Inhibitors of cyclic ADP ribohydrolase, methods of use thereof

Abstract

The present disclosure provides compounds, in part, compounds of Formula I or Formula II, and their use in the treatment of medical diseases or disorders, such as neurodegenerative diseases, e.g., Parkinson's disease. Pharmaceutical compositions and methods of making the compounds of the present disclosure are provided. These compounds are envisaged to be modulators, e.g., inhibitors, of cyclic ADP ribohydrolase (CD38).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to USSN 63 / 424,440, filed November 10, 2022; the contents of which are incorporated herein by reference in their entirety. Background Art

[0002] Glycoprotein CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a multifunctional enzyme that, for example, catalyzes the degradation of nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose (ADP ribose or ADPR). CD38 can also serve as a cyclase that converts NAD+ into cyclic ADP-ribose (cADPR). Its NAD enzyme activity is more significant than its effect as an ADP-ribosyl-cyclase, and is 100 times less efficient in making NAD+ cyclized to cADPR than in making NAD+ hydrolyzed 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 to be an important consumer of NAD+ and a regulator of NAD+ levels.

[0003] Dysregulation of NAD+ levels is associated with a variety of disease states. 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, restoring NAD+ to its normal level in disease states that deplete significant amounts of NAD+ may yield therapeutic benefits.

[0004] For example, decreased NAD+ levels are associated with aging, and this age-related dysfunction may lead to increased neurogeneration and the onset of neurodegenerative disorders. It is contemplated that the expression of CD38, the enzyme responsible for NAD+ degradation, increases with aging, thus providing a plausible rationale for decreased NAD+ levels with aging. Thus, one approach to regulating cellular NAD+ levels could be to inhibit enzymes that consume NAD+, such as CD38.

[0005] Inhibition of CD38 enzymatic activity, which in turn 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 treating diseases or conditions that respond to modulation (e.g., inhibition) of cellular levels of NAD+. Summary of the Invention

[0006] The present disclosure relates, at least in part, to compounds that modulate (eg, 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, disclosed herein are compounds represented by Formula I: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl; wherein R 1 can be optionally selected from one or more independently selected R 11 Substituents substituted; R 2 Choose Free-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -C 3-6 A group consisting of cycloalkyl; wherein R 2 can be optionally selected from one or more independently selected R 22 Substituents substituted; R 3 is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 4-10 membered heterocyclic group and phenyl; wherein R 3 can be optionally selected from one or more independently selected R 33 Substituents substituted; R 4 Selected from hydrogen and -C optionally substituted by one or more halogens 1-3 a group consisting of alkyl groups; R 5 Selected from hydrogen, deuterium, halogen, 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 the group formed; R 11 、R 22 and R 33 Each occurrence is independently selected from the group consisting of halogen, hydroxy, -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; among them -C 1-6 Alkyl and -C 1-6 Alkoxy may be optionally substituted with one or more substituents each independently selected from hydroxy and halogen; and R a and R b Each occurrence is independently selected from hydrogen and -C optionally substituted with one or more halogens 1-3 A group consisting of alkyl groups.

[0008] Also disclosed herein are compounds represented by Formula II: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered heteroaryl group containing at least one ring nitrogen; wherein R 1 It can be optionally replaced by one, two or three independently selected from halogen, hydroxy, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-OH and -C 1-3 Substitution of a substituent consisting of an alkoxy group; R 2 Yes-C 1-6 Alkyl or -C 3-6 Cycloalkyl; wherein R 2 can be optionally replaced by one or more independently selected from halogen, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy and -NR a R b substituted with a substituent consisting of a group; and R a and R b Each occurrence is independently selected from hydrogen and -C 1-3 A group consisting of alkyl groups.

[0009] Also disclosed herein is a method of treating a disease (e.g., a neurodegenerative disease) that benefits from inhibition of CD38 and / or an increase in NAD+ 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

[0010] 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 collected here. These definitions should be interpreted in light of the remainder of this disclosure and 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 of ordinary skill in the art. definition

[0011] 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 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 Alkyl, C 1-4 Alkyl and C 1-3 Alkyl. Exemplary 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0012] As used herein, the term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight or branched groups of 2-6 or 3-4 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.

[0013] 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 2-6, or 3-6 carbon atoms, referred to herein as C 2- 6 alkynyl and C 3-6 Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0014] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached to an oxygen group (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 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.

[0015] The term "aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in the cyclic array) with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl," e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, Coronene, fluoranthene, fluorene, hexacene, hexalene, hexalene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentane-2,4-diene, pentacene, pentalene, pentalene, perylene, phenanthren, pyrenes, pyranthrene, rubrocene, triphenylene and terapthyl. In particular, aryl includes phenyl, naphthyl, indenyl and tetrahydronaphthyl. Examples of representative substituted aryl groups include the following where R 56 and R 57 One of them may be hydrogen and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 、COO alkyl、COO aryl、CONR 58 R 59 、CONR 58 OR 59 NR 58 R 59 、SO2NR58 R 59 , S-alkyl, SO alkyl, SO 2 alkyl, S aryl, SO aryl, SO 2 aryl; or R 56 and R 57 can be linked to form a cyclic ring (saturated or unsaturated) of from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, substituted C6-C 10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0016] The term "carbonyl" as used herein refers to the group -C(O)-.

[0017] The term "cyano" as used herein refers to the group -CN.

[0018] As used herein, the term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbon atoms, respectively, referred to herein as C3-C 10 Cycloalkyl, C 3-6 Cycloalkyl or C 4-6 Cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0019] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0020] As used herein, the term "haloalkyl" refers to an alkyl group in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), 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 1-6, 1-4, or 1-3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), referred to herein as C 1-6 Halogenated alkyl, C 1-4 Haloalkyl and C 1-3 Halogenated alkyl.

[0021] 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 nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the hydrocarbon groups described above, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl), etc., having from 1 to 5 and particularly from 1 to 3 heteroatoms.

[0022] As used herein, the term "heteroaryl" or "heteroaromatic group" refers to an aromatic 5-10 ring system containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur). The term can also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, the heteroaryl ring can be connected to an adjacent group via carbon or nitrogen. 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, or pyrimidine.

[0023] The term "heterocyclyl", "heterocycle" or "heterocyclic group" is generally recognized in the art and refers to a saturated or partially unsaturated 4-10 ring structure, the ring structure of which includes one to three heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, the heterocyclyl ring can be connected to an adjacent group by carbon or nitrogen. The term can also be used to refer to a 4-10 saturated or partially unsaturated ring structure as a bridged, fused or spirocyclic ring structure, the ring structure of which includes one to three heteroatoms, such as nitrogen, oxygen and sulfur. The example of heterocyclyl includes but is not limited to pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran etc. In some embodiments, heterocycle is a spiro heterocycle (for example, 2,8-diazaspiro [4.5] decane). In some embodiments, heterocycle is a bridged heterocycle (for example, octahydro-1H-4,7-methylene isoindole). "Spiro heterocyclyl" or "spiroheterocycle" refers to a polycyclic heterocyclic group having rings joined by a common atom (called a spiro atom), wherein the rings have one or more radicals selected from the group consisting of N, O and S(O) m (wherein m is an integer from 0 to 2) as the ring atoms.

[0024] As used herein, the terms "hydroxy" and "hydroxyl" refer to the group -OH.

[0025] The term "oxo" as used herein refers to the group =0.

[0026] "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 the case may be. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0027] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonicity agents, 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 composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic function.

[0028] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0029] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds that are basic in nature and included in the compositions of the present invention are capable of forming 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, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds that are acidic in nature and included in the compositions of the present invention are capable of forming 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 comprising a basic or acidic moiety included in the compositions of the present invention may also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0030] The compounds of the present disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of substituents around the stereogenic carbon atom, but the skilled person 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 as "(±)" in nomenclature, but the skilled person will recognize that the structure may implicitly represent a chiral center.

[0031] The compounds of the present disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bond. "Z" refers to a bond that can be a single bond, a double bond, or a triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise indicated, structures depicting double bonds encompass both "E" and "Z" isomers. Substituents around a carbon-carbon double bond can alternatively be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond.

[0032] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings and, therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in "Z" or "E" configuration, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise indicated, the structure depicting a carbocyclic or heterocyclic ring encompasses both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," wherein the term "cis" represents a substituent on the same side of the ring plane, and the term "trans" represents a substituent on the opposite side of the ring plane. A mixture of compounds in which substituents are disposed on both the same and opposite sides of the ring plane is designated as "cis / trans."

[0033] 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 preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the auxiliary; (2) forming salts using an optically active resolving agent; (3) directly separating a mixture of optical enantiomers 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 syntheses (chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereogenic center or during the conversion of a pre-existing stereogenic center) are well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0034] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.), and it is intended that the disclosure encompasses 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 crystalline form.

[0035] The present disclosure also encompasses isotopically labeled compounds of the present disclosure identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36Cl. For example, the compounds of the present disclosure can have one or more H atoms replaced by deuterium.

[0036] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) can offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0037] The term "prodrug" refers to a compound that is converted in vivo to produce a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The conversion can occur in various locations (such as in the intestinal lumen or during transport in the intestine, blood or liver) by various mechanisms (such as by esterases, amidases, phosphatases, oxidation and or reduction metabolism). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery [Natural Review Drug Discovery] 2008, 7, 255). For example, if the compound of the present disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (C 1-8 )alkyl, (C 2-12 )alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactone, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 ) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1-2)alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidinyl-, pyrrolidinyl- or morpholino (C 2-3 )alkyl.

[0038] Similarly, if the compounds of the present disclosure contain an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkoxycarbonyloxy)ethyl, (C 1-6 ) alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinyl, (C 1-6 ) alkylcarbonyl, α-amino (C 1-4 )alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl (wherein each α-aminoalkylcarbonyl is independently selected from naturally occurring L-amino acids), P(O)(OH)2, -P(O)(O(C 1-6 )alkyl)2 or glycosyl (a group derived from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0039] If the compounds of the present disclosure contain an amine functional group, a prodrug can be formed, for example, by generating an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolyl)methyl derivative, an N-Mannich base, an imine, or an enamine. In addition, 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. For example, see Simplício, et al., Molecules [Molecules] 2008, 13, 519 and references therein.

[0040] The term "treatment" or "treating" refers to the medical management of a patient for the purpose of improving, alleviating, stabilizing (i.e., not worsening), preventing, or curing a disease, pathological condition, or disorder. "Treatment" includes active treatment (treatment intended to improve a disease, pathological condition, or disorder), etiological treatment (treatment directed to the cause of the relevant disease, pathological condition, or disorder), palliative care (treatment intended to alleviate symptoms), preventive treatment (treatment intended to minimize or partially or completely inhibit the development of a relevant disease, pathological condition, or disorder); and supportive care (treatment to supplement another therapy). Treatment also includes reducing the extent of a disease or disorder; preventing the spread of a disease or disorder; delaying or slowing the progression of a disease or disorder; alleviating or relieving a disease or disorder; and alleviating (whether partial or complete), whether detectable or undetectable. "Relieve" or "relieve" a disease or disorder means that the extent of a disease, disorder, or disorder and / or the time course of reduced and / or undesirable clinical manifestations are slowed or prolonged compared to the extent or time course in the absence of treatment. "Treatment" also includes extending survival compared to the expected survival if not treated. Those in need of treatment include those already with the condition or disorder as well as those prone to having the condition or disorder or those in whom the condition or disorder is to be prevented.

[0041] The terms "effective amount," "therapeutically effective amount," or "sufficient amount" refer to an amount sufficient to achieve treatment (e.g., produce a beneficial or desired result) (including effects at the cellular, tissue, or clinical level, etc.) when administered to a patient (e.g., a mammal, such as a human patient). As such, the term depends on the context in which it is used. For example, in the context of treating a disclosed neurodegenerative disease, it is an amount of the 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 would correspond 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 still be routinely determined by one skilled 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., as compared to a control). The therapeutically effective amount of a composition of the present disclosure can be readily determined by one of ordinary skill in the art by conventional methods known in the art. The dosage regimen can be adjusted to provide the optimal therapeutic response.

[0042] "Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the 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, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0043] In some embodiments, the patient is a human. In some embodiments, the patient is an adult patient. In some embodiments, the patient is 30 years of age or older, for example, at least: 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 years of age. I. Compounds

[0044] The present disclosure relates, in part, to compounds contemplated as modulators (eg, inhibitors) of CD38.

[0045] For example, disclosed herein are compounds represented by Formula I: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl; wherein R 1 can be optionally selected from one or more independently selected R 11 Substituents substituted; R 2 Choose Free-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -C 3-6 A group consisting of cycloalkyl; wherein R 2 can be optionally selected from one or more independently selected R 22 Substituents substituted; R 3 is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 4-10 membered heterocyclic group and phenyl; wherein R 3 can be optionally selected from one or more independently selected R 33 Substituents substituted; R 4 Selected from hydrogen and -C optionally substituted by one or more halogens 1-3 a group consisting of alkyl groups; R 5 Selected from hydrogen, deuterium, halogen, hydroxyl, -C 1-6Alkyl, -C 1-6 Alkoxy, -CN, -NR a R b 、-C(O)-NR a R b and -NR a -C(O)-R b the group formed; R 11 、R 22 and R 33 Each occurrence is independently selected from the group consisting of halogen, hydroxy, -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; among them -C 1-6 Alkyl and -C 1-6 Alkoxy may be optionally substituted with one or more substituents each independently selected from hydroxy and halogen; and R a and R b Each occurrence is independently selected from hydrogen and -C optionally substituted with one or more halogens 1-3 A group consisting of alkyl groups.

[0046] In some embodiments, R 3 Selected, for example, from the group consisting of:

[0047] In other embodiments, when present, R 33 Each occurrence is independently selected from the group consisting of -CF3, fluorine, chlorine, -CN, -C 1-4 Alkyl, -C 3-4 A group consisting of a cycloalkyl group and a phenyl group.

[0048] For example, in some embodiments, R 3 Select from the group consisting of

[0049] In certain other embodiments, R 3 For example

[0050] In some embodiments, the compounds disclosed herein can be represented by:

[0051] In other embodiments, R 4 is hydrogen. In yet other embodiments, R 5 Selected from the group consisting of, for example, hydrogen, chlorine and fluorine.

[0052] In certain embodiments, for example, the compounds disclosed herein can be represented by:

[0053] In some embodiments, R 1 is a 5-6 membered heteroaryl group containing at least one ring nitrogen, wherein R 1 can be optionally replaced by one or two independently selected from R 11 substituted by a substituent.

[0054] For example, in some embodiments, R 1 is selected from the group consisting of imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and pyridinyl, wherein R 1 It may be optionally substituted with one or two substituents each independently selected from the group consisting of -CH2OH, -OH and -NH2.

[0055] In another embodiment, R 1 Select from the group consisting of

[0056] In certain other embodiments, for example, R 1 Select from the group consisting of

[0057] In some embodiments, R 2 is selected from the group consisting of, for example, -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2, cyclopropyl, -CH2CH2OCH2CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In other embodiments, R 2 is selected from the group consisting of, for example, -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2 and cyclopropyl. In yet other embodiments, R 2 It is, for example, -CH2CH2OCH3.

[0058] Also disclosed herein are compounds represented by Formula II: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered heteroaryl group containing at least one ring nitrogen; wherein R1 It can be optionally replaced by one, two or three independently selected from halogen, hydroxy, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-OH and -C 1-3 Substitution of a substituent consisting of an alkoxy group; R 2 Yes-C 1-6 Alkyl or -C 3-6 Cycloalkyl; wherein R 2 can be optionally replaced by one or more independently selected from halogen, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy and -NR a R b substituted with a substituent consisting of a group; and R a and R b Each occurrence is independently selected from hydrogen and -C 1-3 A group consisting of alkyl groups.

[0059] In some embodiments, R 1 Selected, for example, from the group consisting of:

[0060] In other embodiments, R 2 is selected from the group consisting of, for example, -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2 and cyclopropyl. For example, in certain embodiments, R 2 It is -CH2CH2OCH3.

[0061] In some embodiments, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.

[0062] The procedures for preparing the compounds described herein are provided in the following examples. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl) to avoid them from undesirably participating in the reaction. The incorporation of such groups and the introduction and removal of the required methods are well known to those skilled in the art (e.g., referring to Greene, Wuts, Protective Groups in Organic Synthesis [protective groups in organic synthesis]. 2nd edition (1999)). The deprotection step can be the last step in the synthesis so that the removal of the protecting group provides a compound as disclosed herein. The starting material used in the following scheme can be purchased or prepared using methods known to those skilled in the art by the methods described in the chemical literature or by its adaptability. The order in which these steps are carried out may vary depending on the group introduced and the reagent used, but will be apparent to those skilled in the art.

[0063] The compounds disclosed herein or any intermediates described in the above schemes can be further derivatized using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify the disclosed compounds or any of the aforementioned intermediates by modifying, introducing, or removing appropriate functional groups.

[0064] In the case of desiring to obtain the specific enantiomer of the disclosed compound, this can be produced by any suitable conventional procedure for splitting enantiomers known to those skilled in the art by a mixture of corresponding enantiomers. For example, diastereomeric derivatives (such as salts) can be produced by the reaction of a mixture of the enantiomers of the disclosed compound (such as racemates) and a suitable chiral compound (such as chiral bases). The diastereoisomers can then be separated by any conventional means (such as crystallization or chromatography), and the desired enantiomer can be reclaimed (such as by treating with acid when the diastereoisomer is a salt). Alternatively, the racemic mixture of esters can be split by kinetic hydrolysis using a variety of biocatalysts (for example, referring to Patel Stereoselective Biocatalysts [stereoselective biocatalysts], Marcel Decker; New York 2000).

[0065] In another resolution method, chiral high performance liquid chromatography can be used to separate the racemates of the disclosed compounds. Alternatively, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the methods described above. In the case where it is desired to obtain an intermediate or final product of a specific geometric isomer of the present disclosure, chromatography, recrystallization, and other conventional separation procedures can also be used.

[0066] In alternative embodiments, the disclosed compounds may also contain one or more isotopic substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon can be e.g. 13 C or 14 C; oxygen can be e.g. 18 O; nitrogen can be e.g. 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H. 13 C. 14 C. 18 O, or 15 N) can comprise 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 in the compound. II. Methods

[0067] It is contemplated that the compounds disclosed herein inhibit the activity of CD38. For example, provided herein is a method of inhibiting the activity or function of CD38 in a cell or in a patient in need of CD38 inhibition, 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. For example, also disclosed herein is a method of treating a disease in a patient in need thereof that would benefit from inhibition of CD38, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, thereby treating the disease in the patient.

[0068] It is contemplated that the compounds disclosed herein increase the level of NAD+. For example, provided herein is a method of increasing the level of NAD+ in a sample or a patient in need thereof, comprising contacting the sample with an effective amount of a compound disclosed herein 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 increased level of NAD+ is relative to the level of NAD+ prior to contacting or administering. Further disclosed herein is a method of treating a disease in a patient in need thereof that would benefit from an increase in 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.

[0069] The compounds disclosed herein can be used to treat diseases associated with abnormal expression or activity of CD38. For example, the 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 as described herein, for example, a compound of Formula I or Formula II, thereby treating cancer in the patient. In some embodiments, the cancer is characterized by abnormal expression or activity of CD38 compared to normal cells, for example, elevated expression or activity. In other embodiments, the cancer can be selected from the group consisting of, for example, the following cancers: breast, central nervous system, endometrium, kidney, large intestine, lung, esophagus, ovary, pancreas, prostate, stomach, head and neck, urinary tract, and colon. 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 can 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 Burkitt'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 can be selected from the group consisting of, for example, checkpoint-therapy treated cancer, checkpoint-therapy refractory cancer, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0070] For example, the cancers contemplated by the present disclosure that can be treated by administering the compounds described herein can 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 aerodigestive 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, clear cell renal carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. In some embodiments, the cancers contemplated by the present disclosure that are treatable by administration of the compounds described herein can 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 respiratory tract digestive cancer), kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, and breast cancer.

[0071] 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 disorder 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, Hansen's disease, 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, sarcopenic obesity, end-stage renal disease, dyslipidemia, hearing loss, liver disease, steatosis, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, multiple sclerosis, neurocognitive disorders, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnap disease, skin hyperpigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontal disease, chronic lymphocytic leukemia, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Leber's hereditary amaurosis, insulin resistance, type 1 diabetes, and type 2 diabetes.

[0072] It is contemplated that the compounds described herein have therapeutic utility in CD38-related disorders in disease areas such as, for example, cardiology, virology, neurodegeneration, inflammation, and pain, where these diseases are characterized by overexpression or increased activity of CD38.

[0073] Another aspect of the present disclosure provides a method for treating a patient suffering from a neurodegenerative disease or disorder (e.g., Parkinson's disease). As used herein, the term "neurodegenerative disease" or "neurodegenerative disorder" encompasses a disease, disorder, or condition in which cells of the central nervous system stop working or die. Neurodegenerative diseases typically worsen over time and are incurable. Such diseases can be hereditary or caused by tumors or strokes. Neurodegenerative diseases also occur in people who take in 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 disease, spinocerebellar ataxia (SCA), vascular dementia, frontotemporal dementia (FTD), mixed dementia, and Lewy body dementia (LBD). In certain embodiments, the neurodegenerative disease is a late-onset disease. In other embodiments, the present disclosure provides a method for treating a patient suffering from neuroinflammation.

[0074] In some embodiments, the neurodegenerative disease affects the basal ganglia, thalamus, red nucleus, locus coeruleus, parahippocampal gyrus, or a combination thereof. In some embodiments, the neurodegenerative disease affects the basal ganglia and / or thalamus.

[0075] In some embodiments, the neurodegenerative disease is ALS, HD, PD, or SCA. In specific embodiments, the neurodegenerative disease is PD. In certain embodiments, PD is familial Parkinson's disease.

[0076] The patient to be treated according to the methods described herein can be a patient who has been diagnosed with a neurodegenerative disease (e.g., PD) or a patient at risk of developing such a disease. Diagnosis of a neurodegenerative disease or the risk of developing a neurodegenerative disease can be performed by a skilled medical professional using any suitable method or technique known in the art. It will be understood by those skilled in the art that a patient to be treated according to the present disclosure may have undergone standard testing, or may not need to be examined for patients who have been identified as having a risk due to the presence of one or more risk factors associated with a disease or condition.

[0077] 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 of developing a neurodegenerative disease (e.g., PD). In some embodiments, the patient has PD or is at risk of developing PD.

[0078] For example, the present 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.

[0079] 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 an effective amount of any compound described herein (e.g., a compound of Formula I or Formula II), or a pharmaceutical composition comprising any compound described herein, and a pharmaceutically acceptable carrier or excipient.

[0080] Also contemplated are neurodegenerative diseases as ocular 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 is a method of treating an ocular disorder, such as one or more of: 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.

[0081] Another aspect of the present disclosure provides a method for treating a patient with fatty liver disease or disorder (e.g., NAFLD or NASH). As used herein, the term "fatty liver disease" encompasses a disease, disorder, or condition caused by the storage of excess fat in the liver. Alcoholic fatty liver disease is the accumulation of fat in the liver due to heavy drinking. Non-alcoholic fatty liver disease (NAFLD) occurs in people who are not heavy drinkers.

[0082] In certain embodiments, fatty liver disease is NAFLD. NAFLD is a spectrum of liver disease in which hepatic steatosis (bulboidal accumulation of triglycerides in hepatocytes) develops in the absence of secondary causes (e.g., drugs, excessive drinking, or certain heritable conditions). In certain embodiments, NAFLD is simple hepatic steatosis (NAFL). In a specific embodiment, NAFLD is non-alcoholic steatohepatitis (NASH). NASH is an inflammatory subtype of NAFLD, with evidence of steatosis and hepatocellular damage (ballooning) and inflammation, with or without fibrosis.

[0083] Patients to be treated according to methods described herein can be patients who have been diagnosed with fatty liver disease (e.g., NAFLD) or patients who are at risk of developing such a disease. Fatty liver disease or the diagnosis of the risk of developing fatty liver disease can be carried out by skilled medical professionals using any suitable method or technology known in the art. Those skilled in the art will appreciate that subjects to be treated according to this disclosure may have been subjected to standard tests, or may not need to be identified as having risk due to the presence of one or more risk factors associated with a disease or illness.

[0084] 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 NAFLD or is at risk of developing NAFLD. In some embodiments, the patient has NASH or is at risk of developing NASH.

[0085] In some embodiments, the patient has NAFLD (eg, NASH). In some embodiments, the patient also has hypertriglyceridemia, obesity, dyslipidemia, metabolic syndrome, hypertension, or type 2 diabetes, or a combination thereof.

[0086] For example, the present disclosure provides a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor as 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 selected from the group consisting of: e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and diabetes (type I or type II).

[0087] 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.

[0088] In certain embodiments, the present disclosure provides a method of treating a medical indication comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0089] For example, also disclosed herein is a method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound of Formula I or Formula II), or a pharmaceutical composition comprising any compound described herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the neurodegenerative disease is Parkinson's disease.

[0090] Also disclosed herein is a method of treating neuroinflammation in a patient in need thereof, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound of Formula I or Formula II), or a pharmaceutical composition comprising any compound described herein, and a pharmaceutically acceptable carrier or excipient.

[0091] Further disclosed herein is a method for treating fatty liver disease in a patient in need thereof, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound of Formula I or Formula II), or a pharmaceutical composition comprising any compound described herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, fatty liver disease is non-alcoholic fatty liver disease (NAFLD). In other embodiments, fatty liver disease is non-alcoholic steatohepatitis (NASH). In further embodiments, fatty liver disease is simple hepatic steatosis. In certain embodiments, treating fatty liver disease includes slowing down the progression of fatty liver disease.

[0092] In addition, disclosed herein is a method for treating fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound of Formula I or Formula II), or a pharmaceutical composition comprising any compound described herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, fibrosis is multi-organ fibrosis. In other embodiments, fibrosis is associated with systemic sclerosis. For example, a patient with fibrosis also suffers from systemic sclerosis. In yet other embodiments, fibrosis is selected from the group consisting of skin fibrosis, pulmonary fibrosis, and peritoneal fibrosis.

[0093] In certain embodiments, the methods described herein further comprise administering to the patient an additional therapeutic agent that treats the disclosed diseases or disorders, or that treats the disclosed diseases or disorders that are affected by, associated with, or would benefit from selective modulation (e.g., inhibition) of CD38.

[0094] 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 the disclosed compounds and another therapeutic agent as disclosed herein and methods of administering the disclosed compounds and the disclosed therapeutic agents separately are contemplated herein. For example, a pharmaceutical composition is provided herein comprising the compounds described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, the disclosed compounds and one additional therapeutic agent are administered. In some embodiments, the disclosed compounds as defined herein and two additional therapeutic agents are administered. In some embodiments, the disclosed compounds as 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, the disclosed compounds and additional therapeutic agents can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation (e.g., a pharmaceutical composition comprising the disclosed compounds as a therapeutic agent and one or more additional therapeutic agents). For example, the disclosed compounds and additional therapeutic agents can be administered in a single formulation. Combination therapy also encompasses other combinations. Although these two or more medicaments in combination therapy can be used simultaneously, they do not need to be used simultaneously. For example, the use of the first medicament (or the combination of medicament) can be a few minutes, hours, days or weeks before the use of the second medicament (or the combination of medicament). Therefore, these two or more medicaments can be used within a few minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18 or 24 hours or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days or within 2, 3, 4, 5, 6, 7, 8 or 9 weeks of each other. In some cases, even longer intervals are possible. Although in many cases, it is desired that these two or more medicaments used in combination therapy are present in patient body simultaneously, this need not be so.

[0095] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in combination, they can be administered one or more times in any combination sequence, such as in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0096] 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 a therapeutically effective amount of a compound described herein, eg, a compound of Formula I or Formula II. III. Pharmaceutical Compositions and Kits

[0097] Another aspect of the present disclosure provides a pharmaceutical composition, which includes a compound as disclosed herein prepared together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides a pharmaceutical composition, which includes a compound as disclosed herein prepared together with one or more pharmaceutically acceptable carriers. These preparations include those suitable for oral, rectal, local, intranasal, cheek, parenteral (for example, subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the disease being treated and the property of the specific compound used. For example, the disclosed composition can be formulated as a unit dose, and / or can be formulated for oral or subcutaneous administration.

[0098] The exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semisolid or liquid forms, containing one or more of the compounds of the present disclosure as active ingredients in admixture with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. The active ingredient can be compounded, for example, with a generally non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable form for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the progression or condition of the disease.

[0099] In order to prepare solid compositions (such as tablets), the main active ingredient can be mixed with a pharmaceutical carrier, for example, a conventional tableting ingredient (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum), and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a uniform mixture of the compound of the present disclosure or its non-toxic pharmaceutically acceptable salt. When these preformulation compositions are referred to as uniform, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0100] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers (e.g., 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, e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia gum; (3) moisturizers.

[0015] Examples of the present invention include, but are not limited to, glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin wax; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clays; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the composition may also contain a buffering agent. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycols.

[0101] Tablet can be prepared by optionally compressing or molding together with one or more auxiliary components.Compressed tablet can use binding agent (for example, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant preparation.Molded tablet can be prepared by molding the mixture of the subject composition moistening with inert liquid diluent in suitable machine.Tablet and other solid dosage forms, such as dragee, capsule, pill and granule, can optionally be scored or be prepared with coating and shell, such as other coatings known in enteric coating and pharmaceutical formulation field.

[0102] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the liquid dosage form may contain inert diluents commonly used in the art (such as, for example, water or other solvents), solubilizers and emulsifiers (such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol), oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0103] Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0104] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in a body cavity and release the active agent.

[0105] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0106] Ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0107] In addition to the subject composition, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0108] The compositions and compounds of the present disclosure can alternatively be administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic wave nebulizers can be used because they minimize the exposure of reagents to shear, which may cause degradation of the compound contained in the subject composition. Typically, aqueous aerosols are prepared by preparing the subject composition together with an aqueous solution or suspension of a conventional pharmaceutically acceptable carrier and stabilizer. Carriers and stabilizers vary with the requirements of the specific subject composition, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (like serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared by isotonic solutions.

[0109] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted immediately before use into sterile injectable solutions or dispersions which may contain antioxidants, buffers, bacteriostats, solutes (to render the formulation isotonic with the blood of the intended recipient), or suspending or thickening agents.

[0110] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as 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 cyclodextrins. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0111] On the other hand, the present disclosure provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is the portion of the gastrointestinal tract (digestive tract) between the stomach and the large intestine and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5. Thus, for example, the enteric material is insoluble up to a pH of 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), hypromellose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hypromellose acetate succinate (HPMCAS), cellulose acetate trimellitate, hypromellose 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 copolymers, natural resins (such as zein, shellac and copalcollophorium), and several commercially available enteric dispersions (e.g., 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 readily measurable in vitro. The foregoing is a list of possible materials, but those skilled in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that will meet the objectives of this disclosure.

[0112] Advantageously, the present disclosure also provides a test kit for use by, for example, a consumer who needs to treat a disease or disorder described herein. Such test kits include suitable dosage forms (such as those described above) and instructions for describing the method of using such dosage forms to mediate, reduce or prevent inflammation. The instructions will guide consumers or medical personnel to administer the dosage form according to the mode of administration known to those skilled in the art. Such test kits can advantageously be packaged and sold in single or multiple test kit units. An example of such a test kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are generally composed of a sheet of relatively hard material covered with a foil of preferably transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the groove and the sheet of relatively hard material is sealed against the plastic foil on the foil surface opposite to the direction in which the groove is formed. Therefore, the tablet or capsule is sealed in the groove 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 manually applying pressure on the recesses, thereby forming an opening in the sheet at the location of the recess. The tablets or capsules can then be removed through the opening.

[0113] It may be desirable to provide a memory aid on the kit, for example, in the form of numbers next to the tablets or capsules, with the numbers corresponding to the days of the regimen on which the tablets or capsules so specified should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows "Week 1, Monday, Tuesday, ... etc. Week 2, Monday, Tuesday, ... " etc. Other variations of the memory aid will be apparent. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. In addition, 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 several tablets or capsules, or vice versa. The memory aid should reflect this. Examples

[0114] Compounds described herein, for example, compounds of formula I or formula II, can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic method described below, it should be understood that, unless otherwise stated, all proposed reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiment and selection of post-processing procedures) can be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore indicate alternative methods. The starting materials of these examples are commercially available or easily prepared by standard methods from known materials. At least some of the compounds used as intermediates are envisioned as compounds disclosed herein. Example 1: Synthesis of compound (3-(imidazol-1-yl)-5-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 115)

[0115] To a mixture of methyl 3-bromo-5-hydroxybenzoate (500 mg, 2.16 mmol, 1.0 equiv) in dimethylformamide (10 mL) was added KCO (898 mg, 6.49 mmol, 3.0 equiv) and CHI (461 mg, 3.25 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2: 1). The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 5% to 100% gradient in 15 min; detector, UV 254 nm and UV 220 nm. This produced methyl 3-bromo-5-methoxybenzoate (517 mg, 97.48% yield) as a yellow solid.

[0116] To a mixture of methyl 3-bromo-5-methoxybenzoate (300 mg, 1.22 mmol, 1.0 equivalent) in toluene (5 mL) was added 2- (trifluoromethyl) pyridin-4-amine (298 mg, 1.84 mmol, 1.5 equivalents) and trimethylaluminum (176 mg, 2.45 mmol, 2.0 equivalents). The resulting mixture was stirred at 120 ° C under a nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 5% to 100% gradient in 15 min; detector, UV 254 nm and UV 220 nm. This produces 3-bromo-5-methoxy-N-[2-(trifluoromethyl) pyridin-4-yl] benzamide (308 mg, 67.07% yield) as a yellow solid.

[0117] To a mixture of 3-bromo-5-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (200 mg, 0.53 mmol, 1.0 equiv) in DMF (4 mL) was added imidazole (73 mg, 1.07 mmol, 2.0 equiv), CuI (203 mg, 1.07 mmol, 2.0 equiv) and CsCO (221 mg, 1.60 mmol, 3.0 equiv). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered; the filter cake was washed with DCM (3×5 mL). The filtrate was concentrated under reduced pressure. The crude product (111 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus TriartC18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 55% B, 55% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 5.95) to give 3-(imidazol-1-yl)-5-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (61.2 mg, 31.68% yield) as a white solid. LCMS (ESI) [M+H] + :362.95. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.71(d,J=5.6Hz,1H),8.68-8.41(m,1H),8.30(s,1H ),8.18-8.05(m,2H),7.82(s,1H),7.51(d,J=22.8Hz,2H),7.40-7.00(m,1H),3.94(s,3H). Example 2: Synthesis of 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 114)

[0118] A solution of methyl 3-bromo-5-hydroxybenzoate (1.5 g, 6.492 mmol, 1 eq) in DMF (15 mL) was treated with 2-bromoethyl methyl ether (1.80 g, 12.984 mmol, 2 eq) at 0° C. under a nitrogen atmosphere for 5 min, followed by the addition of KCO (2.69 g, 19.476 mmol, 3 eq) in portions at 0° C. The resulting mixture was diluted with water. The resulting mixture was extracted with EA (3×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate 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 in water (0.1% formic acid), gradient from 10% to 100% over 25 min; detector, UV 254 nm. This resulted in methyl 3-bromo-5-(2-methoxyethoxy)benzoate (865 mg, 46.10% yield) as a yellow oil.

[0119] Under a nitrogen atmosphere, 2-(trifluoromethyl)pyridin-4-amine (538 mg, 3.320 mmol, 1.2 equiv) and trimethylaluminum (399 mg, 5.534 mmol, 2 equiv) were added dropwise to a stirred mixture of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (800 mg, 2.767 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 100°C for another 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate 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 in water (0.1% formic acid), gradient from 10% to 100% over 25 min; detector, UV 254 nm. This resulted in 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (400 mg, 34.49% yield) as a yellow oil.

[0120] To a mixture of 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (150 mg, 0.358 mmol, 1 eq) and imidazole (122 mg, 1.790 mmol, 5 eq) in DMF (15 mL) at 120° C. under a nitrogen atmosphere was added portionwise CuI (136 mg, 0.716 mmol, 2 eq) and KCO (148 mg, 1.074 mmol, 3 eq). The resulting mixture was filtered, and the filter cake was washed with MeOH (3×50 mL). The filtrate 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 in water (0.1% formic acid), gradient from 10% to 100% over 25 min; detector, UV 254 nm. This resulted in 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (32.33 mg, 22.23% yield) as a white solid. LCMS (ESI) [M+H] + :407.10. 1 HNMR (400MHz, DMSO-d6) δ10.95(s,1H),8.71(d,J=5.5Hz,1H),8.41(s,1H),8.30(s,1H),8.08(d,J=5.5Hz,1H),7.89 (s,1H),7.80(s,1H),7.54(d,J=19.3Hz,2H),7.16(s,1H),4.30(t,J=4.5Hz,2H),3.73(t,J=4.3Hz,2H),3.34(s,3H). Example 3: Synthesis of 3-(2-methoxyethoxy)-5-(1,3-thiazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 116)

[0121] A solution of methyl 3-bromo-5-hydroxybenzoate (1.5 g, 6.492 mmol, 1 eq) in DMF (15 mL) was treated with 2-bromoethyl methyl ether (1.80 g, 12.984 mmol, 2 eq) at 0°C under a nitrogen atmosphere for 5 min, followed by the addition of KCO (2.69 g, 19.476 mmol, 3 eq) in portions at 0°C. The resulting mixture was stirred at 50°C for 6 h. The mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate 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 in water (0.1% formic acid), gradient from 10% to 100% over 25 min; detector, UV 254 nm. This resulted in methyl 3-bromo-5-(2-methoxyethoxy)benzoate (865 mg, 46.10%) as a yellow oil.

[0122] Under nitrogen atmosphere, at 0 DEG C, to the stirring mixture of 3-bromo-5-(2-methoxyethoxy)benzoic acid methyl ester (400mg, 1.383mmol, 1 equivalent) and 2-(trifluoromethyl)pyridine-4-amine (449mg, 2.766mmol, 2 equivalents) in toluene (5mL) was added dropwise Al(Me) (199mg, 2.766mmol, 2 equivalents). The resulting mixture was stirred for 1h at 100 DEG C under nitrogen atmosphere. The desired product can be detected by LCMS. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 DEG C. The resulting mixture was extracted with EtOAc (3 × 30mL) and dried over anhydrous Na2SO4. After filtration, the filtrate 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 in water (0.1% formic acid), 10% to 100% gradient over 20 min; detector, UV 254 nm. This produced 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (280 mg, 48.28% yield) as a brown oil.

[0123] A mixture of 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (100 mg, 0.239 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (75 mg, 0.358 mmol, 1.5 eq), Pd(dppf)Cl2 (19 mg, 0.024 mmol, 0.1 eq) and K2CO3 (98 mg, 0.717 mmol, 3 eq) in dioxane (5 mL) and H2O (1 mL) was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), 10% to 100% gradient in 25 min; detector, UV 254 nm. This produced 3-(2-methoxyethoxy)-5-(1,3-thiazol-5-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (20 mg, 19.80% yield) as a light yellow solid. LCMS (ESI) [M+H] + :424.20. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.16(s,1H),8.70(d,J=5.5Hz,1H),8.48(s,1H),8.31(d,J=1.9Hz,1H),8 .08(dd,J=5.5,2.0Hz,1H),7.80(s,1H),7.53-7.58(m,2H),4.33-4.21(m,2H),3.76-3.63(m,2H),3.34(s,3H). Example 4: Synthesis of 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-[6-(trifluoromethyl)pyridin-3-yl]benzamide (Compound 112)

[0124] To a mixture of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (1 g, 3.459 mmol, 1 eq) and imidazole (1.18 g, 17.295 mmol, 5 eq) in dioxane (20 mL) was added K 3 PO 4 (2.2 g, 10.377 mmol, 3 eq), Me 4 t BuXPhos (323 mg, 0.692 mmol, 0.2 eq), and Pd 2 (dba) 3 (317 mg, 0.346 mmol, 0.1 eq) at room temperature. The resulting mixture was stirred at 120° C. under nitrogen atmosphere for an additional 1 h. The resulting mixture was filtered; 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm. This produced methyl 3- (imidazol-1-yl) -5- (2-methoxyethoxy) benzoate (600 mg, 62.79% yield) as a yellow oil.

[0125] To a mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.362 mmol, 1 eq) and trimethylaluminum (52 mg, 0.724 mmol, 2 eq) in toluene (5 mL) was added portionwise 6-(trifluoromethyl)pyridin-3-amine (293 mg, 1.810 mmol, 5 eq) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100° C. for an additional 1 h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), gradient from 0% to 100% over 25 min; detector, UV 254 nm. This resulted in 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-[6-(trifluoromethyl)pyridin-3-yl]benzamide (26 mg, 17.68% yield) as a white solid. LCMS (ESI) [M+H] + :407.00. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.10(d,J=2.4Hz,1H),8.54-8.46(m,1H),8.40(s,1H),7.96(d,J=8.7Hz,1H), 7.89(s,1H),7.81(s,1H),7.58-7.44(m,2H),7.15(s,1H),4.30(t,J=4.5Hz,2H),3.73(t,J=4.5Hz,2H),3.32(s,3H). Example 5: Synthesis of N-(3-chloro-4-fluorophenyl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 110)

[0126] Under a nitrogen atmosphere, trimethylaluminum (100 mg, 1.384 mmol, 2 eq) was added dropwise to a mixture of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (200 mg, 0.692 mmol, 1 eq) and quinolin-7-amine (200 mg, 1.384 mmol, 2 eq) in toluene (8 mL) at room temperature. The resulting mixture was stirred at 100° C. for another 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate 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 in water (0.1% formic acid), gradient from 0% to 100% over 25 min; detector, UV 254 nm. This resulted in 3-bromo-5-(2-methoxyethoxy)-N-(quinolin-7-yl)benzamide (180 mg, 64.85% yield) as a white solid.

[0127] To a mixture of 3-bromo-5-(2-methoxyethoxy)-N-(quinolin-7-yl)benzamide (100 mg, 0.249 mmol, 1 eq) and imidazole (26 mg, 0.373 mmol, 1.5 eq) in dioxane (6 mL) was added portionwise CsCO (244 mg, 0.747 mmol, 3 eq), t-BuBrettPhos PD G3 (22 mg, 0.025 mmol, 0.1 eq) and t-BuBrettphos (24 mg, 0.050 mmol, 0.2 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120° C. for an additional 1 h. 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm. This produced N-(3-chloro-4-fluorophenyl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (43 mg, 44.26% yield) as a white solid. LCMS (ESI) [M + H] + :389.10. 1HNMR(400MHz,DMSO-d6)δ10.62(s,1H),8.88(dd,J=4.2,1.7Hz,1H),8.58(s,1H),8.42(s,1H),8.37-8.20(m,1H),7.98(d,J=2.2Hz,2H),7. 91(d,J=1.5Hz,1H),7.84(t,J=1.7Hz,1H),7.53(s,2H),7.49-7.32(m,1H),7.15(s,1H),4.37-4.27(m,2H),3.82-3.66(m,2H),3.35(s,3H). Example 6: Synthesis of 3-(Imidazol-1-yl)-N-(1H-indazol-6-yl)-5-(2-methoxyethoxy)benzamide; Formate Salt (Compound 109)

[0128] To a mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.36 mmol, 1 eq) and 6-aminoindazole (58 mg, 0.43 mmol, 1.2 eq) in toluene (5 mL) was added Al(Me) (0.11 mL) dropwise at 0 ° C over 2 min. The resulting mixture was stirred at 100 ° C for another 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeOH--HPLC; flow rate: 60 mL / min; gradient: 16% B to 35% B, 35% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 9.75) to give 3-(imidazol-1-yl)-N-(1H-indazol-6-yl)-5-(2-methoxyethoxy)benzamide as a white solid; formic acid (63.0 mg, 40.90% yield). LCMS (ESI) [M+H] + :378.05. 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),10.40(s,1H),8.40(s,1H),8.26(s,1H),8.15(s,1H),8.01(d,J=1.0Hz,1H),7.90(d,J=1.5Hz, 1H),7.79(s,1H),7.76-7.60(m,1H),7.48(s,2H),7.41-7.35(m,1H),7.14(s,1H),4.33-4.25(m,2H),3.76-3.70(m,2H),3.35(s,3H). Example 7: Synthesis of N-(6-cyanopyridin-3-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 105)

[0129] To a mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (150 mg, 0.543 mmol, 1 eq) in THF (10 mL) and H₂O (10 mL) was added portionwise LiOH (26 mg, 1.086 mmol, 2 eq) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with CHCl (3 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate 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 in water (0.1% formic acid), gradient from 0% to 100% over 20 min; detector, UV 254 nm. This resulted in 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoic acid (110 mg, 77.26% yield) as a yellow oil.

[0130] Under nitrogen atmosphere, pyridine (45 mg, 0.572 mmol, 1.5 eq) and POCl (87 mg, 0.572 mmol, 1.5 eq) were added dropwise to a mixture of 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoic acid (100 mg, 0.381 mmol, 1 eq) and 5-aminopyridine-2-carbonitrile (45 mg, 0.381 mmol, 1 eq) in DCM (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for another 1 h. The resulting mixture was extracted with DCM (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate 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 in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 45% B, 45% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 10.43) to give N- (6-cyanopyridin-3-yl) -3- (imidazol-1-yl) -5- (2-methoxyethoxy) benzamide (68 mg, 49.08% yield) as a white solid. LCMS (ESI) [M+H] + :364.05. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.13-9.05(s,1H),8.51-8.36(m,2H),8.07(d,J=8.6Hz,1H),7.89 (s,1H),7.79(s,1H),7.60-7.49(m,2H),7.15(s,1H),4.36-4.22(m,2H),3.81-3.69(m,2H),3.34(s,3H). Example 8: Synthesis of N-(3-chloro-4-fluorophenyl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 111)

[0131] Under a nitrogen atmosphere, to a stirred mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.362 mmol, 1 eq) and 3-chloro-4-fluoroaniline (105 mg, 0.724 mmol, 2 eq) in toluene (5 mL) was added dropwise Al(Me) (52 mg, 0.724 mmol, 2 eq) at 0 ° C. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 33% B, 33% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 10.70) to give N-(3-chloro-4-fluorophenyl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (22 mg, 15.59% yield) as a white solid. LCMS (ESI) [M+H] + :390.10. 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.39(d,J=1.2Hz,1H),8.07(dd,J=6.9,2.6Hz,1H),7.88(s,1H),7.80-7.6 9(m,2H),7.51(s,1H),7.49-7.40(m,2H),7.14(s,1H),4.36-4.20(m,2H),3.82-3.65(m,2H),3.34-3.33(m,3H). Example 9: Synthesis of (N-(2-tert-butylpyrimidin-5-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 104)

[0132] Under a nitrogen atmosphere, to a mixture of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (200 mg, 0.692 mmol, 1 eq) and 2-tert-butylpyrimidin-5-amine (209 mg, 1.384 mmol, 2 eq) in toluene (10 mL) was added trimethylaluminum (99 mg, 1.384 mmol, 2 eq) dropwise at room temperature. The resulting mixture was stirred at 100 ° C for another 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate 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 in water (0.1% formic acid), gradient 0% to 100% over 20 min; detector, UV 254 nm to give 3-bromo-N-(2-tert-butylpyrimidin-5-yl)-5-(2-methoxyethoxy)benzamide (160 mg, 56.65% yield) as a yellow solid.

[0133] A mixture of 3-bromo-N-(2-tert-butylpyrimidin-5-yl)-5-(2-methoxyethoxy)benzamide (100 mg, 0.245 mmol, 1 eq), imidazole (25 mg, 0.367 mmol, 1.5 eq), t-BuBrettPhos PD G3 (20 mg, 0.025 mmol, 0.1 eq), t-BuBrettPhos (23 mg, 0.049 mmol, 0.2 eq) and CsCO (239 mg, 0.735 mmol, 3 eq) in dioxane (10 mL) was stirred at 120° C. under a nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3×50 mL). The filtrate 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 in water (10 mmol / L NH4HCO3), gradient 0% to 100% in 25 min; detector, UV 254 nm. The crude product (60 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 52% B, 52% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 8.05) to give N-(2-tert-butylpyrimidin-5-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (45 mg, 46.46% yield) as a white solid. LCMS (ESI) [M+H] +:396.00. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.09(s,2H),8.40(s,1H),7.89(t,J=1.5Hz,1H),7.79(t,J=1.7Hz,1H ),7.45-7.57(m,2H),7.15(t,J=1.2Hz,1H),4.39-4.23(m,2H),3.80-3.66(m,2H),3.34(s,3H),1.37(s,9H). Example 10: Synthesis of N-(3,4-dihydro-1H-2-benzopyran-7-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 103)

[0134] To a solution of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.36 mmol, 1 eq) and 3,4-dihydro-1H-2-chromen-7-amine (65 mg, 0.43 mmol, 1.2 eq) in toluene (4 mL) was added Al(Me) (0.11 mL) dropwise at 0 ° C over 2 min. The resulting mixture was stirred at 100 ° C for another 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B, 50% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 4.84): 9.75) to give N-(3,4-dihydro-1H-2-chromen-7-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (41.7 mg, 28.49% formic acid) as a white solid. LCMS (ESI) [M+H] + :394.20. 1HNMR(400MHz,DMSO-d6)δ10.20(s,1H),8.38(s,1H),7.87(s,1H),7.75(s,1H),7.56-7.42(m,4H),7.14(t,J=4.2Hz ,2H),4.68(s,2H),4.32-4.24(m,2H),3.88(t,J=5.7Hz,2H),3.77-3.68(m,2H),3.33(s,3H),2.76(t,J=5.7Hz,2H). Example 11: Synthesis of N-(5-chloropyridin-3-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide; Formate Salt (Compound 106)

[0135] To a stirred solution of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.36 mmol, 1 eq) and 5-chloropyridin-3-amine (56 mg, 0.43 mmol, 1.2 eq) in toluene (5 mL) was added Al(Me) (0.11 mL) dropwise at 0 ° C over 2 min. The resulting mixture was stirred at 100 ° C for another 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeOH--HPLC; flow rate: 60 mL / min; gradient: 23% B to 44% B, 44% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 9.53) to give N-(5-chloropyridin-3-yl)-3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzamide as a white solid; formic acid (61.2 mg, 40.24% yield). LCMS (ESI) [M+H] + :373.00. 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.89(d,J=2.1Hz,1H),8.43-8.36(m,3H),7.89(s,1H),7.79(t,J =1.7Hz,1H),7.56-7.47(m,2H),7.15(s,1H),4.33-4.26(m,2H),3.76-3.69(m,2H),3.35-3.42(m,3H). Example 12: Synthesis of 3-(imidazol-1-yl)-N-(isoquinolin-7-yl)-5-(2-methoxyethoxy)benzamide (Compound 102)

[0136] To a stirred mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (100 mg, 0.362 mmol, 1 eq) and isoquinolin-7-amine (62.62 mg, 0.434 mmol, 1.2 eq) in toluene (5 mL) was added dropwise Al(Me) (52.18 mg, 0.724 mmol, 2 eq) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using 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: ACN; flow rate: 25 mL / min; gradient: 23% B to 38% B, 38% B in 8 min; wavelength: 254 nm; RT1 (min): 7.75) to give 3-(imidazol-1-yl)-N-(isoquinolin-7-yl)-5-(2-methoxyethoxy)benzamide (24 mg, 17.07% yield) as a white solid. LCMS (ESI) [M+H] + :389.15. 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.29(s,1H),8.66(d,J=2.0Hz,1H),8.47-8.40(m,2H),8.09-7.98(m,2H),7.9 1(t,J=1.4Hz,1H),7.85-7.78(m,2H),7.53(s,2H),7.16(s,1H),4.36-4.28(m,2H),3.77-3.71(m,2H),3.35(s,3H). Example 13: Synthesis of 3-cyclopropyloxy-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 108)

[0137] A mixture of methyl 3-bromo-5-hydroxybenzoate (1 g, 4.33 mmol, 1 eq), iodocyclopropane (3.64 g, 21.64 mmol, 5 eq), NaI (0.32 g, 2.16 mmol, 0.5 eq) and CsCO (4.23 g, 12.984 mmol, 3 eq) in DMA (10 mL) was stirred at 150 ° C for 2 h. The resulting mixture was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 5% to 100% gradient in 30 min; detector, UV 254 nm and UV 220 nm.) to give 3-bromo-5-cyclopropyloxybenzoic acid (250 mg, 22.47% yield) as a yellow oil.

[0138] A mixture of 3-bromo-5-cyclopropyloxybenzoic acid (245 mg, 0.95 mmol, 1 equivalent) and TMSCHN (163 mg, 1.43 mmol, 1.5 equivalents) in THF (4 mL) and MeOH (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1: 1) to give methyl 3-bromo-5-cyclopropyloxybenzoate (170 mg, 65.80% yield) as a light yellow oil.

[0139] At 0 DEG C, over 2min, to 3- bromo- 5- cyclopropyloxybenzoic acid methyl ester (165mg, 0.61mmol, 1 equivalent) and 2- (trifluoromethyl) pyridine -4- amine (118mg, 0.73mmol, 1.2 equivalents) in toluene (5mL) stirring solution, Al (Me) 3 (0.37mL, 3 equivalents) is added dropwise. The resulting mixture is stirred for another 2h at 100 DEG C. The reaction is quenched with saturated NH4Cl (aqueous solution) at 0 DEG C and extracted with EA. The combined organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography with PE / EA (1: 1) elution to obtain 3- bromo- 5- cyclopropyloxy -N- [2- (trifluoromethyl) pyridine -4- bases] benzamide (75mg, 30.72% yield) as a light yellow solid.

[0140] A solution of 3-bromo-5-cyclopropyloxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (70 mg, 0.17 mmol, 1 eq), imidazole (59 mg, 0.87 mmol, 5 eq), t-BuBrettphos (17 mg, 0.04 mmol, 0.2 eq), t-BuBrettphos Pd G3 (15 mg, 0.02 mmol, 0.1 eq) and Cs2CO3 (171 mg, 0.52 mmol, 3 eq) in dioxane (4 mL) was stirred at 120° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), gradient 0% to 100% over 25 min; detector, UV 254 nm) to give 3-cyclopropyloxy-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (10.8 mg, 15.87% yield) as a white solid. LCMS (ESI) [M+H] + :389.20. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.70(d,J=5.5Hz,1H),8.38(s,1H),8.30(d,J=2.0Hz,1H),8.09-8.03(m,1H), 7.90-7.85(m,2H),7.61(d,J=1.6Hz,2H),7.16(s,1H),4.10-4.03(m,1H),0.94-0.83(m,2H),0.74(d,J=3.7Hz,2H). Example 14: Synthesis of 3-[2-(dimethylamino)ethoxy]-5-(imidazol-1-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 107)

[0141] To a stirred solution of methyl 3-bromo-5-hydroxybenzoate (500 mg, 2.16 mmol, 1 eq) and (2-bromoethyl)dimethylamine (493 mg, 3.24 mmol, 1.5 eq) in DMF (10 mL) was added portionwise CsCO (3.52 g, 10.82 mmol, 5 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with EA (2×3 mL). The residual product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 100% gradient in 25 min; detector, UV 254 nm to give methyl 3-bromo-5-[2-(dimethylamino)ethoxy]benzoate (100 mg, 15.29% yield) as a light yellow oil.

[0142] To a stirred solution of methyl 3-bromo-5-[2-(dimethylamino)ethoxy]benzoate (150 mg, 0.49 mmol, 1 eq), K PO 4 (263 mg, 1.24 mmol, 2.5 eq) and imidazole (67 mg, 0.99 mmol, 2 eq) in toluene (3 mL) at room temperature under a nitrogen atmosphere were added portionwise t-BuBrettphos Pd G 3 (84 mg, 0.09 mmol, 0.2 eq) and t-BuBrettphos (95 mg, 0.19 mmol, 0.4 eq). The resulting mixture was stirred at 120° C. under a nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with EA (2×3 mL). The filtrate was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm to give methyl 3-[2-(dimethylamino)ethoxy]-5-(imidazol-1-yl)benzoate (60 mg, 41.77% yield) as a light yellow oil.

[0143] Under a nitrogen atmosphere, at 0 ° C, to a stirred solution of 3- [2- (dimethylamino) ethoxy] -5- (imidazol-1-yl) benzoic acid methyl ester (60 mg, 0.20 mmol, 1 equivalent) and 2- (trifluoromethyl) pyridin-4-amine (50 mg, 0.31 mmol, 1.5 equivalents) in toluene (2 mL) was added trimethylaluminum (44 mg, 0.62 mmol, 3 equivalents) dropwise. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 2 h. At room temperature, the reaction was quenched by adding water. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to give 3- [2- (dimethylamino) ethoxy] -5- (imidazol-1-yl) -N- [2- (trifluoromethyl) pyridin-4-yl] benzamide (2.7 mg, 3.07% yield) as a white solid. LCMS (ESI) [M + H] + :420.25. 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.71(d,J=5.5Hz,1H),8.41(s,1H),8.30(d,J=2.0Hz,1H),8.08(d,J=5.6,1H),7.8 9(s,1H),7.79(s,1H),7.55(s,1H),7.50(s,1H),7.15(s,1H),4.24(t,J=5.7Hz,2H),2.68(t,J=5.7Hz,2H),2.24(s,6H). Example 15: Synthesis of 3-[4-(hydroxymethyl)imidazol-1-yl]-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 101)

[0144] At 0 ° C, over 2 min, to a solution of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (300 mg, 1.04 mmol, 1 equivalent) and 2-(trifluoromethyl)pyridin-4-amine (202 mg, 1.25 mmol, 1.2 equivalents) in toluene (10 mL) was added Al(Me) dropwise (0.33 mL, 3 equivalents). The resulting mixture was stirred for another 2 h at 100 ° C. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1: 1) to obtain 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (180 mg, 41.38%) as a yellow solid.

[0145] A mixture of 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (170 mg, 0.41 mmol, 1 eq), 3H-imidazol-4-ylmethanol (119 mg, 1.22 mmol, 3 eq), t-BuBrettphos (39 mg, 0.08 mmol, 0.2 eq), CsCO (396 mg, 1.22 mmol, 3 eq) and t-BuBrettPhos Pd G (20 mg, 0.04 mmol, 0.1 eq) in dioxane (3 mL) was stirred at 120° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH PrepC18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 28% B, 28% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 6.58) to give 3-[4-(hydroxymethyl)imidazol-1-yl]-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (22.6 mg, 12.62% yield) as a white solid. LCMS (ESI) [M+H] + :437.10. 1H NMR(300MHz,DMSO-d6)δ10.95(s,1H),8.77-8.66(m,1H),8.36(s,1H),8.28(s,1H),8.12-8.01(m,1H),7.80(s,1H),7.7 2(s,1H),7.55(s,1H),7.49(s,1H),5.08(s,1H),4.44(s,2H),4.35-4.26(m,2H),3.80-3.70(m,2H),3.38-3.36(m,3H). Example 16: Synthesis of 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-(quinoxalin-6-yl)benzamide (Compound 128)

[0146] To a mixture of methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (60 mg, 0.22 mmol, 1 eq) and 6-aminoquinoxaline (38 mg, 0.26 mmol, 1.2 eq) in toluene (5 mL) was added trimethylaluminum (47 mg, 0.65 mmol, 3 eq) dropwise at 0 ° C over 2 min. The resulting mixture was stirred at 100 ° C for an additional 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeOH--HPLC; flow rate: 60 mL / min; gradient: 16% B to 35% B, 35% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 9.75) to give 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-(quinoxalin-6-yl)benzamide (28.9 mg, 33.80% yield) as a white solid. LCMS (ESI) [M+H] + :390.15. 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.91(s,1H),8.88(s,1H),8.69(d,J=2.3Hz,1H),8.42(s,1H),8.24-8.18(m,1H),8.12( d,J=9.1Hz,1H),7.92(s,1H),7.85(s,1H),7.54(s,2H),7.15(s,1H),4.36-4.25(m,2H),3.78-3.70(m,2H),3.34-3.32(m,3H). Example 17: Synthesis of 3-(imidazol-1-yl)-N-(1H-indazol-5-yl)-5-(2-methoxyethoxy)benzamide (Compound 126)

[0147] At 0 ° C, over 2 min, trimethylaluminum (47 mg, 0.65 mmol, 3 equivalents) was added dropwise to a solution of methyl 3- (imidazole-1-yl) -5- (2-methoxyethoxy) benzoate (60 mg, 0.22 mmol, 1 equivalent) and tert-butyl 5-aminoindazole-1-carboxylate (61 mg, 0.26 mmol, 1.2 equivalents) in toluene (5 mL). The resulting mixture was stirred for another 2 h at 100 ° C. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 21% B, 21% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 9.55) to give 3-(imidazol-1-yl)-N-(1H-indazol-5-yl)-5-(2-methoxyethoxy)benzamide (17.3 mg, 20.98% yield) as a white solid. LCMS (ESI) [M+H] + :378.10. 1H NMR (400MHz, DMSO-d6) δ13.05(s,1H),10.31(s,1H),8.40(s,1H),8.24(s,1H),8.08(s,1H),7.89(s,1H),7.79(d,J=1.7Hz,1H),7.63 (dd,J=9.0,1.9Hz,1H),7.55(d,J=8.9Hz,1H),7.49(d,J=1.7Hz,2H),7.14(s,1H),4.34-4.21(m,2H),3.79-3.69(m,2H),3.32(s,3H). Example 18: Synthesis of N-(1H-benzo[d]imidazol-6-yl)-3-(1H-imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (Compound 127)

[0148] Under a nitrogen atmosphere, at 0 ° C, to a solution of 3H-1,3-benzodiazol-5-amine (500 mg, 3.755 mmol, 1 equivalent) in THF (10 mL) was added NaH (135 mg, 5.633 mmol, 1.5 equivalents). The mixture was stirred at 0 ° C under a nitrogen atmosphere for 30 min. Under a nitrogen atmosphere, at 0 ° C, [2-(chloromethoxy)ethyl]trimethylsilane (939 mg, 5.633 mmol, 1.5 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 ° C. The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-5-amine (230 mg, 23.25% yield) as a light red solid.

[0149] Under a nitrogen atmosphere, to a stirred mixture of 3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-5-amine (200 mg, 0.759 mmol, 1 eq) and methyl 3-(imidazol-1-yl)-5-(2-methoxyethoxy)benzoate (252 mg, 0.911 mmol, 1.2 eq) in toluene (5 mL) was added dropwise Al(Me) (109 mg, 1.518 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate 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 in water (0.1% formic acid), gradient 10% to 100% over 20 min; detector, UV 254 nm to give 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-(3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-5-yl)benzamide (90 mg, 23.35% yield) as a yellow solid.

[0150] To a stirred solution of 3-(imidazol-1-yl)-5-(2-methoxyethoxy)-N-(3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-5-yl)benzamide (80 mg, 0.158 mmol, 1 eq) in DCM (2 mL) was added TFA (2 mL) dropwise under air at 0° C. The resulting mixture was stirred at room temperature under air for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B to 31% B, 31% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 8.88) to give N-(1H-benzo[d]imidazol-6-yl)-3-(1H-imidazol-1-yl)-5-(2-methoxyethoxy)benzamide (10 mg, 16.81% yield) as a white solid. LCMS (ESI) [M+H] + :378.10. 1H NMR (400 MHz, methanol-d4) δ 8.27 (s, 1H), 8.17 (s, 2H), 7.76 (s, 1H), 7.70 (s, 1H), 7.64-7.54 (m, 2H), 7.48 (s, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 4.33-4.27 (m, 2H), 3.84-3.77 (m, 2H), 3.45 (s, 3H). Example 19: Synthesis of 3-(2-methoxyethoxy)-5-(pyridin-3-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (Compound 120)

[0151] A mixture of methyl 3-bromo-5-(2-methoxyethoxy)benzoate (202 mg, 0.699 mmol, 1 eq), KCO (291 mg, 2.097 mmol, 3 eq), Pd(dppf)Cl (56 mg, 0.070 mmol, 0.1 eq) and pyridin-3-ylboronic acid (103 mg, 0.839 mmol, 1.2 eq) in water (0.2 mL) and 1,4-dioxane (2 mL) was stirred at 90 ° C. under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 3-(2-methoxyethoxy)-5-(pyridin-3-yl)benzoate (200 mg, 99.63% yield) as a yellow oil.

[0152] Under a nitrogen atmosphere, at 0 ° C, to a stirred mixture of 3- (2-methoxyethoxy) -5- (pyridin-3-yl) methyl benzoate (100 mg, 0.348 mmol, 1 equivalent) and 2- (trifluoromethyl) pyridine -4- amine (84 mg, 0.522 mmol, 1.5 equivalents) in toluene (1 mL) was added trimethylaluminum (75 mg, 1.044 mmol, 3 equivalents) dropwise. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The mixture was extracted with EtOAc. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 42% B, 42% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 10.03) to give 3-(2-methoxyethoxy)-5-(pyridin-3-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (15 mg, 10.33% yield) as a yellow oil. LCMS (ESI) [M+H] + :418.15. 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),9.02(s,1H),8.70(d,J=5.6Hz,1H),8.63(dd,J=4.8,1.6Hz,1H),8.31(s,1H),8.25-8.17(m, 1H), 8.10 (dd, J = 5.6, 2.0Hz, 1H), 7.91 (s, 1H), 7.59 (s, 2H), 7.58-7.40 (m, 1H), 4.40-4.26 (m, 2H), 3.82-3.66 (m, 2H), 3.34 (s, 3H). Example 20: Synthesis of 3-(5-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)benzamide (Compound 120)

[0153] A solution of 3-bromo-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (440 mg, 1.05 mmol, 1 eq), tert-butyl carbamate (184 mg, 1.58 mmol, 1.5 eq), t-BuBrettphos (102 mg, 0.21 mmol, 0.2 eq), t-BuBrettPhos Pd G3 (90 mg, 0.11 mmol, 0.1 eq) and Cs2CO3 (1.02 g, 3.15 mmol, 3 eq) in dioxane (10 mL) was stirred at 120° C. under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), gradient from 5% to 100% over 30 min; detector, UV 254 nm and UV 220 nm to give tert-butyl N-[3-(2-methoxyethoxy)-5-{[2-(trifluoromethyl)pyridin-4-yl]carbamoyl}phenyl]carbamate (400 mg, 83.68% yield) as a yellow oil.

[0154] A solution of tert-butyl N-[3-(2-methoxyethoxy)-5-{[2-(trifluoromethyl)pyridin-4-yl]carbamoyl}phenyl]carbamate (400 mg, 0.88 mmol, 1 equivalent) and TFA (5 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% formic acid), 5% to 100% gradient in 30 min; detector, UV 254 nm and UV 220 nm, to obtain 3-amino-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (115 mg, 36.85% yield) as a yellow oil.

[0155] A solution of 3-amino-5-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (105 mg, 0.30 mmol, 1 eq) and ethyl glyoxylate (30 mg, 0.30 mmol, 1 eq) in EtOH (5 mL) was stirred at room temperature overnight. To the above mixture, TosMIC (69 mg, 0.36 mmol, 1.2 eq) and KCO (123 mg, 0.89 mmol, 3 eq) were added portionwise at room temperature. The resulting mixture was stirred at 80° C. for another 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give ethyl 3-[3-(2-methoxyethoxy)-5-{[2-(trifluoromethyl)pyridin-4-yl]carbamoyl}phenyl]imidazole-4-carboxylate (50 mg, 35.37% yield) as a yellow oil.

[0156] To a solution of ethyl 3-[3-(2-methoxyethoxy)-5-{[2-(trifluoromethyl)pyridin-4-yl]carbamoyl}phenyl]imidazole-4-carboxylate (50 mg, 0.11 mmol, 1 eq) in THF (2 mL) was added LiAlH (16 mg, 0.42 mmol, 2 eq) dropwise at 0 ° C over 1 min. The resulting mixture was stirred at room temperature for another 30 min. The reaction was quenched with water at 0 ° C. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 25% B, 25% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 10.62) to give 3-(5-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-methoxyethoxy)-N-(2-(trifluoromethyl)pyridin-4-yl)benzamide (7.8 mg, 16.66% yield) as a yellow oil as formate salt. LCMS (ESI) [M+H] + :437.05. 1H NMR (300MHz, DMSO-d6) δ10.95(s,1H),8.70(d,J=5.6Hz,1H),8.30(d,J=2.0Hz,1H),8.18(s,1H),8.12-8.03(m,1H),8.00(s,1H),7 .76(t,J=1.7Hz,1H),7.65-7.53(m,2H),7.07(s,1H),5.23(s,1H),4.45(s,2H),4.31-4.23(m,2H),3.75-3.71(m,2H),3.45(s,3H). Example 21: Synthesis of (2-fluoro-5-(imidazol-1-yl)-3-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide) (Compound 117)

[0157] Under a nitrogen atmosphere, at room temperature, to a stirred mixture of 5-bromo-2-fluoro-3-methoxybenzoic acid methyl ester (500 mg, 1.901 mmol, 1 equivalent) and 2-(trifluoromethyl)pyridin-4-amine (370 mg, 2.281 mmol, 1.2 equivalents) in toluene (10 mL) was added dropwise Al(Me) (274 mg, 3.801 mmol, 2.00 equivalents). The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layer was 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), gradient 10% to 100% over 20 min; detector, UV 254 nm to give 5-bromo-2-fluoro-3-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (390 mg, 52.19% yield) as a yellow oil.

[0158] Under air atmosphere, to a stirred solution of 5-bromo-2-fluoro-3-methoxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (380 mg, 0.967 mmol, 1 eq) in DCM (5 mL) was added BBr (726 mg, 2.900 mmol, 3.00 eq) dropwise at 0 ° C. The resulting mixture was stirred at room temperature under air atmosphere for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2 (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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), gradient from 10% to 100% in 20 min; detector, UV 254 nm to give 5-bromo-2-fluoro-3-hydroxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (160 mg, 43.66% yield) as a yellow solid.

[0159] To a stirred solution of 5-bromo-2-fluoro-3-hydroxy-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (160 mg, 0.422 mmol, 1 eq) in DMF (10 mL) at 0° C. under an air atmosphere were added KCO (175 mg, 1.266 mmol, 3 eq) and 2-bromoethyl methyl ether (117 mg, 0.844 mmol, 2 eq) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1 h. 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% formic acid), gradient 10% to 100% over 20 min; detector, UV 254 nm to give 5-bromo-2-fluoro-3-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (170 mg, 92.13% yield) as a yellow solid.

[0160] A mixture of 5-bromo-2-fluoro-3-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (160 mg, 0.366 mmol, 1 eq), imidazole (25 mg, 0.366 mmol, 1 eq), t-BuBrettPhos (35 mg, 0.073 mmol, 0.2 eq), t-BuBrettPhos Pd G (31 mg, 0.037 mmol, 0.1 eq) and CsCO (358 mg, 1.098 mmol, 3 eq) in dioxane (10 mL) was stirred at 120° C. under a nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 60 mL / min; gradient: 42% B to 62% B, 62% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 9.67) to give 2-fluoro-5-(imidazol-1-yl)-3-(2-methoxyethoxy)-N-[2-(trifluoromethyl)pyridin-4-yl]benzamide (20.3 mg, 13.07% yield) as a yellow solid. LCMS (ESI) [M+H] + :425.15. 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.71(d,J=5.5Hz,1H),8.34(s,1H),8.23(s,1H),7.94(dd,J=5.4,2.0Hz,1H),7.85(s,1 H),7.68(dd,J=7.1,2.7Hz,1H),7.55(dd,J=4.8,2.6Hz,1H),7.13(s,1H),4.42-4.35(m,2H),3.77-3.69(m,2H),3.34(s,3H). Example 22: CD38 hydrolase inhibition assay

[0161] The CD38 hydrolase inhibition assay measures the glycohydrolase activity of CD38 using NAD analogs as substrates and measuring the formation of fluorescent ADP ribose analogs. 4x buffer was prepared with 1M sucrose and 160mM Tris-HCl at pH 7.4 for a final assay concentration of 250mM sucrose and 40mM Tris-HCl. The 4x solution was kept at 4°C and warmed to room temperature before use. Tween 20 was added to the 1x buffer for a final concentration of 0.05%. Human recombinant CD38 (BPSBioscience) was diluted to 0.4ng / μL in 1x buffer and 12.5μL was added to each plate well. Inhibitors were added and the 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 for a final well concentration of 0.2 ng / μL CD38 and 100 μM ε-NAD. The plate was covered and incubated at room temperature for 15 min and then read on a plate reader using 300 nm excitation and 410 nm emission. 200 nM 78c was included as a well for complete inhibition, and DMSO-only wells were included as uninhibited wells. GraphPad Prism software v9.3 or CDD Vault was used to determine the IC50 of the test compound. The results are shown in Table 2. Table 2. +<0.1; ++0.1 to 1.0; +++>1.0 Incorporation by Reference

[0162] All publications and patents mentioned herein (including those items listed below) are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually incorporated by reference. In the event of conflict, the present application, including any definitions herein, will control. Equivalents and scope

[0163] In the claims, articles such as "a," "an," and "the" may mean one or more, unless indicated to the contrary or otherwise obvious from the context. Claims or descriptions that include "or" between one or more group members are deemed satisfied if one, more than one, or all members of the group are present in, used in, or otherwise relevant to a given product or method, unless indicated to the contrary or otherwise obvious from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or method. The present disclosure includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or method.

[0164] In addition, the present disclosure encompasses all variations, combinations and arrangements, in which one or more limitations, elements, clauses and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is subordinate to another claim can be modified to include one or more limitations found in any other claim that is subordinate to the same basic claim. When an element is presented as a list (for example, in a Markush group format), each subgroup of the element is also disclosed, and any one or more elements can be removed from the group. It should be understood that, generally, when the present disclosure or the aspects of the present disclosure are referred to as comprising specific elements and / or features, some embodiments of the present disclosure or the aspects of the present disclosure are made up of such elements and / or features or are substantially made up of such elements and / or features. For the purpose of brevity, these embodiments have not been specifically described herein verbatim. It should also be noted that the terms "comprising / including (comprising)" and "containing (containing)" are intended to be open and allow the inclusion of other elements or steps. When a range is given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, values expressed as ranges may, in different embodiments of the present disclosure, take any specific value or sub-range within the stated range, up to the tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0165] This application cites various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, this specification shall prevail. In addition, any specific embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered to be known to those skilled in the art, they may be excluded even if the exclusion is not explicitly stated herein. Any specific embodiment of the present disclosure may be excluded from any claim for any reason, regardless of whether it is related to existing prior art.

[0166] Those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments described herein using only routine experimentation. The scope of the embodiments of the present invention described herein is not intended to be limited to the above description, but is defined as in the appended claims. Those skilled in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the present disclosure as defined in the following claims.

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl; wherein R 1 can be optionally selected from one or more independently selected R 11 Substituents substituted; R 2 Choose Free-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -C 3-6 A group consisting of cycloalkyl; wherein R 2 can be optionally selected from one or more independently selected R 22 Substituents substituted; R 3 is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 4-10 membered heterocyclic group and phenyl; wherein R 3 can be optionally selected from one or more independently selected R 33 Substituents substituted; R 4 Selected from hydrogen and -C optionally substituted by one or more halogens 1-3 a group consisting of alkyl groups; R 5 Selected from hydrogen, deuterium, halogen, 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 the group formed; R 11 、R 22 and R 33 Each occurrence is independently selected from the group consisting of halogen, hydroxy, -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; among them -C 1-6 Alkyl and -C 1-6 Alkoxy may be optionally substituted with one or more substituents each independently selected from hydroxy and halogen; and R a and R b Each occurrence is independently selected from hydrogen and -C optionally substituted with one or more halogens 1-3 A group consisting of alkyl groups.

2. The compound according to claim 1, wherein R 3 Select from the group consisting of 3. The compound according to claim 2, wherein When present, R 33 Each occurrence is independently selected from the group consisting of -CF3, fluorine, chlorine, -CN, -C 1-4 Alkyl, -C 3-4 A group consisting of a cycloalkyl group and a phenyl group.

4. The compound according to any one of claims 1 to 4, wherein R 3 Select from the group consisting of 5. The compound according to any one of claims 1 to 4, wherein R 3 yes 6. The compound according to any one of claims 1 to 4, wherein The compound is represented by:

7. The compound according to any one of claims 1 to 6, wherein R 4 It's hydrogen.

8. The compound according to any one of claims 1 to 7, wherein R 5 Selected from the group consisting of hydrogen, chlorine and fluorine.

9. The compound according to any one of claims 1 to 8, wherein The compound is represented by:

10. The compound according to any one of claims 1 to 9, wherein R 1 is a 5-6 membered heteroaryl group containing at least one ring nitrogen, wherein R 1 can be optionally replaced by one or two independently selected from R 11 substituted by a substituent.

11. The compound according to any one of claims 1 to 10, wherein R 1 is selected from the group consisting of imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and pyridinyl, wherein R 1 It may be optionally substituted with one or two substituents each independently selected from the group consisting of -CH2OH, -OH and -NH2.

12. The compound according to any one of claims 1 to 11, wherein R 1 Select from the group consisting of 13. The compound according to any one of claims 1 to 12, wherein R 1 Select from the group consisting of 14. The compound according to any one of claims 1 to 13, wherein R 2 Selected from the group consisting of -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2, cyclopropyl, -CH2CH2OCH2CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

15. The compound according to any one of claims 1 to 14, wherein R 2 Selected from the group consisting of -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2 and cyclopropyl.

16. The compound according to any one of claims 1 to 15, wherein R 2 It is -CH2CH2OCH3.

17. A compound represented by formula II: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: R 1 is a 5-6 membered heteroaryl group containing at least one ring nitrogen; wherein R 1 It can be optionally replaced by one, two or three independently selected from halogen, hydroxy, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-OH and -C 1-3 Substitution of a substituent consisting of an alkoxy group; R 2 Yes-C 1-6 Alkyl or -C 3-6 Cycloalkyl; wherein R 2 can be optionally replaced by one or more independently selected from halogen, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy and -NR a R b substituted with a substituent consisting of a group; and R a and R b Each occurrence is independently selected from hydrogen and -C 1-3 A group consisting of alkyl groups.

18. The compound according to claim 17, wherein R 1 Select from the group consisting of 19. The compound according to claim 17 or 18, wherein R 2 Selected from the group consisting of -CH3, -CH2CH2OCH3, -CH2CH2N(CH3)2 and cyclopropyl.

20. The compound according to any one of claims 17 to 19, wherein R 2 It is -CH2CH2OCH3.

21. A compound selected from the group consisting of: or a pharmaceutically acceptable salt and / or stereoisomer thereof.

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

23. A method of treating a disease that would benefit from inhibition of CD38 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.

24. A method of treating a disease in a patient in need thereof that would benefit from an increase in NAD+, 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.

25. 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. 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 1-21 or a pharmaceutical composition according to claim 22.

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. A method of treating a patient in need thereof having fibrosis, 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.

30. The method of claim 30, wherein: The patient with fibrosis also suffers from systemic sclerosis.

31. The method of claim 30 or 31, wherein: The fibrosis is selected from the group consisting of skin fibrosis, lung fibrosis and peritoneal fibrosis.

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

33. 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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