods. At least some of the compounds used as intermediates are contemplated as compounds of the present disclosure.

[0119] Example 1: Synthesis of 3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 104) [ka] A solution of methyl 3-bromo-5-iodobenzoate (1 g, 2.933 mmol, 1 equiv.), 2-(trifluoromethyl)pyridin-4-amine (475 mg, 2.933 mmol, 1 equiv.), and AlMe3 (422 mg, 5.866 mmol, 2 equiv.) in toluene (20 mL) was stirred at 100 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, gradient from 10% to 100% in 25 min; detector, UV at 254 nm. This gave 3-bromo-5-iodo-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (800 mg, 57.91% yield) as a white solid.

[0120] A solution of 3-bromo-5-iodo-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (700 mg, 1.486 mmol, 1 equiv.), imidazole (505 mg, 7.430 mmol, 5 equiv.), CuI (566 mg, 2.972 mmol, 2 equiv.), and KCO (616 mg, 4.458 mmol, 3 equiv.) in DMF (6 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, gradient from 10% to 100% in 25 min; detector, UV at 254 nm. This gave 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (470 mg, 76.91% yield) as a brown oil.

[0121] A solution of 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamil (100 mg, 0.243 mmol, 1 equiv.), prolinol (36 mg, 0.364 mmol, 1.5 equiv.), Pd(dba) (22 mg, 0.024 mmol, 0.1 equiv.), BINAP (30 mg, 0.049 mmol, 0.2 equiv.), and CsCO (237 mg, 0.729 mmol, 3 equiv.) in dioxane (8 mL) was stirred at 100 °C under a nitrogen atmosphere for 48 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 10% to 100% gradient in 25 min; detector, UV 254 nm. This afforded 3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (10.6 mg, 10.10% yield) as a white solid. LCMS (ESI) [M+H] + :432.15. 1 H NMR(300MHz,DMSO-d6)δ 10.87(s,1H),8.70(d,J=5.6Hz,1H),8.30(s,2H),8.07(dd,J=5.6,2.0Hz,1H),7.79(s,1H),7.37(s,1H),7.12(d,J=1 4.5Hz,2H),6.99(s,1H),4.87(t,J=5.7Hz,1H),3.90(s,1H),3.61-3.48(m,2H),3.30-3.11(m,2H),1.80-2.11(m,4H).

[0122] Example 2: Synthesis of 3-(imidazol-1-yl)-5-(1-methylpyrazol-4-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 106) [ka] A stirred solution of 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (100 mg, 0.243 mmol, 1 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (50 mg, 0.243 mmol, 1 equiv.), Pd(dppf)Cl (17 mg, 0.024 mmol, 0.1 equiv.), and KCO (100 mg, 0.729 mmol, 3 equiv.) in dioxane (4 mL) and HO (1 mL) was prepared under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 10% to 100% gradient in 25 min; detector, UV 254 nm. This afforded 3-(imidazol-1-yl)-5-(1-methylpyrazol-4-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (19.4 mg, 18.86% yield) as a gray solid. LCMS (ESI) [M+H] + :413.10. 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),8.72(d,J=5.5Hz,1H),8.42(d,J=20.2Hz,2H),8.30(d,J=2.0Hz ,1H),8.15-8.08(m,4H),8.00(s,1H),7.94(s,1H),7.18(s,1H),3.91(s,3H).

[0123] Example 3 Synthesis of 3-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 103) [ka] To a stirred mixture of methyl 3-bromo-5-iodobenzoate (2 g, 5.86 mmol, 1 equiv.) and 2-(trifluoromethyl)pyridin-4-amine (1.42 g, 8.799 mmol, 1.5 equiv.) in toluene (20 mL) was added trimethylaluminum (5.87 mL, 17.59 mmol, 3 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-bromo-5-iodo-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (450 mg, yield 16.29%) as a white solid.

[0124] 3-Bromo-5-iodo-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (403 mg, 0.85 mmol, 1 equiv.), K2CO3 (357 mg, 2.56 mmol, 3 equiv.), copper(I) iodide (32 mg, 0.17 mmol, 0.2 equiv.), (1S,2S)-N 1 ,N 2 The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (136 mg, 38.66% yield) as a white solid.

[0125] A stirred mixture of 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (80 mg, 0.19 mmol, 1 equiv.), (3S)-pyrrolidin-3-ylmethanol (29 mg, 0.29 mmol, 1.5 equiv.), CsCO (190 mg, 0.58 mmol, 3 equiv.), and Ruphos Pd G (16 mg, 0.02 mmol, 0.1 equiv.) in 1,4-dioxane (2 mL) was stirred at 90° C. under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC under the following conditions (Column: XBridge Prep C18 OBD column, 19*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH-HPLC; Flow rate: 25 mL / min; Gradient: 48% B to 72% B, 72% B in 8 min; Wavelength: 254 nm; RT1 (min): 7.12) to give 3-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (10 mg, 11.91% yield) as a white solid. LCMS (ESI) [M+H] + :432.00. 1 H NMR (400 MHz, DMSO-d6) δ 10.86(s,1H),8.69(d,J=5.5Hz,1H),8.32(d,J=1.2Hz,1H),8.29(d,J=2.0Hz, 1H),8.08(dd,J=5.6,2.0Hz,1H),7.82(s,1H),7.37(s,1H),7.13(s,1H),7.02 (s,1H),6.92(s,1H),4.77(t,J=5.2Hz,1H),3.54-3.39(m,4H),3.37(d,J=9.5 Hz,1H),3.20-3.11(s,1H),2.47(s,1H),2.01-2.08(m,1H),1.87-1.73(m,1H).

[0126] Example 4: Synthesis of 3-(imidazol-1-yl)-5-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 102) [ka] To a stirred mixture of tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (300 mg, 1.491 mmol, 1 equiv) in THF (30 mL) was added NaH (71 mg, 2.982 mmol, 2 equiv) under a nitrogen atmosphere at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 30 minutes. To the above mixture was added methyl iodide (423 mg, 2.981 mmol, 2.00 equiv) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, gradient from 10% to 100% in 25 min; detector, UV 254 nm to give tert-butyl (3S)-3-(methoxymethyl)pyrrolidine-1-carboxylate (100 mg, 31.16% yield) as a white solid.

[0127] A mixture of tert-butyl (3S)-3-(methoxymethyl)pyrrolidine-1-carboxylate (100 mg, 0.464 mmol, 1 equiv.) in HCl / 1,4-dioxane (3 mL) was stirred at room temperature for 1 hour, and the resulting mixture was concentrated under reduced pressure to give (3S)-3-(methoxymethyl)pyrrolidine hydrochloride (70 mg, 99.39% yield) as a white solid.

[0128] To a stirred mixture of 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (150 mg, 0.365 mmol, 1.0 equiv.) in dioxane (6 mL), (3S)-3-(methoxymethyl)pyrrolidine hydrochloride (66 mg, 0.438 mmol, 1.2 equiv.), Pd(dba) (33 mg, 0.036 mmol, 0.1 equiv.), BINAP (45 mg, 0.073 mmol, 0.2 equiv.), and CsCO (356 mg, 1.095 mmol, 3 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 10% to 100% gradient in 25 min; detector, UV 254 nm to give 3-(imidazol-1-yl)-5-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (13.5 mg, 8.31% yield) as a pale yellow solid. LCMS (ESI) [M+H] + :446.20. 1 H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.62(d,J=5.5Hz,1H),8.05(s,1H),7.78-7.74(m,1H),7.6 6(s,1H),7.30(d,J=8.7Hz,1H),7.20(s,1H),6.93(s,1H),6.81-6.73(m,2 H),3.45(dd,J=9.8,7.5Hz,1H),3.43-3.36(m,3H),3.40-3.34(m,3H),3. 19-2.99(m,1H),2.69-2.61(m,1H),2.01-2.18(m,1H),1.82-1.70(m,1H).

[0129] Example 5: Synthesis of 3-(imidazol-1-yl)-5-(morpholin-4-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 101) [ka] A solution of 3-bromo-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (90 mg, 0.219 mmol, 1 equiv.), morpholine (22 mg, 0.263 mmol, 1.2 equiv.), Pd(AcO) (5 mg, 0.022 mmol, 0.1 equiv.), BINAP (27 mg, 0.044 mmol, 0.2 equiv.), and CsCO (213 mg, 0.657 mmol, 3 equiv.) in toluene (5 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% formic acid), gradient from 10% to 100% in 25 min; detector, UV 254 nm to give 3-(imidazol-1-yl)-5-(morpholin-4-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (9.2 mg, 10.07% yield) as a white solid. LCMS (ESI) [M+H] + :418.05. 1 H NMR (300 MHz, methanol-d₄) δ 8.53 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.82-7.60 (m, 2H), 7.46-7.35 (m, 1H), 7.35-7.19 (m, 3H), 7.02 (s, 1H), 3.95-3.80 (m, 4H), 3.27 (s, 4H).

[0130] Example 6: Synthesis of 3-(1-methylpyrazol-4-yl)-5-(1,3-thiazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 105) [ka] A solution of 3-bromo-5-iodobenzoic acid (1 g, 3.059 mmol, 1 equiv.) and TMSCHN2 (699 mg, 6.118 mmol, 2 equiv.) in THF (6 mL) and MeOH (1.5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, gradient from 10% to 50% in 10 min; detector, UV at 254 nm. This afforded methyl 3-bromo-5-iodobenzoate (500 mg, 47.94% yield) as a white solid.

[0131] A mixture of methyl 3-bromo-5-iodobenzoate (500 mg, 1.467 mmol, 1 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (457.71 mg, 2.200 mmol, 1.5 equiv.), Pd(dppf)Cl (107 mg, 0.147 mmol, 0.1 equiv.), and KCO (608 mg, 4.401 mmol, 3 equiv.) in dioxane (6 mL) and HO (1.5 mL) was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 10% to 50% gradient in 10 min; detector, UV at 254 nm. This gave methyl 3-bromo-5-(1-methylpyrazol-4-yl)benzoate (150 mg, 34.66% yield) as a white solid.

[0132] A solution of methyl 3-bromo-5-(1-methylpyrazol-4-yl)benzoate (500 mg, 1.694 mmol, 1 equiv.), Pd(dppf)Cl (123.96 mg, 0.169 mmol, 0.1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (715.23 mg, 3.388 mmol, 2 equiv.), and KCO (702.41 mg, 5.082 mmol, 3 equiv.) in HO (0.5 mL) and dioxane (2 mL) was stirred at 90 °C under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% formic acid) in water, 10% to 50% gradient over 10 min; UV at 254 nm. This afforded methyl 3-(1-methylpyrazol-4-yl)-5-(1,3-thiazol-5-yl)benzoate (150 mg, 29.58% yield) as a white solid. To a mixture of methyl 3-(1-methylpyrazol-4-yl)-5-(1,3-thiazol-5-yl)benzoate (100 mg, 0.334 mmol, 1 equiv.) and 2-(trifluoromethyl)pyridin-4-amine (64 mg, 0.401 mmol, 1.2 equiv.) in toluene (5 mL) was added Al(Me)3 (48 mg, 0.668 mmol, 2 equiv.) at 0 °C. The resulting mixture was stirred at 100° C. for 1 hour under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% formic acid), gradient from 10% to 100% in 25 min; detector, UV 254 nm to afford 3-(1-methylpyrazol-4-yl)-5-(1,3-thiazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (15 mg, 10.46% yield) as a gray solid. LCMS (ESI) [M+H] + :430.10. 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),9.18(s,1H),8.71(d,J=5.6Hz,1H),8.53(s,1H),8.39-8.30(m,2H),8.18-8.09(m,4H),8.00(s,1H),3.91(s,3H).

[0133] Example 7: CD38 hydrolase inhibition assay The CD38 hydrolase inhibition assay measures the glycohydrolase activity of CD38 by measuring the formation of a fluorescent ADP-ribose analog using an NAD analog as a substrate. A 4x buffer containing 1 M sucrose and 160 mM Tris-HCl at pH 7.4 was prepared to give final assay concentrations of 250 mM sucrose and 40 mM Tris-HCl. The 4x solution was stored at 4°C and warmed to room temperature before use. Tween® 20 was added to the 1x buffer to a final concentration of 0.05%. Human recombinant CD38 (BPS Bioscience) was diluted to 0.4 ng / μL in the 1x buffer, and 12.5 μL was added to each well of the plate. Inhibitors were added, and DMSO content was normalized to the highest concentration on the plate, with an upper limit of 0.5%. Finally, ε-NAD was diluted to 200 μM in 1x buffer and 12.5 μL was added to each plate well, resulting in a final well concentration of 0.2 ng / μL CD38 and 100 μM ε-NAD. Plates were covered and incubated at room temperature for 15 minutes, then read on a plate reader using excitation at 300 nm and emission at 410 nm. 200 nM 78c was included as a fully inhibited well, and DMSO-only wells were included as no inhibition. IC50s for test compounds were determined using GraphPad Prism software v9.3 or CDD Vault. Results are shown in Table 2.

[0134] [Table 2]

[0135] Incorporation by Reference All publications and patents mentioned herein, including those listed below, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0136] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless indicated to the contrary or otherwise clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the members of the group are present in, employed in, or associated with a given product or process, unless indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or associated with a given product or process. The present disclosure includes embodiments in which more than one or all of the members of the group are present in, employed in, or associated with a given product or process.

[0137] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the present disclosure or aspects of the disclosure are referred to as including certain elements and / or features, it is understood that particular embodiments of the disclosure or aspects of the disclosure consist of or consist essentially of such elements and / or features. For the sake of brevity, these embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges set forth in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0138] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly set forth herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0139] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. Formula I: 【Chemistry 24】 (In the formula, R １ is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R １ is R １１ and optionally substituted by one or more substituents each independently selected from R ２ is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R ２ is R ２２ and optionally substituted by one or more substituents each independently selected from R ３ is -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ selected from the group consisting of alkynyl and halogen; １～６ Alkyl, —C ２～６ Alkenyl and —C ２～６ The alkynyl may be optionally substituted with one or more halogens; R ４ is —C optionally substituted with hydrogen and one or more halogens １～３ is selected from the group consisting of alkyl, R ５ and R ６ is independently at each occurrence hydrogen, halogen, deuterium, hydroxyl, -C １～６ Alkyl, —C １～６ Alkoxy, -CN, -NR ａ R ｂ , —C(O)—NR ａ R ｂ and -NR ａ -C(O)-R ｂ is selected from the group consisting of R １１ , R ２２ and R ３３ is independently at each occurrence a halogen, a hydroxyl, -C １～６ Alkyl, —C １～６ Alkoxy, -C ３～６ Cycloalkyl, phenyl, —CN, —CF ３ , -NR ａ R ｂ , —C(O)—NR ａ R ｂ , -NR ａ -C(O)-R ｂ and deuterium, １～６ Alkyl and -C １～６ Alkoxy is a group selected from hydroxyl, halogen and -C １～３ may be optionally substituted by one or more substituents each independently selected from alkoxy, and R ａ and R ｂ is independently at each occurrence -C optionally substituted with hydrogen and one or more halogens. １～３ alkyl) or a pharmaceutically acceptable salt and / or stereoisomer thereof.

2. R ５ and R ６ The compound of claim 1 , wherein is absent. 【Request Item 3】 【Chemistry 25】 3. The compound of claim 1 or 2, represented by:

4. R １ is a 5-6 membered heteroaryl containing at least one ring nitrogen, and R １ is R １１ The compound of any one of claims 1 to 3, optionally substituted by one or two substituents each independently selected from:

5. R １ is selected from the group consisting of imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridyl; R １ is -CH ２ OH, —OH and —NH ２ The compound of any one of claims 1 to 4, optionally substituted with one or two substituents each independently selected from the group consisting of:

6. R １ teeth, 【Chemistry 26】 The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. R １ teeth, 【Chemistry 27】 The compound according to any one of claims 1 to 6, selected from the group consisting of:

8. R ２ is a 5-membered heteroaryl, and R ２ is hydroxyl or -C １～３ may be optionally substituted by alkyl, １～３ Alkyl is hydroxyl or -C １～３ The compound of any one of claims 1 to 7, optionally substituted with alkyl.

9. R ２ teeth, 【Chemistry 28】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. R ２ is a 5- to 6-membered heterocyclyl, and R ２ is hydroxyl or -C １～３ may be optionally substituted by alkyl, １～３ Alkyl is hydroxyl or -C １～３ The compound of any one of claims 1 to 7, optionally substituted by alkoxy.

11. R ２ teeth, 【Chemistry 29】 The compound of any one of claims 1 to 7 or 10, selected from the group consisting of:

12. R ３ is —C optionally substituted with one, two or three fluoro groups １～３ The compound of any one of claims 1 to 11, which is alkyl.

13. R ３ is -CF ３ The compound according to any one of claims 1 to 12, 【Request Item 14】 【Chemistry 30】 The compound according to any one of claims 1 to 13, represented by:

15. R ４ The compound according to any one of claims 1 to 14, wherein is hydrogen.

16. Formula II: 【Chemistry 31】 (In the formula, R １ is a 5-6 membered heteroaryl containing at least one ring nitrogen, and R １ is a halogen, hydroxyl, -NH ２ , -C １～３ Alkyl, —C １～３ Alkyl-OH and -C １～３ may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of alkoxy, and R ２ is halogen, hydroxyl or -C １～３ is a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl optionally substituted by alkyl, １～３ Alkyl and -C １～３ Alkoxy is a group selected from hydroxyl, halogen and -C １～３ and optionally substituted with one or more groups selected from alkoxy. or a pharmaceutically acceptable salt and / or stereoisomer thereof.

17. R １ teeth, 【Chemistry 32】 17. The compound of claim 16, selected from the group consisting of:

18. R １ teeth, 【Transformation 33】 18. The compound of claim 16 or 17, selected from the group consisting of:

19. R ２ teeth, 【Transformation 34】 The compound according to any one of claims 16 to 18, selected from the group consisting of: 【Request Item 20】 【Chemistry 35】 or a pharmaceutically acceptable salt and / or stereoisomer thereof.

21. Formula III: 【Transformation 36】 (In the formula, X and Y are each independently selected from N and CH, and at least one of X and Y is N; R １ is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and R １ is R １１ and optionally substituted by one or more substituents each independently selected from R ２ is selected from the group consisting of 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and phenyl; R ２ is R ２２ and optionally substituted by one or more substituents each independently selected from R ３ is —C optionally substituted with hydrogen and one or more halogens １～３ is selected from the group consisting of alkyl, R ４ and R ５ is independently at each occurrence hydrogen, halogen, deuterium, hydroxyl, -CF ３ , -C １～６ Alkyl, —C １～６ Alkoxy, -CN, -NR ａ R ｂ , —C(O)—NR ａ R ｂ and -NR ａ -C(O)-R ｂ is selected from the group consisting of R １１ and R ２２ is independently at each occurrence a halogen, a hydroxyl, -C １～６ Alkyl, —C １～６ Alkoxy, -C ３～６ Cycloalkyl, phenyl, —CN, —CF ３ , -NR ａ R ｂ , —C(O)—NR ａ R ｂ , -NR ａ -C(O)-R ｂ and deuterium, １～６ Alkyl and -C １～６ Alkoxy is a group selected from hydroxyl, halogen and -C １～３ may be optionally substituted by one or more substituents each independently selected from alkoxy, and R ａ and R ｂ is independently at each occurrence -C optionally substituted with hydrogen and one or more halogens. １～３ alkyl) or a pharmaceutically acceptable salt and / or stereoisomer thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

23. 23. A method of treating a disease that benefits from the inhibition of CD38 in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 21 or a pharmaceutical composition of claim 22.

24. 23. A method of treating a disease that benefits from increased NAD+ in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 21 or a pharmaceutical composition of claim 22.

25. 23. A method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

26. 26. The method of claim 25, wherein the neurodegenerative disease is Parkinson's disease.

27. A method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

28. 28. The method of claim 27, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, melanoma, and colon cancer.

29. 23. A method of treating a patient suffering from fibrosis in need thereof, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

30. 31. The method of claim 30, wherein the patient suffering from fibrosis also suffers from systemic sclerosis.

31. 32. The method of claim 30 or 31, wherein the fibrosis is selected from the group consisting of dermal fibrosis, pulmonary fibrosis and peritoneal fibrosis.

32. 23. A method of treating fatty liver disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

33. 30. The method of claim 29, wherein the fatty liver disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

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