Novel aminocarboxymconate semialdehyde decarboxylase inhibitor

Abstract

This specification discloses inhibitors of aminocarboxymuconate semialdehyde decarboxylase (ACMSD), pharmaceutical compositions, and methods for treating or preventing one or more ACMSD-related diseases, such as muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic diseases, cancer, vascular diseases, ophthalmic vascular diseases, ocular muscle diseases, liver diseases, inflammatory diseases, or kidney diseases.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Applications No. 63 / 544,005, No. 63 / 623,470, and No. 63 / 696,524, filed under 13 October 2023, 22 January 2024, and 19 September 2024, respectively. These applications are incorporated herein by reference in their entirety for any purpose.

[0002] This specification discloses inhibitors of aminocarboxymuconate semialdehyde decarboxylase (ACMSD), pharmaceutical compositions, and methods of using these compounds to treat or prevent one or more ACMSD-related diseases, such as muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic diseases, cancer, vascular diseases, ophthalmic vascular diseases, ocular muscle diseases, liver diseases, inflammatory diseases, or kidney diseases. [Background technology]

[0003] ACMSD is NAD from tryptophan + ACMSD is an important enzyme in tryptophan metabolism, which regulates biosynthesis. ACMSD is involved in picolinic acid (PA), quinolinic acid (QA), and NAD. + ACMSD is a zinc-dependent amide hydrolase involved in homeostasis. ACMSD is derived from tryptophan and NAD + Located at a branching point in the biosynthetic pathway, this amino acid's final fate is determined by either conversion to PA, complete oxidation via the citric acid cycle, or NAD synthesis via QA synthesis. + Decide to convert to.

[0004] ACMSD has been purified from liver, kidney, and human brain tissues. There are two isoforms, ACMSD1 and ACMSD2, derived from alternative splicing of the ACMSD gene transcript, but only ACMSD1 has enzymatic activity. ACMSD1 directs ACMS (α-amino-ω-carboxymuconate semialdehyde) into the acetyl-CoA pathway. When ACMSD1 is inhibited, ACMS is non-enzymatically converted to quinolinic acid (QA), resulting in NAD + is generated, and intracellular NAD + concentration increases.

[0005] NAD + elevation in concentration has been shown to prevent neurodegeneration, improve muscle function and oxidative metabolism in mice, and extend the lifespan of nematodes. On the other hand, decreased NAD + concentration is associated with various pathophysiological conditions, including type 2 diabetes (T2D), hyperlipidemia (elevated cholesterol and TAG), mitochondrial diseases, neutropenia, cancer, liver injury, and kidney injury. In particular, inhibition of ACMSD ameliorates inflammation and fibrosis associated with mitochondrial dysfunction and excessive DNA damage response (DDR) in various acute and chronic liver diseases, regardless of the etiology of the disease.

[0006] Accordingly, inhibition of ACMSD is a novel approach for increasing NAD + concentration and modifying the pathophysiology of diseases associated with abnormal NAD + biosynthesis. Therefore, there is a need for new and improved ACMSD inhibitors. SUMMARY OF THE INVENTION

[0007] The present disclosure provides a compound of Structural Formula (I): ##STR## or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X is R 3 C- or -N-; Y is CN-C- or -N-; R 1(C2~C 20 ) alkyl, substituted alkyl, alkenyl, substituted alkenyl, -OR 12 , -NR 13 R 14 aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkenyl; R 2 Ha-(CR 4 R 5 ) n -AB is;R 3 -H, -CN, -CH2OH, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, -C(O)NR 6 R 7 , -CO2R 8 , -NR 15 R 16 , -OR 17 A is an aryldiyl, substituted aryldiyl, heteroaryldiyl, substituted heteroaryldiyl, or absent; B is -(CR 9 R 10 ) r CO2R 11 , [ka] , or their prodrugs; n is 1 or 2; r is 0 or 1; each R 4 R is independently -H, -F, alkyl, or alkenyl; each R 5 R is independently -H, -F, alkyl, or alkenyl; 6 , R 7 , R 13 ~R16 These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, or together with the atom to which they are bonded, form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring; R 8 and R 11 R is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl; each R 9 R is independently -H, -F, alkyl, or alkenyl; each R 10 R is independently -H, -F, alkyl, or alkenyl; and R 12 and R 17 R is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, or substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl; however, R is only defined if X is -N-. 1 (C2~C 20 ) is alkyl, substituted alkyl, or cycloalkyl; however, R is only valid if X and Y are -N-. 1 は-OR 12 And; however, Y is CN-C- and R 3 When R is -H or -CN, 1 is not phenyl, (C1-C5)alkyl, (C1-C5)haloalkyl, halo, -CN, or -NO2-substituted phenyl, monocyclic heteroaryl, (C1-C5)alkyl(C1-C5)haloalkyl, halo, -CN, or -NO2-substituted monocyclic heteroaryl; provided that Y is -CN-C- and R 3 When R is -F, Cl, CH3, or -CO2H, 1 is not phenyl; however, Y is -CN-C- and R 3 is -CO2Et and R2 When R is -CH2CO2Me or -CH(CH3)CO2Me, 1 is not p-chlorophenyl; however, Y is -CN-C- and R 3 is -CO2Et and R 2 When R is -CH2CO2Me, -CH2CO2Et, or -CH(CH3)CO2Me, 1 is not 2-furanyl; however, Y is -N- and R 3 is -CN and R 2 but [ka] When R 1 is not 2-thiophenyl; and provided that X and Y are -N- and R 2 When is -CH2CO2Et, R 1 teeth [ka] This need is met by providing compounds that are not of the nature described above.

[0008] Derivatives comprising salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs of the compounds described herein are also provided. Furthermore, pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable vehicles are also provided.

[0009] In yet another embodiment, methods are provided for treating, preventing, or alleviating symptoms of medical disorders such as, for example, muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic diseases, cancer, vascular diseases, ocular vascular diseases, ocular muscle diseases, liver diseases, inflammatory diseases, or kidney diseases. [Modes for carrying out the invention]

[0010] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains. If there are multiple definitions for a term used herein, the definition set forth in this section shall prevail unless otherwise stated.

[0011] In this specification and the appended claims, the indefinite articles “a” and “an,” and the definite article “the,” may include singular and plural references unless otherwise stated or unless the context clearly indicates otherwise. As used herein, the term “exemplary” means “serving as an example, case, or explanatory role.” Embodiments or features described herein as “exemplary” are not necessarily construed as being preferable or advantageous to other embodiments or features.

[0012] When elements are presented in list form (e.g., a group of markers), it is understood that all possible subgroups of those elements are also disclosed, and any one or more elements can be excluded from the list or group.

[0013] Furthermore, disclosure of a numerical range is understood to be a specific disclosure of all possible subranges and all possible individual numerical values ​​(whether integers or fractions) within that range, regardless of the breadth of that range. Also, unless otherwise expressly stated, in any method described or claimed herein that involves multiple acts or steps, the order of the acts or steps of that method is not necessarily limited to the order in which the acts or steps of that method are described, although this disclosure is understood to encompass embodiments in which the order is limited.

[0014] Furthermore, wherever an embodiment described in the specification or claims is referred to as including one or more features, this disclosure is understood to also include embodiments comprising, or substantially comprising, such features.

[0015] It is also understood that any embodiment of this disclosure, for example, any embodiment or compound included in the prior art, may be expressly excluded from the claims, regardless of whether or not specific exclusions are stated in the specification.

[0016] When the terms “at least” or “greater than” are placed before or after the first number in a set of two or more numbers, the terms “at least” or “greater than” apply to each number in that set.

[0017] When the term “less than or equal to” or “less than” is placed after the first number in a set of two or more numbers, the term “less than or equal to” or “less than” applies to each number in that set.

[0018] In this specification, unless otherwise specified, the terms “about” and “approximately” used in relation to a numerical or numerical range characteristic indicate that the value or numerical range may deviate to a degree that is reasonable for a person skilled in the art, given that it describes the particular characteristic. Specifically, as used in this context, the terms “about” and “approximately” indicate that the numerical value or numerical range may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% from the stated numerical value or numerical range. Also, unless otherwise clearly specified in the context, the singular “a” and “the” include the plural. Thus, for example, “the compound” includes multiple such compounds, and “the assay” includes one or more assays and their equivalents well known to a person skilled in the art.

[0019] A dash ("-") that is not between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and the chemical group can be represented with or without one or more dashes without losing its usual meaning. A wavy line drawn through a line in a structural formula indicates the bonding point of a group. Unless chemically or structurally required, the order in which chemical groups are described or named does not suggest or imply direction.

[0020] Prefix “C” u~v The notation indicates that the following group has u to v carbon atoms. It should be understood that u to v carbon atoms include u+1 to v, u+2 to v, u+3 to v, u+1 to u+3 to v, u+1 to u+4 to v, u+2 to u+4 to v, and so on, encompassing all possible combinations of u and v atoms.

[0021] "Alkyl" refers to a saturated, branched, or linear monovalent hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of a parent alkane, either alone or as part of another substituent. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl (e.g., propan-1-yl, propan-2-yl); and butyl (e.g., butan-1-yl, butan-2-yl, 2-methylpropan-1-yl, 2-methylpropan-2-yl). In some embodiments, an alkyl group consists of 1 to 20 carbon atoms (C1-C2). 20 Alkyl) is included. In other embodiments, alkyl is composed of 1 to 10 carbon atoms (C1 to C 10 It contains alkyl. In other embodiments, the alkyl group contains 1 to 6 carbon atoms (C1 to C6 alkyl).

[0022] An "alkenyl" refers to an unsaturated branched or linear chain having at least one carbon-carbon double bond, obtained by removing one hydrogen atom from a single carbon atom of a parent alkene, either alone or as part of another substituent. This group may be in a cis or trans structure around the double bond(s). Representative alkenyl groups include, but are not limited to, ethenyl; propenyl such as propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl), propa-2-en-2-yl; and butenyl such as buta-1-en-1-yl, buta-1-en-2-yl, 2-methyl-propa-1-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl. In some embodiments, the alkenyl group contains 2 to 20 carbon atoms (C2 to C2). 20 Alkenyl). In other embodiments, the alkenyl group contains 2 to 10 carbon atoms (C2 to C2). 10 (Alkenyl). In other embodiments, the alkenyl group contains 2 to 6 carbon atoms (C2-C6 alkenyl).

[0023] "Alkynyl" refers to an unsaturated branched or linear chain having at least one carbon-carbon triple bond, obtained by removing one hydrogen atom from a single carbon atom of a parent alkyne, either alone or as part of another substituent. Representative alkynyl groups include, but are not limited to, ethynyl; propynyl (such as propa-1-in-1-yl, propa-2-in-1-yl); and butynyl (such as buta-1-in-1-yl, buta-1-in-3-yl, buta-3-in-1-yl). In some embodiments, the alkynyl group contains 2 to 20 carbon atoms (C2-C2). 20 Alkynyl). In other embodiments, the alkynyl group contains 2 to 10 carbon atoms (C2 to C2). 10 Alkynyl). In other embodiments, the alkynyl group contains 2 to 6 carbon atoms (C2-C6 alkynyl).

[0024] "Aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of a hydrophilic aromatic ring system as defined herein, either alone or as part of another substituent. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafene, octaene, ovalene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. In some embodiments, the aryl group contains 6 to 30 carbon atoms (C6 to C6). 30 In other embodiments, the aryl group contains 6 to 20 carbon atoms (C6 to C6). 20 (aryl). In yet another embodiment, the aryl group contains 6 to 15 carbon atoms (C6 to C6). 15 (aryl). In yet another embodiment, the aryl group contains 6 to 10 carbon atoms (C6 to C6). 10 Ariel).

[0025] "Arylalkyl" refers to a carbon atom, usually terminal or sp, either alone or as part of another substituent. 3 This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with an aryl group as defined herein. Representative arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 1-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 1-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl. In some embodiments, the arylalkyl group is (C7~C 40 ) is an arylalkyl, and for example, the alkyl part of an arylalkyl group is (C1~C 10 ) is alkyl, and the aryl portion is (C6~C 30 )aryl. In other embodiments, arylalkyl groups are (C7~C 30) arylalkyl, for example, the alkyl moiety of the arylalkyl group is (C1~C 10 ) alkyl, and the aryl moiety is (C6~C 20 ) aryl. In another embodiment, the arylalkyl group is (C7~C 20 ) arylalkyl, for example, the alkyl moiety of the arylalkyl group is (C1~C8) alkyl, and the aryl moiety is (C6~C 12 ) aryl. In yet another embodiment, the arylalkyl group is (C7~C 15 ) arylalkyl, for example, the alkyl moiety of the arylalkyl group is (C1~C5) alkyl, and the aryl moiety is (C6~C 10 ) aryl.

[0026] "Arylalkenyl", alone or as part of another substituent, refers to an acyclic alkenyl group in which one hydrogen atom bonded to a carbon atom is substituted with an aryl group as defined herein. In some embodiments, the arylalkenyl group is (C8~C 40 ) arylalkenyl, for example, the alkenyl moiety of the arylalkenyl group is (C2~C 10 ) alkenyl, and the aryl moiety is (C6~C 30 ) aryl. In another embodiment, the arylalkenyl group is (C8~C 30 ) arylalkenyl, for example, the alkenyl moiety of the arylalkenyl group is (C2~C 10 ) alkenyl, and the aryl moiety is (C8~C 20 ) aryl. In another embodiment, the arylalkenyl group is (C8~C 20 ) arylalkenyl, for example, the alkenyl moiety of the arylalkenyl group is (C2~C8) alkenyl, and the aryl moiety is (C6~C 12 ) aryl. In yet another embodiment, the arylalkenyl group is (C8~C 15 ) arylalkenyl, for example, the alkenyl moiety of the arylalkenyl group is (C2~C5) alkenyl, and the aryl moiety is (C6~C 10 ) aryl.

[0027] "Arylalkynyl", alone or as part of another substituent, refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as defined herein. In some embodiments, the arylalkynyl group is (C8-C 40 ) arylalkynyl, for example, the alkynyl moiety of the arylalkynyl group is (C2-C 10 ) alkynyl, and the aryl moiety is (C6-C 30 ) aryl. In other embodiments, the arylalkynyl group is (C8-C 30 ) arylalkynyl, for example, the alkynyl moiety of the arylalkynyl group is (C2-C 10 ) alkynyl, and the aryl moiety is (C6-C 20 ) aryl. In other embodiments, the arylalkynyl group is (C8-C 20 ) arylalkynyl, for example, the alkynyl moiety of the arylalkenyl group is (C2-C8) alkynyl, and the aryl moiety is (C6-C 12 ) aryl. In still other embodiments, the arylalkynyl group is (C8-C 15 ) arylalkynyl, for example, the alkynyl moiety of the arylalkynyl group is (C2-C5) alkynyl, and the aryl moiety is (C6-C 10 ) aryl.

[0028] "Aryldiyl" refers to a divalent aromatic hydrocarbon group obtained by removing two hydrogen atoms from two different carbon atoms of a hydrophilic aromatic ring system as defined herein, either alone or as part of another substituent. Typical aryldiyl groups include, but are not limited to, groups obtained from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalen, ovalene, pentacene, pentalene, pentafen, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. In some embodiments, the aryldiyl group contains 6 to 30 carbon atoms (C6 to C6). 30 (aryldiyl). In some embodiments, the aryldiyl group contains 6 to 20 carbon atoms (C6 to C20). 20 (aryldiyl). In other embodiments, the aryldiyl group contains 6 to 15 carbon atoms (C6 to C6). 15 (aryldiyl). In yet another embodiment, the aryldiyl group contains 6 to 10 carbon atoms (C6 to C6). 10 (Arylzyil).

[0029] "Carbohydrate derivatives" are those with the general formula C n H 2n O nThis refers to a carbohydrate having a carbon atom bonded to a compound's base. In some embodiments, carbohydrate derivatives typically contain five or six carbon atoms. In other embodiments, carbohydrate derivatives are monosaccharides (e.g., glucose, fructose, galactose, ribose). In yet another embodiment, carbohydrate derivatives include disaccharides (e.g., lactose, sucrose, maltose, cellobiose, chitobiose, gentobiose, etc.). In yet another embodiment, carbohydrate derivatives include oligosaccharides (e.g., oligofructose, oligogalactose, raffinose, plantose, veracose, etc.). In yet another embodiment, carbohydrate derivatives include polysaccharides (e.g., cellulose, amylose, starch, chitin, pectin, galactogen, etc.). In yet another embodiment, carbohydrate derivatives include protected carbohydrates such as esters (e.g., acetate or benzoic acid esters), silyl derivatives, or carbohydrates protected with other known alcohol protecting groups.

[0030] "Compound" refers to the compounds contained in the structural formulas disclosed herein, and includes any specific compound within these formulas whose structures are disclosed herein. Compounds may be identified by their chemical structure and / or chemical name. The chemical structure is deterministic of the identity of a compound. Compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, the chemical structures shown herein include the stereoisomerically pure forms shown in the structure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure). The chemical structures shown herein also include enantiomer and stereoisomeric derivatives of the illustrated compounds. Mixtures of enantiomers and stereoisomers can be separated into enantiomers or stereoisomers of their components using separation techniques or chiral synthesis techniques known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Therefore, the chemical structures shown herein encompass all possible tautomer forms of the illustrated compounds. The compounds may also be atropisomers. The compounds described also include isotope-labeled compounds in which the atomic weight of one or more atoms differs from the atomic weights commonly found in nature. Examples of isotopes that may be included in the compounds disclosed herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 Examples include, but are not limited to, O. Compounds can exist in both non-solvated and solvated forms, including hydrated forms. Generally, compounds can exist in either a hydrated or solvated state. Certain compounds can exist in multiple crystalline or amorphous forms. Generally, all physical forms are considered equivalent in the applications envisioned herein and are within the scope of this disclosure. Furthermore, where substructures of a compound are illustrated, parentheses should be understood to indicate the position where that substructure binds to the rest of the molecule.

[0031] "Cycloalkyl" refers to a saturated cyclic monovalent hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of a parent cycloalkane, either alone or as part of another substituent. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclopentenyl. In some embodiments, cycloalkyl groups contain 3 to 20 carbon atoms (C3-C3). 15 (Cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C3-C3). 10 (Cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C3-C8 cycloalkyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having a monovalent group and 5 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include norbornyl, pinyl, and adamantyl, for example.

[0032] A "cycloalkenyl" refers to an unsaturated cyclic monovalent hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of a parent cycloalkene, either alone or as part of another substituent. Typical cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, and cyclopentenyl. In some embodiments, a cycloalkenyl group contains 3 to 20 carbon atoms (C3-C2). 20 (Cycloalkenyl). In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C3 to C 10 (Cycloalkenyl). In yet another embodiment, the cycloalkenyl group contains 3 to 8 carbon atoms (C3-C8 cycloalkenyl).

[0033] "Cycloheteroalkyl" refers to a cycloalkyl group as defined herein, in which one or more carbon atoms (and optionally any associated hydrogen atoms), either alone or as part of other substituents, are independently substituted with the same or different heteroatoms or heteroatomic groups as defined below by "heteroalkyl". In some embodiments, a cycloheteroalkyl group contains 3 to 20 carbon atoms and heteroatoms (3 to20 (Cycloheteroalkyl). In other embodiments, the cycloheteroalkyl comprises 3 to 10 carbon atoms and heteroatoms (3 to 10 (Cycloheteroalkyl). In yet another embodiment, the cycloheteroalkyl group comprises 3 to 8 carbon atoms and a heteroatom (3-8 cycloheteroalkyl). The term “cyclic monovalent heteroalkyl group” also includes polycyclic heteroalkyl ring systems having a monovalent group, 3 to 12 carbon atoms, and at least one heteroatom. Exemplary cycloheteroalkyl groups include, for example, azetidine, pyrrolidine, piperazine, piperidine, morpholine, and tetrahydrofuran.

[0034] "Cycloheteralkenyl" refers to a cycloalkenyl group as defined herein, in which one or more carbon atoms (and optionally any associated hydrogen atoms), either alone or as part of other substituents, are independently substituted with the same or different heteroatoms or heteroatomic groups as defined below by "heteralkenyl". In some embodiments, a cycloheteralkenyl group contains 3 to 20 carbon atoms and heteroatoms (3 to 20 (Cycloheteralkenyl). In other embodiments, the cycloheteralkenyl group comprises 3 to 10 carbon atoms and heteroatoms (3 to 10 (Cycloheteralkenyl). In other embodiments, the cycloheteralkenyl group comprises 3 to 8 carbon atoms and a heteroatom (3-8 cycloheteralkenyl). The term "cyclic monovalent heteroalkenyl group" also includes polycyclic heteroalkenyl ring systems having a monovalent group, 2 to 12 carbon atoms, and at least one heteroatom.

[0035] "Halo" refers to a -F, -Cl, -Br, or -I group, either alone or as part of another substituent.

[0036] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently substituted with the same or different heteroatoms or heteroatomic groups. Representative heteroatoms or heteroatomic groups that can substitute carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O), -S(O)2-, -S(O)NH-, -S(O)2NH-, and combinations thereof. Heteroatoms or heteroatomic groups can be located at any internal position of an alkyl group, alkenyl group, or alkynyl group. Representative heteroatomic groups that may be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 ,=NN=,-N=N-,-N=N-NR 503 R 404 ,-PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 These are some examples, but are not limited to these, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 These are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group contains 1 to 20 carbon atoms and heteroatoms (1 to 20 carbon atoms). 20 (heteroalkyl). In other embodiments, the heteroalkyl group comprises 1 to 10 carbon atoms and heteroatoms (1 to 10 (heteroalkyl). In other embodiments, the heteroalkyl group comprises 1 to 6 carbon atoms and heteroatoms (1 to 6 heteroalkyl).

[0037] A "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently substituted with the same or different heteroatoms or heteroatomic groups. Representative heteroatoms or heteroatomic groups that can substitute for carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O), -S(O)2-, -S(O)NH-, -S(O)2NH-, and combinations thereof. Heteroatoms or heteroatomic groups can be located at any internal position of an alkyl group, alkenyl group, or alkynyl group. Representative heteroatomic groups that may be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 ,=NN=,-N=N-,-N=N-NR 503 R 404 ,-PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 These are some examples, but are not limited to these, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 These are independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkenyl group contains 1 to 20 carbon atoms and heteroatoms (1 to 20 (heteroalkenyl). In other embodiments, the heteroalkenyl group comprises 1 to 10 carbon atoms and heteroatoms (1 to 10 (heteroalkenyl). In yet another embodiment, the heteroalkenyl group contains 1 to 6 carbon atoms and a heteroatom (1 to 6 heteroalkenyl).

[0038] "Heteroaryl" refers to a monovalent heteroaromatic group obtained by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system as defined herein, either alone or as part of another substituent. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indidine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and others. In some embodiments, the heteroaryl group contains 5 to 20 ring atoms (5 to 20-membered heteroaryl). In other embodiments, the heteroaryl group contains 5 to 10 ring atoms (5 to 10-membered heteroaryl). Exemplary heteroaryl groups are derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0039] "Heteroarylalkyl" refers to a carbon atom, usually terminal or sp, either alone or as part of another substituent. 3 This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl group, for example, the alkyl portion of the heteroarylalkyl group is (C1-C6) alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl group. In other embodiments, the heteroarylalkyl group is a 6- to 13-membered heteroarylalkyl group, for example, the alkyl portion is (C1-C3) alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl group.

[0040] A "heteroarylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with a heteroaryl group, either alone or as part of another substituent. In some embodiments, the heteroarylalkenyl group is a 7- to 21-membered heteroarylalkenyl, for example, the alkenyl portion of the heteroarylalkenyl is a (C2-C6) alkenyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkenyl is a 7- to 13-membered heteroarylalkenyl, for example, the alkenyl portion is a (C2-C3) alkenyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0041] A "heteroarylalkynyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is substituted with a heteroaryl group, either alone or as part of another substituent. In some embodiments, the heteroarylalkynyl group is a 7- to 21-membered heteroarylalkynyl, for example, the alkynyl portion of the heteroarylalkynyl is a (C2-C6)alkynyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkynyl is a 7- to 13-membered heteroarylalkynyl, for example, the alkynyl portion is a (C2-C3)alkynyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0042] "Heteroaryldiyl" refers to a divalent group obtained by removing two hydrogen atoms from two different atoms of a heteroaromatic ring system as defined herein, either alone or as part of another substituent. Typical heteroaryldiyl groups include, but are not limited to, groups derived from acridine, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indidine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and others. In some embodiments, the heteroaryldiyl group contains 5 to 20 ring atoms (5 to 20-membered heteroaryldiyl). In other embodiments, the heteroaryldiyl group contains 5 to 10 ring atoms (5 to 10-membered heteroaryldiyl). Exemplary heteroaryldiyl groups are derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0043] "Hydrate" refers to an adduct formed when water is incorporated in a stoichiometric ratio into the form of a compound described herein. Methods for producing hydrates include, but are not limited to, storage in a steam-containing atmosphere, water-containing dosage forms, or conventional pharmaceutical processes such as crystallization (i.e., from water or a mixed aqueous solvent), freeze-drying, wet granulation, aqueous film coating, or spray drying. Under certain conditions, hydrates may also be formed by exposing a crystalline solvate to steam or by suspending an anhydrous substance in water. Hydrates may crystallize in multiple forms, resulting in polymorphisms of hydrates. See, for example, Guillory, K., Polymorphism in Pharmaceutical Solids, Britain, H. ed., Marcel Dekker, Inc., New York, NY, 1999, Chapter 5, pp. 202-205. The above methods for preparing hydrates are entirely conventional and within the scope of the art, and do not require experiments beyond the usual scope in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single-crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy (Brittain, H., Polymorphism in Pharmaceutical Solids, Britain, H. ed., Marcel Dekker, Inc. New York, 1999, Chapter 6, pp. 205-208). Furthermore, many private companies routinely offer services including the preparation and / or characterization of hydrates, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0044] "N-oxide" refers to a compound containing an NO bond to which three additional hydrogens or side chains are bonded, or a compound containing an NO bond to which two additional hydrogens or side chains are bonded to which the nitrogen is positively charged. The N-oxides of this disclosure can be synthesized by oxidation procedures well known to those skilled in the art.

[0045] A "philophilic aromatic ring system" refers to an unsaturated monocyclic or polycyclic ring system that has a conjugated π-electron system. Specifically, the definition of a "philophilic aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as fluorene, indane, indene, and phenalene. Representative aromatic ring systems include, but are not limited to, acetantrylene, acetanaphthylene, acetphenantrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalen, ovalen, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0046] A "hetero-aromatic ring system" refers to a ring system in which one or more carbon atoms (and optionally any related hydrogen atoms) are independently substituted with the same or different heteroatoms. Typical heteroatoms that substitute for carbon atoms include, but are not limited to, N, P, O, S, and Si. Specifically, the definition of a "hetero-aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as benzodioxane, benzofuran, chroman, chromene, indole, indoline, and xanthene. Representative heteroaromatic ring systems include, but are not limited to, arsindol, carbazole, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indoridine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthoridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinoridine, quinoxaline, tetrazoline, thiadiazole, thiazole, thiophene, triazole, and xanthene.

[0047] "Pharmacologically acceptable salts" refer to salts of compounds that have the desired pharmacological activity of the parent compound. Such salts may be formed with (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl Acid addition salts formed with organic acids such as tilbicyclo[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.

[0048] "Prevention" or "prevention" refers to reducing the risk of developing a disease or disorder (i.e., the development of at least one clinical symptom of the disease in a patient who is exposed to or predisposed to the disease but has not yet experienced or presented with symptoms of the disease). The application of therapeutic agents to prevent a disease or disorder is known as "preventive action." In some embodiments, the compounds provided herein offer superior preventive action due to their low incidence of long-term side effects over extended periods.

[0049] As used herein, "prodrug" refers to a derivative of a drug molecule that requires conversion in the body to release an active drug. Prodrugs are often, though not always, pharmacologically inactive until they are converted to their parent drug.

[0050] As used herein, “promoyety” refers to a form of protecting group that converts a drug into a prodrug by being used to mask functional groups within a drug molecule. Typically, promoyeties bind to a drug via one or more bonds that are cleaved in vivo by enzymatic or non-enzymatic means.

[0051] A "protecting group" refers to a group of atoms that, by attaching to a reactive functional group within a molecule, masks, reduces, or prevents the reactivity of that functional group during chemical synthesis. An example of a protecting group is found in Green et al.'s "Protective Groups in Organic Chemistry" (Wiley, 2020). nd This is described in the ed. 1991 edition and in Harrison et al.'s "Compendium of Synthetic Organic Methods" Volumes 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitroveratryloxycarbonyl ("NVOC"). Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxyl group is acylated or alkylated (such as benzyl), as well as trityl ethers, alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0052] A “solvate” refers to an adduct formed when a solvent is incorporated in a stoichiometric ratio into the crystal lattice of a compound described herein. Methods for producing solvates include, but are not limited to, storage in a solvent-containing atmosphere, a solvent-containing dosage form, or conventional pharmaceutical processes such as crystallization (i.e., from a solvent or mixed solvent) or vapor diffusion. Under certain circumstances, solvates may also be formed by exposing other crystalline solvates or hydrates to a solvent, or by suspending a material in a solvent. Solvates may crystallize in multiple forms, resulting in polymorphisms of the solvate. See, for example, Guillory, K., Polymorphism in Pharmaceutical Solids, Britain, H. ed., Marcel Dekker, Inc., New York, NY, 1999, Chapter 5, pp. 202-205. The above methods for preparing solvates are entirely conventional and within the scope of the art, and do not require experiments beyond the usual scope in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single-crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy (Brittain, H., Polymorphism in Pharmaceutical Solids, Britain, H. ed., Marcel Dekker, Inc. New York, 1999, Chapter 6, pp. 205-208). Furthermore, many private companies routinely offer services including the preparation and / or characterization of solvates, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0053] "Substitution," when used to modify a particular group or radical, means that one or more hydrogen atoms of that particular group or radical are substituted, independently of each other, with one or more identical or different substituents. Substituents useful for substituting saturated carbon atoms of a particular group or radical include R a Hello, -O - ,=O,-OR b , -SR b , -S - ,=S,-NR c R c ,=NR b 、=N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b -S(O)2NR b R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b -OS(O)2NR c NR c ,-P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b -C(O)NR b -OR b -C(S)R b -C(NR b )R b ,-C(O)O - , -C(O)OR b , -C(S)OR b -C(O)NR c R c -C(NR b )NR c R c -OC(O)Rb , -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(O)NR c R c , -OC(NCN)NR c R c -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)2NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b , and NR b C(NR b )NR c R c are present, and each R aEach R is independently a substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, or substituted heteroaryl; each R b These are independently hydrogen, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; and each R c R is independent of R b And, or alternatively, two R c However, together with the nitrogen atom to which they are bonded, they form a 4, 5, 6, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl ring, or a cycloheteroalkyl or cycloheteroalkenyl condensed with an aryl group, the aryl group may optionally contain 1 to 4 additional identical or different heteroatoms selected from the group consisting of O, N, and S. A specific example is -NR c R c It is intended to include -NH2, NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for substituting a saturated carbon atom of a particular group or radical are R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b -C(O)NR b -ORb , -C(O)OR b -C(O)NR c R c ,-OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c -OC(O)NR c R c , and -NR b C(O)OR b There is, R a , R b , and R c R is defined as described above. In other embodiments, a substituent useful for substituting a saturated carbon atom of a particular group or radical is R. a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b -OC(O)NR c R c , and -NR b C(O)OR b There is, R a , R b , and R c It is defined as described above.

[0054] Substituents useful for substituting unsaturated carbon atoms of specific groups or radicals include substituted alkyl groups and -R a Hello, -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2OR b -OS(O)2O - ,-P(O)(O- )2、-P(O)(OR b )(O - )、-P(O)(OR b )(OR b )、-C(O)R b 、-C(S)R b 、-C(NR b )R b 、-C(O)O - 、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R b 、-OC(O)O - 、-OC(O)OR b 、-OC(S)OR b 、-OC(O)NR c R c 、-OS(O)2NR c NR c 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)O - 、-NR b C(O)OR b 、-NR b S(O)2OR a 、-NR b S(O)2R a 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b 、-NR b C(NR b )NR c R c 、および-C(NR b )NR b C(NR b )NR c R c があり、Ra , R b , and R c It is defined as described above. In other embodiments, substituents useful for substituting an unsaturated carbon atom of a particular group or radical are substituted alkyl, -R a Hello, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c , -NR b C(O)R b , and -NR b C(O)OR b There is, R a , R b , and R c It is defined as described above. In other embodiments, substituents useful for substituting an unsaturated carbon atom of a particular group or radical are substituted alkyl, -R a Hello, -OR b , -NR c R c , trihalomethyl, -S(O)2OR b , -C(O)R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -NR b C(O)R b , and -NR b C(O)OR b There is, R a , R b , and R c It is defined as described above.

[0055] Alkyl and -R substituents are useful for substituting nitrogen atoms in heteroalkyl and cycloheteralkyl groups. a、-O - 、-OR b 、-SR b 、-S - 、-NR c R c 、トリハロメチル、-CF3、-CN、-NO、-NO2、-S(O)2R b 、-S(O)2O - 、-S(O)2OR b 、-OS(O)2R b 、-OS(O)2O - 、-OS(O)2OR b 、-P(O)(O - )2、-P(O)(OR b )(O - )、-P(O)(OR b )(OR b )、-C(O)R b 、-C(S)R b 、-C(NR b )R b 、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R b 、-OC(O)OR b 、-OC(S)OR b 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)OR b 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b 、-NR b C(NR b )NR c R c 、および-C(NR b )NR b C(NR b)NR c R c There are, but are not limited to, R a , R b , and R c It is defined as described above. In some embodiments, substituents useful for substituting the nitrogen atom of heteroalkyl and cycloheteralkyl groups are alkyl, R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b -OS(O)2R b , -C(O)R b -C(NR b )R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -OC(O)OR b -OS(O)2NR c NR c , -NR b C(O)R b , and -NR b C(O)OR b There is, R a , R b , and R c It is defined as described above. In other embodiments, substituents useful for substituting the nitrogen atom of heteroalkyl and cycloheteralkyl groups include alkyl and R a Hello, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b -C(NR b )R b , -C(O)OR b -C(O)NR c R c -OC(O)R b , -NR b C(O)R b , and -NR b C(O)OR b There is, R a , Rb , and R c It is defined as described above.

[0056] The substituents listed above, which are useful for substituting other specific groups or atoms, will be obvious to those skilled in the art.

[0057] The substituents used to replace a particular group can typically be further substituted using one or more identical or different groups selected from the various groups identified above.

[0058] "Subject," "individual," or "patient" are used synonymously herein and refer to vertebrates, preferably mammals. Mammals include, but are not limited to, rodents, apes, humans, domestic animals, sports animals, and pets. In some embodiments, a subject, individual, or patient belongs to the species Homo sapiens. In other embodiments, a subject, individual, or patient includes all mammals other than Homo sapiens.

[0059] In some aspects, “therapeutic act” or “treatment” of any disease or disorder means alleviating the disease or disorder (i.e., preventing or reducing the manifestation of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to alleviate, prevent, or prevent the manifestation of at least one of the disease or clinical symptoms. A further characteristic is that the treatment performed is unlikely to have long-term side effects over several years or more. In other aspects, “therapeutic act” or “treatment” means improving at least one physical parameter that the patient may not be aware of. In yet another aspect, “therapeutic act” or “treatment” means suppressing the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another aspect, “therapeutic act” or “treatment” means delaying the onset of the disease or disorder.

[0060] The "therapeutic dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a patient. The therapeutic dose varies depending on the compound, the disease and its severity, as well as the age, weight, adsorption, distribution, metabolism, and excretion of the patient being treated.

[0061] "Vehicle" refers to a diluent, excipient, or carrier used to administer a compound to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0062] compound In this specification, the compound of structural formula (I): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof: X is R 3 It is C- or -N-; Y is CN-C- or -N-; R 1 (C2~C 20 ) alkyl, substituted alkyl, alkenyl, substituted alkenyl, -OR 12 , -NR 13 R 14 aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkenyl; R 2 Ha-(CR 4 R 5 ) n -AB is;R 3-H, -CN, -CH2OH, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, -C(O)NR 6 R 7 , -CO2R 8 , -NR 15 R 16 , -OR 17 A is an aryldiyl, substituted aryldiyl, heteroaryldiyl, substituted heteroaryldiyl, or absent; B is -(CR 9 R 10 ) r CO2R 11 , [ka] , or their prodrugs; n is 1 or 2; r is 0 or 1; each R 4 R is independently -H, -F, alkyl, or alkenyl; each R 5 R is independently -H, -F, alkyl, or alkenyl; 6 , R 7 , R 13 ~R 16 These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, or together with the atom to which they are bonded, form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring; R 8 and R 11 R is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl; each R 9 R is independently -H, -F, alkyl, or alkenyl; each R 10 R is independently -H, -F, alkyl, or alkenyl; and R 12 and R 17R is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, or substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl; however, R is only defined if X is -N-. 1 (C2~C 20 ) is alkyl, substituted alkyl, or cycloalkyl; however, R is only valid if X and Y are -N-. 1 は-OR 12 And; however, Y is CN-C- and R 3 When R is -H or -CN, 1 is not phenyl, (C1-C5)alkyl, (C1-C5)haloalkyl, halo, -CN, or -NO2-substituted phenyl, monocyclic heteroaryl, (C1-C5)alkyl(C1-C5)haloalkyl, halo, -CN, or -NO2-substituted monocyclic heteroaryl; provided that Y is -CN-C- and R 3 When R is -F, Cl, CH3, or -CO2H, 1 is not phenyl; however, Y is -CN-C- and R 3 is -CO2Et and R 2 When R is -CH2CO2Me or -CH(CH3)CO2Me, 1 is not p-chlorophenyl; however, Y is -CN-C- and R 3 is -CO2Et and R 2 When R is -CH2CO2Me, -CH2CO2Et, or -CH(CH3)CO2Me, 1 is not 2-furanyl; however, Y is -N- and R 3 is -CN and R 2 but [ka] When R 1is not 2-thiophenyl; and provided that X and Y are -N- and R 2 When is -CH2CO2Et, R 1 teeth [ka] A compound that is not this one is provided.

[0063] In some embodiments, the compound of structural formula (II): [ka] In other embodiments, R 1 is an aryl or substituted aryl. In yet another embodiment, A is absent, n is 1, and R 4 and R 5 In another embodiment, R 1 is biphenyl or substituted biphenyl. In further embodiments, R 1 teeth [ka] And R 18 , R 19 , R 20 , and R 21 These are independently -H, alkyl, substituted alkyl, halo, -CN, -NO2, -OR 22 , -NR 23 R 24 , -NR 25 COR 26 , -CO2R 27 ,-CONR 28 R 29 , or cycloalkyl; R 22 R is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; 25 ~R 27 R is independently -H, alkyl, or alkenyl; and R 23 , R 24 , R 28 , and R 29R is -H, alkyl, alkenyl, aryl, substituted aryl, or together with the atom to which they are bonded, they form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring. In further embodiments, R 21 is -H, and R 22 , R 23 , and R 24 One of these is H, alkyl, substituted alkyl, halo, -CN, -NO2, -OCR 22 , -NR 23 R 24 , -NR 25 COR 26 , -CO2R 27 ,-CONR 28 R 29 , or cycloalkyl.

[0064] In some embodiments, A is absent, n is 1, and R 4 and R 5 In other embodiments, R 1 is an aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, or substituted heteroaryl. In further embodiments, R 1 R is a substituted phenyl. In yet another embodiment, R 1 teeth [ka] And R 30 is -H or alkyl, R 31 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or cycloalkyl, or R 30 and R 31 These, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In yet another embodiment, R 30 is -H or methyl, R 31 is alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl, or cyclopropyl, or R 30 and R31 These, together with the atoms to which they are bonded, form pyrrolidine, substituted pyrrolidine, piperazine, or substituted piperazine rings.

[0065] In some embodiments, A is absent, n is 1, and R 4 and R 5 In other embodiments, R 3 is -H, and R 27 is -H or methyl, and R 28 is phenyl or substituted phenyl. In yet another embodiment, the structure: [ka] A compound having the following is provided.

[0066] In some embodiments, R 3 is -H, and R 30 is -H or methyl, R 31 is alkyl, substituted alkyl, cycloheteroalkyl, or cycloalkyl, or R 27 and R 28 These, together with the atoms to which they are bonded, form a pyrrolidine, substituted pyrrolidine, piperazine, or substituted piperazine ring. In other embodiments, the structure: [ka] A compound having the following is provided.

[0067] In some embodiments, A is an aryl silyl, n is 1, and R 4 and R 5 In other embodiments, R 3 is -H, and R 30 is -H or methyl, and R 31 is phenyl or substituted phenyl. In yet another embodiment, the structure: [ka] A compound having the following is provided.

[0068] In some embodiments, R 3 is -CN, n is 1, and R 4 and R 5 is -H. In other embodiments, the structure: [ka] A compound having the following is provided.

[0069] In some embodiments, R 1 is a heteroaryl or substituted heteroaryl, A is absent, n is 1, and R 4 and R 5 In other embodiments, R 3 is -H. In yet another embodiment, the structure: [ka] A compound having the following is provided.

[0070] In some embodiments, R 1 is an aryl or substituted aryl, A is absent, n is 1, and R 4 and R 5 In other embodiments, R 3 is -H. In yet another embodiment, the structure: [ka] [ka] A compound having the following is provided.

[0071] In some embodiments, R 3 -CH2OH, halo, alkyl, substituted alkyl, -C(O)NR 6 R 7 , or -CO2R 8 In other embodiments, the structure is: [ka] [ka] [ka] A compound having the following is provided.

[0072] In some embodiments, R 3 is -CN. In other embodiments, the structure is: [ka] [ka] [ka] [ka] A compound having the following is provided.

[0073] In some embodiments, R 1 is a cycloheteroalkyl or substituted cycloheteroalkyl, A is absent, n is 1, and R 4 and R 5 In other embodiments, R 3 is -CN. In some embodiments, the structure: [ka] A compound having the following is provided.

[0074] In some embodiments, the compound of structural formula (III): [ka] In other embodiments, R 1is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, or -NR 13 R 14 That is the case.

[0075] In some embodiments, A is absent, n is 1, and R 4 and R 5 is -H. In other embodiments, the structure: [ka] [ka] A compound having the following is provided.

[0076] In some embodiments, A is an aryldiyl, a substituted aryldiyl, n is 1, and R 4 and R 5 is -H. In other embodiments, the structure: [ka] A compound having the following is provided.

[0077] In some embodiments, the compound of structural formula (IV): [ka] In other embodiments, R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, -OR 12 , or -NR 13 R 14 That is the case.

[0078] In some embodiments, C is absent, n is 1, and R 4 and R 5 is -H. In other embodiments, the structure: [ka] A compound having the following is provided.

[0079] In some embodiments, A is an aryldiyl, a substituted aryldiyl, n is 1, and R 4 and R 5 is -H. In other embodiments, the structure: [ka] A compound having the following is provided.

[0080] The above compounds can be produced by well-known methods, some of which are described below and illustrated in the experimental section. Synthesis method [ka]

[0081] R 3A general method for preparing the compound of structural formula (I) where R3 is -CN or -CO2R is shown above. Aldehyde A is commercially available or can be prepared by procedures well known to those skilled in the art. Compound A can be condensed with 2-cyanoethanethioamide in a solvent such as toluene or EtOH at ambient temperature ~approximately 120°C in the presence of a base such as Et3N, DIPEA, piperidine, or ammonium acetate to prepare compound B. After the reaction is complete (i.e., 2-24 hours), compound B is isolated and purified by standard methods. Compound C can be prepared by reacting compound B with an alkyl 2-cyanoacetate if R3 is -CN, or with a dialkylmalonate if R3 is -CO2R, in an alcohol solvent such as EtOH at ambient temperature ~approximately 120°C in the presence of a base such as KOH. After the reaction is complete (i.e., 2-24 hours at ambient temperature ~approximately 120°C), compound C is separated and purified by standard methods. Compound C can be alkylated with a suitable electrophile in a suitable solvent such as acetonitrile, DMSO, or EtOH, in the presence of a base such as K2CO3 or DIPEA, to prepare (I'). After the reaction is complete (i.e., at ambient temperature ~50°C for 4 to 24 hours), compound (I') is isolated and purified by standard methods. [ka]

[0082] R 3A general method for preparing compounds of formula (I') where is H, alkyl, or halo is shown above. Compound D is commercially available or can be prepared by procedures well known to those skilled in the art. Compound D can be activated with carbonyl diimidazole or converted to an acid halide and treated with potassium 3-alkoxy-3-oxopropanoate in a solvent such as THF in the presence of a base such as TEA and MgCl2 to prepare compound E. After the reaction is complete (i.e., at ambient temperature ~about 80°C for 2 to 24 hours), compound E is isolated and purified by standard methods. Alternatively, compound E can be formed by reacting the corresponding methyl ketone of D with diethyl carbonate in a solvent such as THF or toluene at a temperature of about 50 to about 140°C for 30 minutes to 5 hours with a base such as NaH. To prepare compound C, compound E can be reacted with 2-cyanoethanethioamide in a solvent such as EtOH in the presence of a base such as KOH. After the reaction is complete (i.e., at approximately 100°C from ambient temperature for 1 to 24 hours), compound C is isolated and purified using standard methods. Compound (I') can be prepared by the method already described. 3 Further modification of compound (I') where is Cl or Br is R 3 This can be produced by reacting a compound of formula (I') where is H with a halogenating reagent such as NBS or NCS in a solvent such as DMF or ACN, and optionally with an activator such as AIBN, at a temperature of ambient temperature ~ approximately 80°C.

[0083] R 3 or R 1 A common method for preparing compounds of formula (I) containing an amide is to use R at the position where you want to form the amide. 3 or R 1The process can begin by preparing a precursor containing the ester using the method described above. First, the ester is converted to an acid using a base such as LiOH or NaOH in a solvent such as a mixture of alcohol (e.g., MeOH, EtOH) and / or water and / or THF. The resulting acid is isolated and purified using standard methods and can be coupled with the amine at ambient temperature ~ approximately 80°C in a suitable solvent such as DCM, DMF, or siRNA, and optionally using a base such as DIPEA, TEA, or morpholine, in the presence of a coupling agent such as HATU, EDC, HOBt, DCC, or T3P. After reacting for 2 to 24 hours, compound (I') is isolated and purified using standard methods. [ka]

[0084] A general method for preparing the compound of formula (I'') is shown above. Aldehyde A, alkylcyanoacetate, and urea may be stirred with a base such as K2CO3 in a solvent such as EtOH and heated at ambient temperature ~100°C for 2 to 24 hours. Compound F is isolated after standard processing and purification, and reacted with a chlorinating reagent such as POCl3 and optionally an additive such as diethylaniline at a temperature of about 50 to about 140°C to obtain compound G after standard processing and purification. Compound G may be reacted with methanol or ethanol as solvents, or with an alcohol or phenol in a non-reactive solvent such as THF, DMF, or DMSO, in the presence of a base such as TEA or the corresponding alkoxide, at a temperature of 0 to 60°C for 1 to 16 hours, if methoxy ether or ethoxy ether is desired. Compound H, obtained by standard processing and purification, is reacted with a sulfur nucleophile, such as NaSH, in a solvent such as DMF at a temperature of approximately 50 to 140°C for 4 to 10 hours. Compound I, obtained by standard processing and purification, can be converted to the compound of formula (I'') by the method described above. [ka]

[0085] A general method for preparing the compound of formula (I''') is shown above. Compound J can be reacted with methanol or ethanol as solvents, or with an alcohol or phenol in a non-reactive solvent such as THF, DMF, or DMSO, in the presence of a base such as TEA, NaH, or the corresponding alkoxide, at a temperature of about -50 to about 20°C for 1 to 10 hours, if a methoxy ether or ethoxy ether is desired. Compound K, which may be obtained after standard processing and purification, can be reacted with a sulfur nucleophile such as NaSH, at a temperature of about 50 to about 140°C for 4 to 24 hours in a solvent such as DMF. Compound L, obtained by standard processing and purification, can be converted to I''' by the method described above.

[0086] Composition and administration method The compositions provided herein contain one or more therapeutically effective amounts of the compounds provided herein, and a vehicle, which are useful for the prevention, treatment, or alleviation of one or more symptoms of the diseases or disorders described herein. Vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art as suitable for a particular method of administration. Furthermore, the compounds may be formulated as the sole active ingredient in a composition, or in combination with other active ingredients.

[0087] The compositions contain one or more compounds provided herein. In some embodiments, the compounds are prepared into solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs for oral administration, or into sterile solutions or suspensions for parenteral administration, as well as formulations suitable for topical administration, transdermal administration, and oral inhalation using nebulizers, pressurized metered-dose inhalers, and dry powder inhalers. In some embodiments, the compounds described above are formulated into compositions using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0088] In the composition, one or more compounds or derivatives thereof in an effective concentration are mixed with a suitable vehicle. The compounds may be derivatized before formulation as corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, ion pairs, hydrates, or prodrugs, as described above. The concentration of the compounds in the composition is effective in delivering an amount at the time of administration that leads to the treatment, prevention, or relief of one or more symptoms of the disease or disorder described herein. In some embodiments, the composition is formulated for single-dose administration. To formulate the composition, a weight fraction of the compounds is dissolved, suspended, dispersed, or otherwise mixed with a selected vehicle in an effective concentration that reduces, prevents, or relieves one or more symptoms of the condition under treatment.

[0089] The active compound is contained in the vehicle in an amount sufficient to exert a therapeutically beneficial effect without causing undesirable side effects in the target patient. The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and from there the dose for humans can be estimated. Subsequently, the human dose is usually fine-tuned in clinical trials, and the dose is determined based on the response.

[0090] The concentration of the active compound in the composition depends on the absorption rate, inactivation rate, and excretion rate of the active compound, the physicochemical properties of the compound, the administration schedule, and the dosage, as well as other factors well known to those skilled in the art. For example, delivering an amount sufficient to alleviate one or more symptoms of the disease or disorder described herein.

[0091] If the solubility of a compound is insufficient, solubilization methods such as liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions, or tertiary template methods can be used. Such methods are well known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrin, or dissolution by ionization enhancement (i.e., dissolution in aqueous sodium bicarbonate solution). Derivatives of the compound, such as prodrugs, can also be used to formulate effective compositions.

[0092] The mixture obtained by mixing or adding compound(s) may be a solution, suspension, emulsion, or other form. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the chosen vehicle. The effective concentration sufficient to alleviate the symptoms of the disease, disorder, or condition being treated can be determined empirically.

[0093] The compositions are provided to be administered in suitable dosage forms, such as dry powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / biodegradable strips, transdermal application devices / formulations such as tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast-dissolving tablets, and transdermal patches, sterile injection solutions or suspensions, oral solutions or suspensions, and oil-in-water emulsions containing suitable amounts of the compounds or their derivatives. In some embodiments, the therapeutically active compounds and their derivatives are formulated and administered as unit dosage forms or multi-dose dosage forms. As used herein, unit dosage forms refer to physically separate units suitable for human and animal subjects, individually packaged as is well known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, along with the necessary vehicle. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dosage forms may be administered in divided doses or multi-dose doses. A multi-dose formulation consists of multiple identical unit dosages packaged in a single container, which are administered in divided units. Examples of multi-dose formulations include vials, bottles containing tablets or capsules, or pint or gallon bottles. Therefore, a multi-dose formulation is one in which multiple unit doses are not individually packaged.

[0094] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compounds defined above and any excipients in a vehicle such as water, physiological saline, aqueous dextrose, glycerol, glycol, or ethanol, thereby forming solutions, suspensions, colloidal dispersions, emulsions, or liposome formulations. If necessary, the administered composition may contain trace amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, and pH buffers, such as acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, and other similar agents.

[0095] The practical preparation methods for such dosage forms are well known or will become apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, or later editions.

[0096] Dosage forms or compositions can be prepared containing the active ingredient in an amount ranging from 0.005 to 100%, with the remainder being prepared with a vehicle or carrier. Methods for preparing these compositions are well known to those skilled in the art. The intended compositions may contain the active ingredient in an amount ranging from 0.001 to 100%, 0.1 to 95% in one embodiment, and 0.4 to 10% in another embodiment.

[0097] In certain embodiments, the composition is a lactose-free composition containing excipients well known in the art, for example, those described in the United States Pharmacopeia (USP) 25-NF20 (2002). Generally, lactose-free formulations contain active ingredients, binders / fillers, and lubricants in miscible amounts. Certain lactose-free formulations contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0098] Furthermore, since water can accelerate the decomposition of some compounds, anhydrous compositions and dosage forms containing active ingredients are provided. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as shelf life or long-term stability of the formulation. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be extremely important, as formulations are often exposed to moisture and / or humidity during manufacturing, handling, packaging, storage, transport, and use.

[0099] The anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture-containing components under low-moisture or low-humidity conditions.

[0100] Anhydrous compositions should be prepared and stored in such a way that their anhydrous nature is maintained. Therefore, anhydrous compositions are generally packaged using materials known to prevent exposure to water so that they can be placed in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, airtight foil, plastic, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0101] Oral dosage forms are solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and powders. Types of oral tablets include compressed tablets, chewable lozenges, and tablets that may be coated with enteric coating, sugar coating, or film coating. Capsules may be hard or soft gelatin capsules, and granules and powders may be provided in non-foaming or effervescent forms in combination with other components well known to those skilled in the art.

[0102] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc., may contain one or more of the following components or compounds having similar properties: binders, lubricants, diluents, flow enhancers, disintegrants, colorants, sweeteners, flavorings, wetting agents, enteric coatings, film coatings, and release regulators. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, gum arabic mucus, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salts, mannitol, and dicalcium phosphate. Flow enhancers include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Colorants include, for example, any approved and certified water-soluble FD&C dyes, mixtures thereof, and water-insoluble FD&C dyes suspended in alumina hydrate, as well as modern colorants or anti-counterfeiting color / milky white additives well known to those skilled in the art. Sweeteners include artificial sweeteners such as sucrose, lactose, mannitol, and saccharin, as well as various spray-dried flavorings. Flavorings include natural flavors extracted from plants such as fruits, as well as synthetic blends of compounds that produce pleasant sensations or mask unpleasant tastes, including, but are not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, oils and fats, waxes, shellac, ammonia-treated shellac, and cellulose phthalate acetate.Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Release regulators include polymers and cellulose esters such as the Eudragit® series.

[0103] Compounds or their derivatives can be incorporated into compositions that protect them from the acidic environment of the stomach. For example, a composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestines. The composition may also be formulated in combination with antacids or other similar components.

[0104] When the unit dosage form is a capsule, in addition to the above-mentioned types of materials, a liquid carrier such as fatty oil may be included. Furthermore, the unit dosage form may contain various other materials that modify the physical form of the drug unit, such as a coating of sugar and other enteric solvents. The compound can also be administered as an ingredient in elixirs, suspensions, syrups, wafers, sprinkles, chewing gum, etc. In addition to the active compound, the syrup may contain sucrose as a sweetener, and certain preservatives, colorants, and flavorings.

[0105] The active material may also be mixed with other active materials that do not impair the desired effect, or with substances that complement the desired effect, such as antacids, H2 blockers, and diuretics. The active ingredient is one of the compounds described herein or their derivatives. The active ingredient may be included in high concentrations up to about 98% by weight.

[0106] In all embodiments, tablet and capsule formulations may be coated in methods well known to those skilled in the art to modify or prolong the dissolution of the active ingredient. Thus, they may be coated with conventional enteric coatings such as phenyl salicylate, wax, and cellulose phthalate acetate.

[0107] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil-in-water or water-in-oil.

[0108] Elixirs are clear, sweetened water-alcohol preparations. Vehicles used in elixirs contain solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of droplets in the other liquid. Carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Permitted substances used in non-foaming granules reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Permitted substances used in foaming granules reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources. Colorants and flavorings are used in all of the above dosage forms.

[0109] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methylparaben, propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include surfactants such as gelatin, gum arabic, tragacanth gum, bentonite, and polyoxyethylene sorbitan monooleate. Suspensioning agents include sodium carboxymethylcellulose, pectin, tragacanth gum, Veegum, and gum arabic. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved water-soluble FD&C dyes and mixtures thereof. Flavorings include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that provide a pleasant taste.

[0110] In the case of solid dosage forms, in some embodiments, solutions or suspensions in, for example, propylene carbonate, vegetable oil, or triglycerides are encapsulated in gelatin capsules. Such solutions, as well as their preparation and encapsulation, are disclosed in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. In the case of liquid dosage forms, for example, solutions in polyethylene glycol can be easily measured at the time of administration by diluting them with a sufficient amount of liquid vehicle such as water.

[0111] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oil, glycol, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other similar carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations are described in U.S. Patents RE 28,819 and 4,358,603. In short, such formulations may contain, but are not limited to, the compounds provided herein, including, 1,2-dimethoxyethane, diglyme, triglyceride, tetraglyceride, polyethylene glycol 350 dimethyl ether, polyethylene glycol 550 dimethyl ether, polyethylene glycol 750 dimethyl ether (350, 550, and 750 represent the approximate average molecular weight of polyethylene glycol), dialkylated mono or polyalkylene glycols, and one or more antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0112] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals. The alcohol used in these formulations is any water-miscible solvent having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. The acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0113] In some embodiments, parenteral administration, characterized by subcutaneous, intramuscular, or intravenous injection, is also intended. The injectable formulation can be prepared in conventional forms, as a liquid solution or suspension, as a solid form suitable for dissolving or suspending in liquid before injection, or as an emulsion. The injectable formulation, solution, and emulsion also contain one or more excipients. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. Furthermore, if necessary, the administered composition may also contain wetting or emulsifying agents, pH buffers, stabilizers, dissolution accelerators, and other similar agents, such as trace amounts of non-toxic adjuncts including sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrin.

[0114] Sustained-release or sustained-release embeddings that maintain a constant dose (see, for example, U.S. Patent No. 3,710,795) are also intended herein. Briefly, the compounds provided herein are dispersed in a solid internal matrix, such as hydrophilic polymers including polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylate esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, with this matrix being the outer high-molecular-weight matrix. The compounds are encased in a polymer membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer, and this polymer membrane is insoluble in body fluids. The compounds diffuse through the outer polymer membrane at a stage where the release rate is controlled. The content of active compounds in such parenteral compositions depends largely on their properties, the activity of the compounds, and the needs of the subject.

[0115] Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Parenteral formulations include sterile solutions for injection, tablets for subcutaneous injection, sterile-dried soluble products such as lyophilized powders to be mixed with a solvent immediately before use, sterile suspensions for injection, sterile-dried insoluble products to be mixed with a vehicle immediately before use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[0116] For intravenous administration, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and solubilizers such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0117] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspensions, dispersants, emulsifiers, chelating agents or sequestering agents, and other substances.

[0118] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, and dextrose-lactate Ringer's injection. Non-aqueous parenteral vehicles include plant-derived fixative oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Parenteral formulations filled into multi-dose containers require the addition of antibacterial agents at bacteriostatic or antifungal concentrations, such as phenol or cresol, mercury preparations, benzyl alcohol, chlorobutanol, methyl and propyl-p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspensions and dispersants include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Polysorbate 80 (Tween® 80) is used as an emulsifier. EDTA is used as a chelating or sequestering agent for metal ions. Other carriers include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles, as well as sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0119] The concentration of the compound is adjusted to an effective dose that produces the desired pharmacological effect upon injection. The exact dose depends on the age, weight, body surface area, and condition of the patient or animal, as is well known in the art.

[0120] The unit dose of parenteral formulations is filled into ampoules, vials, or syringes with needles. All parenteral formulations must be sterile, as is well known and practiced in the art.

[0121] Exemplary, intravenous or intra-arterial injection of a sterile aqueous solution containing the active compound is an effective method of administration. In another embodiment, a sterile aqueous solution, oily solution, or suspension containing the active material is injected as needed to obtain the desired pharmacological effect.

[0122] The injectable formulations are designed for local and systemic administration. In some embodiments, therapeutically effective doses are formulated to contain at least about 0.01 to about 90% by weight of the active compound relative to the target tissue, and in certain embodiments, more than 0.1% by weight.

[0123] The compound can be suspended in a preferred form, such as micronized, or derivatized to produce a more soluble active product or prodrug. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the chosen carrier or vehicle. The effective concentration should be sufficient to alleviate the symptoms of the disease and can be determined empirically.

[0124] The active ingredients provided herein can be administered using release control means or delivery devices well known to those skilled in the art. For example, U.S. Patents No. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,9 This includes, but is not limited to, specifications No. 72,891, No. 5,980,945, No. 5,993,855, No. 6,045,830, No. 6,087,324, No. 6,113,943, No. 6,197,350, No. 6,248,363, No. 6,264,970, No. 6,267,981, No. 6,376,461, No. 6,419,961, No. 6,589,548, No. 6,613,358, No. 6,699,500, and No. 6,740,634. Such dosage forms can achieve sustained release or controlled release of one or more active ingredients by providing desired release profiles in various ratios, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0125] All controlled-release formulations share the common objective of improving pharmacotherapy beyond what can be achieved with non-controlled-release formulations. Ideally, the optimal use of controlled-release formulations in medicine is characterized by using the minimum amount of drug to cure or control a condition in the shortest possible time. Advantages of controlled-release formulations include extended drug activity, reduced administration frequency, and improved patient adherence. Furthermore, the use of controlled-release formulations may influence characteristics such as onset of action and drug blood concentration, and consequently, the occurrence of side effects (e.g., adverse events).

[0126] Most controlled-release formulations are designed to release an initial, rapid dose of the drug (active ingredient) to produce the desired therapeutic effect, followed by a gradual and continuous release of the remaining drug to maintain this therapeutic or preventive level over a long period. To maintain a constant drug concentration in the body, the drug must be released from the formulation at a rate that compensates for the amount of drug metabolized and excreted. The control of active ingredient release can be facilitated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0127] In certain embodiments, the drug may be administered by methods such as intravenous infusion, implantable osmotic pumps, transdermal patches, or liposomes. In some embodiments, pumps may be used (see Sefton, CRC Crit.Ref.Biomed.Eng.14:201(1987); Buchwald et al., Surgery 88:507(1980); Saudek et al., N.Engl.J.Med.321:574(1989)). In other embodiments, polymer materials may be used. In other embodiments, the release control system may be placed near the therapeutic target, i.e., so that only a small fraction of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138(1984)). In some embodiments, the release control device is introduced near an inappropriate immunoactivated site or tumor in the subject. Other release control systems are discussed in a review by Langer (Science 249:1527-1533 (1990)).The active ingredient can be dispersed in a solid internal matrix, such as hydrophilic polymers including polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic acid and methacrylate esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, and this matrix can be dispersed in an outer polymer film, such as poly The active ingredients are encapsulated in polymeric membranes such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate copolymer, vinylidene chloride, ethylene, and propylene copolymer, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer, and this polymeric membrane is insoluble in body fluids. Subsequently, the active ingredients diffuse through the outer polymeric membrane in a stage where the release rate is controlled. The content of active compounds in such parenteral compositions depends largely on their properties, the activity of the compounds, and the needs of the subject.

[0128] Lyophilized powders are also of interest herein and can be reconstituted and administered as solutions, emulsions, and other mixtures. These can also be reconstituted and formulated as solids or gels.

[0129] Sterile lyophilized powders are prepared by dissolving the compounds provided herein or their derivatives in a suitable solvent. The solvent may contain excipients that improve the pharmacological properties of the powder or the reconstituted solution prepared from the powder, such as stability. Available excipients include, but are not limited to, antioxidants, buffers, and fillers. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain buffers such as citrate, sodium phosphate, potassium phosphate, or other such buffers well known to those skilled in the art, at a neutral pH. Subsequently, the solution is sterilized and then lyophilized under standard conditions well known to those skilled in the art to obtain the desired formulation. In some embodiments, the obtained solution is dispensed into vials for lyophilization. Each vial contains a single dose or multiple dose of the compound. The lyophilized powder can be stored under suitable conditions, such as from about 4°C to room temperature.

[0130] By reconstituting this lyophilized powder with sterile water for injection, a formulation for parenteral administration can be obtained. For reconstitution, the lyophilized powder is added to a suitable carrier such as sterile water. The exact amount depends on the selected compound. This amount can be determined empirically.

[0131] The topical mixture is prepared as described for topical and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, wash, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0132] The compounds or their derivatives may be formulated as aerosols for topical application, such as by inhalation (see, for example, U.S. Patents 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for respiratory administration may be in the form of aerosols or solutions for nebulizers, or in the form of fine powders for inhalation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a median geometric diameter of less than 5 microns in some embodiments and less than 10 microns in other embodiments.

[0133] Oral inhalation formulations of compounds or derivatives suitable for inhalation include metered-dose inhalers, dry powder inhalers, and liquid formulations for administration from nebulizers or metered-dose liquid dispensing systems. In both metered-dose inhalers and dry powder inhalers, the crystalline form of the compound or derivative is preferred as the physical form of the drug for longer product stability.

[0134] In addition to pulverization methods well known to those skilled in the art, crystalline particles of compounds or derivatives can be produced using supercritical fluid processing. This process offers significant advantages in the production of inhalable delivery particles because it can produce inhalable particles of a desired size in a single step (e.g., International Publication No. 2005 / 025506). The controlled particle size of the microcrystals can be selected so that the majority of the compound or derivative is deposited in the lungs. In some embodiments, the mass-median aerodynamic diameter of these particles is about 0.1 to about 10 microns, in other embodiments about 1 to about 5 microns, and in yet another embodiment about 1.2 to about 3 microns.

[0135] The inert and non-flammable HFA propellants are selected from HFA134a (1,1,1,2-tetrafluoroethane) and HFA227e (1,1,1,2,3,3,3-heptafluoropropane) and are supplied individually or in ratios appropriate to the density of the crystalline particles of the compound or derivative. The ratios are also selected so that the product suspension does not undergo undesirable sedimentation or creaming (which can cause irreversible aggregation), but instead forms a loosely aggregated system that disperses easily upon shaking. This loosely aggregated system is highly valued for providing optimal stability in pMDI containers. Due to these formulation characteristics, the formulation does not contain ethanol or surfactants / stabilizers.

[0136] The compound can be formulated in gel, cream, and lotion form for topical application to the skin and mucous membranes such as the eyes, as well as for local or topical applications such as application to the eyes, or intracerebral or intraspinal cavity applications. Topical administration is intended for transdermal delivery and administration to the eyes or mucous membranes, or for inhalation therapy. Nasal sprays of the active compound alone or in combination with other excipients are also available.

[0137] For intranasal administration, the formulation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier for aerosol application, particularly an aqueous carrier. The carrier may contain a solubilizer or suspending agent such as propylene glycol, a surfactant, an absorption enhancer such as lecithin or cyclodextrin, or a preservative.

[0138] Solutions, especially those intended for ophthalmic use, can be formulated using appropriate salts as 0.01–10% isotonic solutions with a pH of approximately 5–7.4.

[0139] Transdermal patches including iontophoresis devices and electrophoresis devices, as well as other routes of administration such as rectal administration, are also intended in this specification.

[0140] Transdermal patches including iontophoresis and electrophoresis devices are well known to those skilled in the art. For example, such patches are disclosed in U.S. Patents Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

[0141] For example, dosage forms for rectal administration include rectal suppositories, capsules, and tablets intended for systemic effects. As used herein, a rectal suppository means a solid inserted into the rectum that melts or softens at body temperature to release one or more pharmacologically or therapeutically active components. Substances used in rectal suppositories are vehicles and agents that raise the melting point. Examples of vehicles include cocoa butter (cocoa fat), glycerin / gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids. Combinations of various vehicles may also be used. Agents that raise the melting point of suppositories include whale wax and wax. Rectal suppositories may be prepared by either compression or molding. In one embodiment, the weight of a rectal suppository is about 2-3 g. Tablets and capsules for rectal administration are manufactured using the same substances and methods as those used for oral formulations.

[0142] The compounds or derivatives thereof provided herein may also be formulated to target specific tissues, receptors, or other bodily regions of the subject being treated. Many of these targeting methods are well known to those skilled in the art. All of these targeting methods are intended herein for use in the compositions. For non-limiting examples of targeting methods, see, for example, U.S. Patents Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0143] In some embodiments, liposome suspensions containing tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as carriers. These can be prepared according to methods well known to those skilled in the art. For example, liposome formulations can be prepared by the method described in U.S. Patent No. 4,522,811. Briefly, liposomes, such as multilayer vesicles (MLVs), can be formed by drying phosphatidylcholine and phosphatidylserine (molar ratio 7:3) inside a flask. A solution of the compounds provided herein dissolved in phosphate-buffered saline (PBS) free of divalent cations is added to the flask, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelletized by centrifugation, and then resuspended in PBS.

[0144] The compound or derivative may be packaged as a product including packaging material, the compound or derivative provided herein which is effective in treating, preventing, or alleviating one or more symptoms of the disease or disorder, and a label indicating that the compound or composition or its derivative is used to treat, prevent, or alleviate one or more symptoms of the disease or disorder.

[0145] Products provided herein include packaging materials. Packaging materials used for packaged products are well known to those skilled in the art. See, for example, U.S. Patents No. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for selected formulations, as well as the intended method of administration and treatment. A wide range of formulations of compounds and compositions provided herein are intended for the treatment of various diseases or disorders described herein.

[0146] Dosage When used for the treatment or prevention of a disease, the compounds described herein, or their pharmaceutical compositions, should be administered or applied in a therapeutically effective dose. In human treatment, the physician will determine the most appropriate dosage regimen depending on the preventive or therapeutic treatment, and on specific factors such as the age, weight, and stage of disease progression of the subject being treated. The amount of active ingredient in the formulations provided herein that is effective in preventing or treating a disease will vary depending on the nature and severity of the disease or condition, as well as the route of administration of the active ingredient. The frequency and dose will also vary depending on the specific treatment being administered (e.g., therapeutic or prophylactic), the severity of the disease, the route of administration, and on specific factors of each subject, such as the age, weight, response, and medical history of the subject.

[0147] Exemplary dosages of the formulation include milligrams or micrograms of the active compound per kilogram of subject (e.g., approximately 1 μg / kg to 50 mg / kg, approximately 10 μg / kg to 30 mg / kg, approximately 100 μg / kg to 10 mg / kg, or approximately 100 μg / kg to 5 mg / kg).

[0148] In some embodiments, therapeutically effective doses should result in serum active ingredient concentrations ranging from approximately 0.001 ng / mL to approximately 50–200 μg / mL. In other embodiments, the composition should provide a daily dose of approximately 0.0001–70 mg of the compound per kilogram of body weight. Unit dosage forms are prepared to provide combinations of active or essential ingredients in amounts of approximately 0.01, 0.1, or 1–500 mg, 1000 mg, or 5000 mg per unit dosage form, and in some embodiments, approximately 10–500 mg.

[0149] The active ingredient may be administered as a single dose or divided into multiple small doses and administered at regular intervals. It is understood that the exact dosage and duration of treatment depend on the disease being treated and can be determined empirically using known test protocols, or by extrapolation from in vivo or in vitro test data or subsequent clinical trials. It should also be noted that the concentration and dosage may vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that a unique long-term dosing plan should be tailored for each individual subject based on their individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges specified herein are illustrative only and are not intended to limit the scope or implementation of the claimed composition.

[0150] As will be apparent to those skilled in the art, in some cases it may be necessary to use active ingredients in doses exceeding those disclosed herein. Furthermore, clinicians or treating physicians should take note of understanding how and when to interrupt, adjust, or discontinue treatment in accordance with the subject's response.

[0151] In the case of systemic administration, the therapeutically effective dose can initially be estimated from in vitro assays. For example, in animal models, the IC determined in cell culture... 50 (i.e., the concentration of the test compound that is effective in 50% of cases) or IC determined in cell culture 95Dosages can be formulated to achieve a blood concentration range that includes the concentration of the compound that is effective in 95% of cases. Using this information, effective doses in humans can be determined more accurately.

[0152] The initial dose can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can easily optimize the dose to humans based on animal data.

[0153] Alternatively, ICs of certain compounds disclosed herein 50 and / or IC 95 By comparing this initial dose with that of a known drug and adjusting the initial dose accordingly, the initial dose can be determined from the dose of a known drug. From these initial values, the optimal dose can be obtained through normal optimization.

[0154] In the case of topical administration or selective uptake, the effective topical concentration of the compound used may not be related to the plasma concentration. Those skilled in the art will be able to optimize the therapeutically effective topical dose without excessive experimentation.

[0155] Ideally, therapeutically effective doses of the compounds described herein should produce a therapeutic effect without substantial toxicity. The toxicity of the compounds should be determined by standard pharmaceutical procedures using cell cultures or experimental animals, e.g., LD 50 (A lethal dose for 50% of the population) or LD 100This can be determined by determining the dose that is lethal to 100% of the population. The dose-to-toxicity ratio is the therapeutic index. Compounds with a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a dose range that does not exhibit toxicity in use in subjects. The doses of the compounds described herein are preferably within a blood concentration range that includes an effective dose with little to no toxicity. The dose may vary within this range depending on the dosage form adopted and the route of administration used. The exact formulation, route of administration, and dose can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0156] Treatment may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, with intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0157] Methods of using compounds and compositions Methods are provided for treating, preventing, or alleviating symptoms of medical disorders such as muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic diseases, cancer, vascular diseases, ocular vascular diseases, ocular muscle diseases, liver diseases, inflammatory diseases, fibrotic disorders, acute and chronic liver and kidney diseases, by inhibiting ACMSD. One or more of the disclosed compounds or pharmaceutically acceptable salts thereof, or an effective amount of the corresponding pharmaceutical composition, is administered to a subject in need.

[0158] In some embodiments, muscle structure disorders include Bethlem myopathy, central core disease, congenital muscle fiber disproportion, distal muscular dystrophy (MD), Duchenne and Becker muscular dystrophy, Emery-Dreyfus type MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, myosodium muscle channel disorder, myotonic chondrodysplasia, myotonic dystrophy, myotonic tubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence.

[0159] In other embodiments, neuronal activation disorders include amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, neurological lesions, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve palsy, or toxic neuromuscular disorders.

[0160] In further embodiments, muscle fatigue disorders include chronic fatigue syndrome, diabetes mellitus (type I or type II), glycogen storage disorder, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid-storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, or thyroid-toxic myopathy.

[0161] In further embodiments, muscle mass impairment may be cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, severe disease myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus.

[0162] In further embodiments, β-oxidation disorders include systemic carnitine transporter deficiency, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trisomal enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, or riboflavin-responsive β-oxidation disorder (RR-MADD).

[0163] In further embodiments, metabolic diseases include hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and / or HDL noncholesterolemia, VLDL hyperproteinemia, abnormal lipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerosis, cardiovascular disease, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, and diabetes. This includes diabetes (type I or type II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, or pancreatitis.

[0164] In further embodiments, vascular diseases include peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), or peripheral artery occlusive disease.

[0165] In further embodiments, the ophthalmic vascular disease is age-related macular degeneration (AMD), Stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, or glaucoma.

[0166] In yet another embodiment, the ocular muscle disease is strabismus, progressive extraocular muscle paralysis, esotropia, exotropia, refractive and accommodation disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodation disorders, or intrinsic ocular muscle paralysis.

[0167] In further embodiments, the liver disease may be metabolic liver disease, alcoholic liver disease, drug-induced disorders, cholestatic liver disease, hereditary, etiological / enzyme deficiency and storage disorders, or viral hepatitis. The above are acute and chronic causes of liver disease with inflammation and fibrosis.

[0168] In yet another embodiment, the kidney disease is glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure (also known as acute kidney injury), chronic renal failure, diabetic nephropathy, or Bartter syndrome. In yet another embodiment, the kidney disease is autosomal dominant polycystic kidney disease. In yet another embodiment, the kidney disease is associated with tubular dysfunction, ischemia, drug-induced disorders, immune-mediated disorders, or alcoholic steatohepatitis.

[0169] In further embodiments, diseases that can be alleviated by inhibiting ACMSD include hereditary lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne and Becker muscular dystrophy, diabetes mellitus (type I or type II), obesity, and sarcopenia.

[0170] In further embodiments, diseases that can be alleviated by inhibiting ACMSD include Alper's disease, CPEO (chronic progressive extraocular palsy), Kearns-Sayre syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like seizures), MERRF (myoclonus epilepsy with red ragged fibers), NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), Pearson syndrome, chemotherapy-induced ototoxicity by platinum-based agents, Cockayne syndrome, xeroderma pigmentosum A, Waller degeneration, and HIV-induced lipodystrophy.

[0171] In yet another embodiment, diseases that can be treated or prevented by inhibiting ACMSD include acute kidney injury, including ischemic, embolic, or drug-induced acute kidney injury.

[0172] In yet another embodiment, a disease that can be treated or prevented by inhibiting ACMSD is hepatorenal syndrome - acute kidney injury.

[0173] In yet another embodiment, the disease that can be alleviated by inhibiting ACMSD is acute liver injury.

[0174] Inhibitors of ACMSD may offer therapeutic benefits in the prevention and treatment of mitochondrial dysfunction and disorders involving an excessive DNA damage response, particularly in relation to the prevention and treatment of renal or hepatic failure.

[0175] Inhibitors of ACMSD may offer therapeutic benefits in the regeneration of liver and kidney tissue.

[0176] Inhibitors of ACMSD may offer therapeutic benefits in the treatment of compensated and decompensated cirrhosis and ACLF.

[0177] In some embodiments, the compounds and their pharmaceutical compositions disclosed herein may be useful for a variety of therapeutic applications, including the treatment and / or alleviation of a wide variety of diseases and disorders, such as age-related or stress-related diseases or disorders, diabetes, obesity, neurodegenerative diseases, cardiovascular diseases, blood coagulation disorders, inflammation, cancer, and / or flushing. The method involves administering a pharmaceutically effective amount of one or more of the compounds and / or their pharmaceutical compositions of the present invention to a subject in need thereof.

[0178] In some embodiments, the compounds and their pharmaceutical compositions disclosed herein may be used for the treatment of cells useful for transplantation or cell therapy, including, for example, solid tissue grafts, organ grafts, cell suspensions, stem cells, bone marrow cells, etc. The cells or tissues may be autologous grafts, allogeneic grafts, syngeneic grafts, or xenografts. The cells or tissues may be treated with the compounds and their pharmaceutical compositions disclosed herein before administration / transplantation to a subject, concurrently with administration / transplantation, and / or after administration / transplantation. The cells or tissues may be treated before harvesting cells from a donor individual, ex vivo after harvesting cells or tissues from a donor individual, or after transplantation to a recipient. For example, a donor or recipient individual may be treated systemically with a nicotinamide riboside chloride preparation or one of the pharmaceutical compositions described herein, or a portion of the cells / tissues may be treated topically with the compounds and their pharmaceutical compositions described herein. In certain embodiments, cells or tissues (or the donor / recipient individual) may be further treated with other therapeutic agents useful for extending the survival time of the graft, such as immunosuppressants, cytokines, or angiogenic factors.

[0179] In other embodiments, the compounds and / or their pharmaceutical compositions described herein can be used to treat skin diseases. Examples of skin diseases that can be treated according to the methods described herein include disorders or diseases associated with or resulting from inflammation, sun damage, or natural aging. For example, the compositions are useful in treating contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), epidermolysis bullosa (including pemphigus (penfigus)), exfoliative dermatitis, seborrheic dermatitis, erythema (including erythema multiforme and erythema nodosum), sun or other light source damage, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer, and the effects of natural aging. In yet other embodiments, the compounds and their pharmaceutical compositions described herein can be used to treat and promote the healing of wounds and / or burns, such as first-degree, second-degree, or third-degree burns, and / or burns caused by heat, chemical, or electricity.

[0180] The compounds and their pharmaceutical compositions described herein may also be administered to subjects for the treatment of diseases associated with cell death, such as chronic diseases, in order to protect cells from cell death. Exemplary diseases include those associated with neuronal cell death, neurological dysfunction, or muscle cell death or dysfunction, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and muscular dystrophy; AIDS; fulminant hepatitis; diseases associated with brain degeneration, such as Creutzfeldt-Jakob disease, retinitis pigmentosa, and cerebellar degeneration; spinal malformations, such as aplastic anemia; ischemic diseases, such as myocardial infarction and stroke; liver diseases, such as alcoholic hepatitis, hepatitis B, and hepatitis C; joint diseases, such as osteoarthritis; atherosclerosis; alopecia; ultraviolet skin damage; lichen planus; skin atrophy; cataracts; and graft rejection. Cell death can also be caused by surgery, drug therapy, exposure to chemicals, or radiation exposure.

[0181] The compounds and their pharmaceutical compositions described herein can also be administered to subjects suffering from acute diseases, such as organ or tissue damage, such as subjects suffering from stroke or myocardial infarction, or subjects suffering from spinal cord injury. The compounds and their pharmaceutical compositions described herein can also be used for liver repair in patients with alcohol dependence.

[0182] Further embodiments provide a method for treating cardiovascular disease by administering one or more of the compounds and / or their pharmaceutical compositions described herein to subjects who require it. Cardiovascular diseases treatable with the compounds and their pharmaceutical compositions described herein include cardiomyopathy or myocarditis, such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy. Atherosclerotic diseases of major blood vessels such as the aorta, coronary arteries, carotid arteries, cerebrovascular arteries, renal arteries, iliac arteries, femoral arteries, and popliteal arteries (diseases of the large vessels) can also be treated with the compounds, compositions, and methods described herein. Other treatable vascular diseases include those related to platelet aggregation, retinal arterioles, glomerular arterioles, neurovascular arteries, cardiac arterioles, as well as those related to the eyes, kidneys, heart, and associated capillary beds of the central and peripheral nervous systems. The compounds and their pharmaceutical compositions described herein can also be used to increase HDL levels in an individual's plasma.

[0183] Combination therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination with or sequentially with other therapeutic agents. Such other therapeutic agents include those known for the treatment, prevention, or relief of one or more conditions associated with, for example, muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic disorders, cancer, vascular diseases, ophthalmic vascular diseases, ocular muscle diseases, and acute and chronic liver and kidney diseases.

[0184] In some embodiments, the compounds and compositions disclosed herein include, for example, nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR), reduced form of NR (NRH), nicotinic acid riboside (NAR), reduced form of NAR (NARH), nicotinamide mononucleotide (NMN), poly(ADP-ribose) polymerase (PARP), SARMi (Sterile Alpha and TIR Motif Containing 1), CD38i, or combinations thereof, and other NADs.+ It can be used in conjunction with augmentation methods.

[0185] In some embodiments, the compounds and compositions disclosed herein can be used in combination with other compounds that enhance mitochondrial function, such as protonophores (e.g., 2,4-dinitrophenol (DNP), TLC-6740), acetyl-CoA carboxylase 2 inhibitors (ACC2i; TLC-3595, etc.), fibroblast growth factor 21 (FGF21), their analogues, or thyroid hormone receptor β (THRb) agonists, their prodrugs, or their controlled formulations.

[0186] Any suitable combination of the compounds and compositions provided herein with one or more of the above-mentioned therapeutic agents and optionally one or more further pharmacologically active substances should be understood to be within the scope of this disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after one or more additional active ingredients.

[0187] While various embodiments of the Disclosure are described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Numerous modifications and changes, as well as variations and substitutions, to the embodiments described herein will be apparent to those skilled in the art without departing from the Disclosure. It will be understood that various alternatives to the embodiments described herein can be adopted in the practice of the Disclosure. It will also be understood that any embodiment of the Disclosure may be arbitrarily combined with any one or more other embodiments described herein that are consistent with that embodiment.

[0188] Finally, it should be noted that alternative means of carrying out the present invention exist. Therefore, these embodiments should be considered illustrative and not limiting, and the present invention is not limited to the details described herein but can be modified within the scope of the appended claims and their equivalents. All publications and patents referenced herein are incorporated by reference in their entirety.

[0189] The following examples are provided for illustrative purposes only and do not limit the scope of the present invention. [Examples]

[0190] The compound names in this application were created using ChemDraw Professional version 22, but it should be understood that other names may also be used to identify compounds with the same structure.

[0191] The following are common abbreviations used in the experimental section described later.

[0192] ACMS α-amino-ω-carboxymuconate semialdehyde

[0193] ACMSD (Aminocarboxymuconate semialdehyde decarboxylase)

[0194] ACN Acetonitrile

[0195] AIBN Azobisisobutyronitrile

[0196] DCM Methylene Chloride

[0197] DIPEA Diisopropylethylamine

[0198] DME (Dimethoxyethane)

[0199] DMF Dimethylformamide

[0200] DMSO (Dimethyl Sulfoxide)

[0201] dppf bis(diphenylphosphino)ferrocene

[0202] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0203] EDTA (Ethylenediaminetetraacetic acid)

[0204] Et3N triethylamine

[0205] HCl ethyl acetate

[0206] EtOH Ethanol

[0207] HATU Hexafluorophosphate azabenzotriazole tetramethyluronium

[0208] HOBt hydroxybenzotriazole

[0209] HPLC (High-Pressure Liquid Chromatography)

[0210] MeOH methanol

[0211] MS mass spectrometry

[0212] NAD (Nicotinamide Adenine Dinucleotide)

[0213] NBS N-bromosuccinimide

[0214] NCS N-chlorosuccinimide

[0215] NMR nuclear magnetic resonance

[0216] PA picolinic acid

[0217] PBS (phosphate-buffered saline)

[0218] RT room temperature

[0219] pMDI (Pressurized Metered-Dose Inhaler)

[0220] QA quinolinic acid

[0221] T2D type 2 diabetes

[0222] T3P Propylphosphonic Acid Anhydride

[0223] TEA (Triethylamine)

[0224] THF (Tetrahydrofuran)

[0225] TLC (Thin-Layer Chromatography)

[0226] The following sections describe the preparation of synthetic intermediates 1000-1099 used to prepare the compounds of formula (I)(1-63).

[0227] Preparation of 1-(3-cyclopropylphenyl)ethenone (1000) [ka] 1-(3-bromophenyl)ethenone (3 g, 15.075 mmol) and cyclopropylboronic acid (2.71 g, 30.15 mmol) were dissolved in toluene (30 mL) and stirred. K3PO4 (9.58 g, 45.225 mmol) dissolved in H2O (4.5 mL) was added. Pd(dppf)Cl2 (1.1 g, 1.507 mmol) was added, and the reaction was stirred at 100 °C for 16 hours while monitoring by TLC. After dilution with water and ethyl acetate, the organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 1-(3-cyclopropylphenyl)ethenone (1000). MS: m / z: 161.14 (M+H + ).

[0228] Preparation of 3-(3-ethoxy-3-oxopropanoyl)methyl benzoate (1001) [ka] A solution of potassium 3-ethoxy-3-oxopropionate (49 g, 0.288 mol) dissolved in anhydrous THF (100 mL), Et3N (16 mL, 0.11 mol), and MgCl2 (10.5 g, 0.11 mmol) was stirred at ambient temperature for 4 hours. In a separate flask, 3-(methoxycarbonyl)benzoic acid (20 g, 0.11 mol) dissolved in anhydrous THF (100 mL) was mixed with CDI (14 g, 86 mmol) at ambient temperature, and the reaction mixture was heated at 50 °C for 2 hours. After cooling to ambient temperature, the first solution was added to the second solution, and the mixed solution was stirred at 50 °C for 16 hours, with the progress of the reaction monitored by TLC. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with ELISA. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by column chromatography to obtain the target compound (1001). MS: m / z: 251.15 (M+H + ).

[0229] The following compounds were prepared by the same method: 4-(3-ethoxy-3-oxopropanoyl)benzoic acid (1002); 2-(3-ethoxy-3-oxopropanoyl)benzoic acid (1003): MS: m / z: 251.15 (M+H + ); and ethyl 3-oxo-3-(6-phenylpyridine-3-yl)propionate (1004): MS: m / z: 270.20 (M+H + ).

[0230] Preparation of ethyl 3-([1,1'-biphenyl]-3-yl)-3-oxopropionate (1005) [ka] To a stirred solution of potassium 3-ethoxy-3-oxopropionate (4.2 g, 25.22 mmol) dissolved in anhydrous THF (25 mL), Et3N (3.5 mL, 25.22 mmol) and MgCl2 (1.43 g, 15.13 mmol) were added under RT and the mixture was stirred under RT for 4 hours. In a separate flask, to a stirred solution of [1,1'-biphenyl]-3-carboxylic acid (2.5 g, 12.6 mol) dissolved in anhydrous THF (25 mL), CDI (4 g, 25.2 mmol) was added and the mixture was stirred at 50°C for 2 hours, then cooled to ambient temperature. The two mixtures were combined and heated at 50°C for 16 hours while monitoring by TLC. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with ELISA. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by column chromatography to obtain ethyl 3-([1,1'-biphenyl]-3-yl)-3-oxopropionate (1005). MS: m / z: 269.20 (M+H + ).

[0231] Preparation of ethyl 3-(3-cyclopropylphenyl)-3-oxopropionate (1006) [ka] Diethyl carbonate (3.3 mL, 27.50 mmol) was added to a stirred solution of NaH (1.54 g, 38.50 mmol) dissolved in anhydrous toluene (13.2 mL). After stirring at 100°C for 15 minutes, 1-(3-cyclopropylphenyl)ethanone (100) (2.2 g, 13.75 mmol) dissolved in anhydrous toluene (4.4 mL) was added dropwise. Stirring was continued at 120°C for 1 hour, and the progress of the reaction was monitored by TLC. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by column chromatography to obtain ethyl 3-(3-cyclopropylphenyl)-3-oxopropionate (1006). MS: m / z: 233.22 (M+H + ).

[0232] Preparation of ethyl 3-([1,1'-biphenyl]-3-yl)-2-methyl-3-oxopropionate (1007) [ka] Ethyl 3-([1,1'-biphenyl]-3-yl)-3-oxopropionate (1 g, 3.7 mmol) was dissolved in DMF (10 mL) and stirred. Cs2CO3 (1.2 g, 3.7 mmol) was added to the mixture. After stirring for 10 minutes, MeI (0.23 mL, 3.731 mmol) was added and stirring continued for 1 hour. The reaction mixture was diluted with cold water and extracted with RINKAN. The organic layer was separated, dried, and the solvent was removed under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain ethyl 3-([1,1'-biphenyl]-3-yl)-2-methyl-3-oxopropionate (1007). MS: m / z: 283.19 (M+H + ).

[0233] Preparation of 3-formyl-N-phenylbenzamide (1008) [ka] To a stirred solution of 3-formylbenzoic acid (2 g, 13 mmol) dissolved in DCM (34 mL), Et3N (2 mL, 15 mmol) and isobutyl chloroformate (1.9 mL, 15 mmol) were added at -5°C. After stirring for 40 minutes, aniline (1.3 mL, 15 mmol) was added at -5°C. After stirring at RT for 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by chromatography to obtain 3-formyl-N-phenylbenzamide (1008). MS: m / z: 226.16 (M+H + ).

[0234] Preparation of 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde (1009) [ka] 4-bromobenzaldehyde (500 mg, 2.7 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (564 mg, 2.97 mmol) were dissolved in MeOH (3.8 mL) and toluene (7.5 mL) and stirred. Na2CO3 (1.14 g, 10.8 mmol) dissolved in H2O (2.5 mL) was added to the mixture. After degassing and stirring under N2, Pd(PPh3)4 (156 mg, 0.135 mmol) was added. The reaction mixture was heated to 90°C and stirred for 16 hours while monitoring by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic layers were mixed, dried, and evaporated under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde (1009). MS 251.19(M+H + ).

[0235] The following compound was prepared by the same method: 2'-chloro-[1,1'-biphenyl]-4-carbaldehyde(1010):MS 217.14(M+H + );4'-Methoxy-[1,1'-biphenyl]-4-carbaldehyde(1011):MS 213.10(M+H + );4'-chloro-[1,1'-biphenyl]-4-carbaldehyde(1012):MS 217.03(M+H + );4'-Chloro-[1,1'-biphenyl]-3-carbaldehyde(1013);MS 217.25(M+H + );4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde(1014);4'-methoxy-[1,1'-biphenyl]-3-carbaldehyde(1015):MS 213.17(M+H + ); 4-(pyridine-3-yl)benzaldehyde(1016):MS:m / z:184.30(M+H + );4'-Formyl-[1,1'-biphenyl]-4-carboxylic acid(1017):MS 241.22(M+H + ); 4'-formyl-[1,1'-biphenyl]-4-carbonitrile(1018): 1¹H NMR (400MHz, DMSO-d6): δ 10.09 (s, 1H), 8.01 (d, J=8.0Hz, 2H), 7.76 (q, J=8.8Hz, 6H); 4'-nitro-[1,1'-biphenyl]-4-carbaldehyde (10¹⁹): 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 8.38-8.34 (m, 3H), 8.10-8.02 (m, 5H); and 4'-(pyrroridine-1-yl)-[1,1'-biphenyl]-4-carbaldehyde (1020): MS: m / z: 252.22 (M+H) + ).

[0236] Preparation of 4-(pyrimidine-2-yl)benzaldehyde (1021) [ka] 2-bromopyrimidine (5 g, 31.4 mmol) and (4-formylphenyl)boronic acid (5.6 g, 37.7 mmol) were dissolved in CH3CN (25 mL) and stirred. K2CO3 (13 g, 94.3 mmol) dissolved in H2O (25 mL) was added to the solution. The mixture was degassed under N2 and stirred for 15 minutes, after which Pd(PPh3)2Cl2 (1.8 g, 1.6 mmol) was added. The reaction mixture was heated at 90°C for 16 hours while monitoring by TLC. The reaction mixture was diluted with water, extracted with ELISA, and the organic layer was dried over (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4-(pyrimidine-2-yl)benzaldehyde (1021). MS: m / z: 185.07 (M+H + ).

[0237] Preparation of 4'-(dimethylamino)-[1,1'-biphenyl]-4-carbaldehyde (1022) [ka] 4-bromobenzaldehyde (3 g, 16 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.8 g, 19 mmol) were dissolved in dioxane (48 mL) and added to a stirred solution. Cs2CO3 (7.9 g, 24 mmol) dissolved in H2O (12 mL) was added. The reaction mixture was degassed with N2 and Pd(PPh3)4 (936 mg, 0.81 mmol) was added by RT. The mixture was heated at 100 °C for 16 hours, and the completion of the reaction was confirmed by TLC. The reaction mixture was then diluted with water and extracted with ELISA. The organic layer was separated, dried, and evaporated under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain 4'-(dimethylamino)-[1,1'-biphenyl]-4-carbaldehyde (1022). MS:m / z:226.34(M+H + ).

[0238] Preparation of 4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-carbaldehyde (1023) [ka] 1-(4-bromophenyl)pyrrolidine (5 g, 22 mmol) and (4-formylphenyl)boronic acid (3.3 g, 26 mmol) were dissolved in 1,4-dioxane (40 mL) and stirred. Na2CO3 (6.9 g, 66 mmol) dissolved in H2O (10 mL) was added. Pd(dppf)Cl2 (1.6 g, 21 mmol) was added, and the reaction was stirred at 90°C for 16 hours while monitoring by TLC. After dilution with water and ethyl acetate, the organic layer was separated, dried, and evaporated under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain 4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-carbaldehyde (1023). MS: m / z: 252.22 (M+H + ).

[0239] Preparation of 4'-formyl-[1,1'-biphenyl]-4-carboxylate methyl(1024) [ka] 4-bromobenzaldehyde (5 g, 27 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (5.8 g, 32 mmol) were dissolved in DME (32 mL) and stirred. Cs2CO3 (17.5 g, 54.05 mmol) dissolved in H2O (8 mL) was added to the solution. The mixture was degassed under an N2 atmosphere, flushed, and then Pd(PPh3)4 (624 mg, 0.540 mmol) was added. The mixture was heated at 90°C for 16 hours, monitored by TLC, and the reaction product was diluted with water and extracted with ELISA. The organic layer was separated, dried, and the solvent was evaporated under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain 4'-formyl-[1,1'-biphenyl]-4-methyl carboxylate (1024). MS: m / z: 241.22 (M+H + ).

[0240] Preparation of 4'-formyl-[1,1'-biphenyl]-4-carboxylic acid (1025) [ka] 4'-Formyl-[1,1'-biphenyl]-4-carboxylic acid methyl (124) (2g, 8.324 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (60 mL) and LiOH·H2O (1g, 24.999 mmol) was added to the stirred solution. The mixture was stirred for 2 hours, and the progress was monitored by TLC. After that, volatile matter was removed under reduced pressure. The residue was diluted with H2O and acidified with 1N HCl (pH approximately 1). The precipitate was collected by filtration and dried under vacuum to obtain 4'-Formyl-[1,1'-biphenyl]-4-carboxylic acid (1025). MS: m / z: 225.15 (MH) + ).

[0241] Preparation of 4'-formyl-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (1026) [ka] 4'-Formyl-[1,1'-biphenyl]-4-carboxylic acid (125) (800 mg, 3.5 mmol) was dissolved in DCM (13.6 mL) and stirred. Isobutyl chloroformate (0.5 mL, 3.9 mmol) and Et3N (0.54 mL, 3.9 mmol) were added at 0°C. After stirring at 0°C for 30 minutes, dimethylamine (2 M in THF, 1.94 mL, 3.89 mmol) was added. The mixture was stirred at RT for 16 hours, and the progress was monitored by TLC. The reaction product was then diluted with water and extracted with DCM. The organic layer was separated, dried, and the solvent was removed under reduced pressure using (Na2SO4). The residue was purified by column chromatography to obtain 4'-Formyl-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (1026). MS: m / z: 254.21 (M+H + ).

[0242] Preparation of methyl 3-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)benzoate (1027) [ka] 3-Formylmethyl benzoate (5 g, 30 mmol) was dissolved in EtOH (50 mL) and stirred. 2-Cyanoethanethioamide (3 g, 30 mmol) and piperidine (0.55 mL, 0.60 mmol) were added under RT. The resulting mixture was heated at 50°C for 15 minutes, then stirred under RT for 16 hours. The reaction was monitored by TLC. Volatile substances were evaporated under reduced pressure, and the residue was purified by column chromatography to obtain 3-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)methyl benzoate (1027). MS: m / z: 247.08 (M+H + ).

[0243] The following compound was prepared by the same method: 2-cyano-3-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1028). MS: m / z: 306.22 (MH) + ).

[0244] Preparation of 2-cyano-3-(4'-nitro-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1029) [ka] 4'-nitro-[1,1'-biphenyl]-4-carbaldehyde (119) (2.5 g, 11 mmol) was dissolved in toluene (25 mL) and stirred. 2-cyanoethanethioamide (1.1 g, 11 mmol) and ammonium acetate (169 mg, 2.20 mmol) were added by RT. The mixture was heated at 120 °C for 2 hours, monitored by TLC, and volatiles were removed under reduced pressure. The residue was purified by column chromatography to obtain 2-cyano-3-(4'-nitro-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1029). MS: m / z: 309.85 (M+H + ).

[0245] Preparation of 2-cyano-3-(4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1030) [ka] 4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-carbaldehyde (123) (1.8 g, 7.2 mmol) was dissolved in ethanol (18 mL) and stirred. 2-cyanoethanethioamide (573 mg, 5.74 mmol) and Et3N (0.2 mL, 1.4 mmol) were added by RT. The mixture was heated at 60 °C for 16 hours, and the progress was monitored by TLC. After evaporating the volatiles under reduced pressure, the residue was purified by column chromatography to obtain 2-cyano-3-(4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1030). MS: m / z: 334.24 (M+H + ).

[0246] Preparation of 3-([1,1'-biphenyl]-4-yl)-2-cyanoprop-2-enthioamide (1031) [ka] [1,1'-biphenyl]-4-carbaldehyde (2 g, 11 mmol) was dissolved in EtOH (20 mL) and 2-cyanoethanethioamide (1.1 g, 11 mmol) and Et3N (0.16 mL, 1.1 mmol) were added by RT. The resulting mixture was heated at 40 °C for 1 hour, and the progress was monitored by TLC. The volatile matter was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain 3-([1,1'-biphenyl]-4-yl)-2-cyanoprop-2-enethioamide (1031). 1 H NMR (400MHz, DMSO-d6): δ10.15 (br s, 1H), 9.67 (br s,1H), 8.13(s,1H), 8.05(d,J=8.4Hz,2H), 7.91(d,J=8.4Hz,2H), 7.79(d,J=7.2Hz,2H), 7.52(t,J=7.2Hz,2H), 7.45-7.42(m,1H). MS:m / z:265.15(M+H + ).

[0247] The following compound was prepared by the same method: 3-([1,1'-biphenyl]-2-yl)-2-cyanoprop-2-enthioamide(1032): 1 H NMR (400MHz, DMSO-d6): δ10.04(br s,1H), 9.43(br s,1H), 8.01(d,J=8.0Hz,1H), 7.97(s,1H), 7.67(t,J=7.60Hz,1H), 7.60-7.44(m,6H), 7.33(d,J=6.80Hz,2H). MS:m / z:265.12(M+H + );3-([1,1'-biphenyl]-3-yl)-2-cyanoprop-2-enthioamide(1033):MS:m / z:265.16(M+H + );2-Cyano-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)prop-2-enthioamide(1034);3-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-cyanoprop-2-enthioamide(1035):MS:m / z:299.11(M+H +);2-Cyano-3-(4'-Methoxy-[1,1'-biphenyl]-4-yl)prop-2-enthioamide(1036):MS:m / z:295.11(M+H + );3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-cyanoprop-2-enthioamide(1037):MS:m / z:299.18(M+H + );(2-cyano-3-(4-iodophenyl)prop-2-enthioamide(1038):MS:m / z:315.01(M+H + );3-(4'-chloro-[1,1'-biphenyl]-3-yl)-2-cyanoprop-2-enthioamide(1039);2-cyano-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)prop-2-enthioamide(1040):MS:m / z:333.19(M+H + );2-Cyano-3-(4'-Methoxy-[1,1'-biphenyl]-3-yl)prop-2-enthioamide(1041):MS:m / z:295.17(M+H + );2-Cyano-3-(4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)prop-2-enthioamide(1042):MS:m / z:334.24(M+H + ); and 3-(4-chlorophenyl)-2-cyanoprop-2-enthioamide(1043):MS:m / z:223.07(M+H + ).

[0248] Preparation of 3-(4-(1H-pyrazole-1-yl)phenyl)-2-cyanoprop-2-enthioamide (1044) [ka] 4-(1H-pyrazole-1-yl)benzaldehyde (3 g, 17.4 mmol) was dissolved in EtOH (60 mL) and stirred. 2-cyanoethanethioamide (2.1 g, 20.9 mmol) and piperidine (86 μL, 0.87 mmol) were added under RT. While monitoring by TLC, the resulting mixture was heated at 50°C for 15 minutes and stirred under RT for 16 hours. Volatile substances were evaporated under reduced pressure, and the residue was purified by column chromatography to obtain 3-(4-(1H-pyrazole-1-yl)phenyl)-2-cyanoprop-2-enthioamide (1044). MS: m / z: 255.18 (M+H + ).

[0249] The following compound was prepared by the same method: 2-cyano-3-(4-(pyridine-3-yl)phenyl)prop-2-enthioamide(1045): MS: m / z: 266.18 (M+H + ); and 2-cyano-3-(4-(pyrimidine-2-yl)phenyl)prop-2-enthioamide(1046):MS:m / z:267.12(M+H + ).

[0250] Preparation of 4'-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl (1047) [ka] 4'-Formyl-[1,1'-biphenyl]-4-carboxylate methyl (117) (2 g, 8.3 mmol) was dissolved in toluene (20 mL) and stirred. 2-Cyanoethanethioamide (833 mg, 8.33 mmol) and NH4OAc (128 mg, 1.67 mmol) were added to this solution. The resulting mixture was heated at 120 °C for 16 hours and monitored by TLC. Volatile substances were removed under reduced pressure, and the residue was purified by column chromatography to obtain 4'-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl (1047). MS: m / z: 323.12 (M+H + ).

[0251] The following compound was prepared by the same method: 2-cyano-3-(4'-cyano-[1,1'-biphenyl]-4-yl)prop-2-enthioamide (1048): MS: m / z: 287.89 (MH + ); and 4'-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide(1049).

[0252] Preparation of 3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)ethyl benzoate (1050) [ka] 3-(3-ethoxy-3-oxopropanoyl)methyl benzoate (1001) (800 mg, 3.2 mmol) and 2-cyanoethanethioamide (320 mg, 3.2 mmol) were dissolved in EtOH (2 mL) and stirred. KOH (179 mg, 3.2 mmol) was added at RT. The mixture was heated at 90°C for 16 hours, then cooled to RT. The resulting precipitate was filtered and dried under vacuum to obtain 4-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1050). MS: m / z: 299.22 (MH) + ).

[0253] The following compounds were prepared by the same method: 4-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1051); 2'-mercapto-6'-oxo-6-phenyl-1',6'-dihydro-[3,4'-bipyridine]-3'-carbonitrile (1052): MS: m / z: 306.17 (M+H + ); and 4-([1,1'-biphenyl]-3-yl)-2-mercapto-5-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(1053):MS:m / z:319.10(M+H + ).

[0254] Preparation of 3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1054) [ka] 4-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1053) (3.2 g, 11 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (96 mL) and a stirred solution was prepared. LiOH·H2O (1.4 g, 34 mmol) was added by RT. The mixture was stirred for 2 hours, and the progress was monitored by TLC. After that, volatile matter was removed under reduced pressure. The residue was diluted with H2O and acidified with 1N HCl (pH approximately 1). The resulting precipitate was filtered and dried under vacuum to obtain 3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1054). MS: m / z: 272.95 (M+H + ).

[0255] Preparation of 2-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1055) [ka] 2-(3-ethoxy-3-oxopropanoyl)methyl benzoate (1003) (1 g, 4.00 mmol) and 2-cyanoethanethioamide (400 mg, 4.00 mmol) were dissolved in EtOH (2 mL) and stirred. Potassium tert-butoxide (448 mg, 4.00 mmol) was added at RT. The reaction mixture was heated at 90°C for 1 hour, then cooled to RT. The resulting precipitate was filtered and dried under vacuum to obtain 2-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (155). MS: m / z: 272.98 (M+H + ).

[0256] Preparation of 3-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1056) [ka] 3-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)methyl benzoate (1027) (1 g, 4.1 mmol) and 2-ethyl cyanoethyl (0.43 mL, 4.1 mmol) were dissolved in EtOH (6 mL) and mixed. KOH (454 mg, 8.12 mmol) was added to this mixture. After heating at 90°C for 1 hour, the reaction mixture was cooled to RT, and the resulting precipitate was filtered and dried to obtain 3-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1056). MS: m / z: 310.11 (MH) + ).

[0257] Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)ethyl benzoate (1057) [ka] 3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (150 mg, 0.5 mmol) was dissolved in CH3CN (2 mL) and stirred. K2CO3 (126 mg, 1 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (35 mg, 0.3 mmol) under RT. The reaction mixture was stirred under RT for 16 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain ethyl 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoate (1057). 1H NMR (400MHz, DMSO-d6): δ8.12-8.11(m,2H), 7.88(d,J=8.00Hz,1H), 7.71(t,J=7.6 0Hz,1H), 6.63(s,1H), 4.85(s,2H), 4.35(q,J=6.80Hz,2H), 1.34(t,J=6.80Hz,3H). MS:m / z:383.12(M+H + ).

[0258] The following compound was prepared by the same method: 4-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1058).

[0259] Preparation of 2-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (159) [ka] 2-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1055) (400 mg, 1.47 mmol) was dissolved in DMSO (4 mL) and stirred. DIPEA (0.38 mL, 2.2 mmol) was added, followed by 5-(chloromethyl)-1H-tetrazole (73.8 mg, 0.738 mmol) under RT. The mixture was stirred under RT for 1 hour and monitored by TLC. The reaction mixture was then acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure to obtain 2-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1059). MS:m / z:355.21(M+H + ).

[0260] Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1060) [ka] 3-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1056) (700 mg, 2.248 mmol) was dissolved in CH3CN (14 mL) and stirred. K2CO3 (621 mg, 4.496 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (133 mg, 1.124 mmol). After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)methyl benzoate (1060). 1 H NMR (400MHz, DMSO-d6): δ8.16(d,J=8.0Hz,1H), 8.11(s,1H), 7.85(d,J=8.0Hz,1H), 7.75(t,J=7.6Hz,1H), 4.87(s,2H), 3.90(s,3H). MS:m / z:394.06(M+H + ).

[0261] Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1061) [ka] Ethyl 3-(6-(((1H-tetrazole-5-yl)methyl))-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoate (1060) (400 mg, 1.047 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (9 mL) and LiOH·H2O (87 mg, 2.09 mmol) was added to the stirred solution. The reaction mixture was stirred in RT for 2 hours and monitored by TLC. The solvent was removed under reduced pressure. The residue was diluted with H2O, acidified with 1N HCl (pH approximately 1), and extracted by DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1061). 1 H NMR(400MHz,DMSO-d6):δ8.09(d,J=7.20Hz,2H), 7.84(d,J=7.60Hz,1H), 7.70(d,J=8.00Hz,1H), 6.62(s,1H), 4.84(s,2H).MS:m / z:354.78(M+H + ).

[0262] The following compounds were prepared by the same method: 4-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1062); and 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1063): MS: m / z: 378.13 (MH + ).

[0263] Preparation of 3-(6-((3-(1H-tetrazole-5-yl)benzyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1064) [ka] 3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1054) (500 mg, 1.838 mmol) was dissolved in CH3CN (10 mL) and a stirred solution was prepared. K2CO3 (507 mg, 3.676 mmol) and 5-(3-(bromomethyl)phenyl)-1H-tetrazole (351 mg, 1.470 mmol) were added to this solution. The reaction mixture was stirred at RT for 16 hours, and the progress was monitored by TLC. Volatile substances were evaporated under reduced pressure, the residue was diluted with H2O, and acidified with 1N HCl (pH approximately 1). The precipitate was filtered and dried under vacuum to obtain 3-(6-((3-(1H-tetrazole-5-yl)benzyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1064) as a white solid. MS:m / z:431.25(M+H + ).

[0264] The following compounds were prepared by the same method: 3-(5-cyano-6-((3-(2-methoxy-2-oxoethyl)benzyl)thio)-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1065); 3-(5-cyano-6-((2-methoxy-2-oxoethyl)thio)-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1066) as a white solid: MS: m / z: 345.21 (M+H + ); and 3-(5-cyano-6-((3-(methoxycarbonyl)benzyl)thio)-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1067):MS:m / z:421.26(M+H + ).

[0265] Preparation of 4-([1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1068) [ka] A stirred solution of 3-([1,1'-biphenyl]-4-yl)-2-cyanoprop-2-enthioamide (1031) (600 mg, 2.27 mmol) and 2-ethyl cyanoethyl (256 mg, 2.27 mmol) dissolved in EtOH (6 mL) was added to KOH (127 mg, 2.27 mmol) at RT, and the reaction mixture was heated at 90°C for 4 hours. The reaction mixture was cooled to RT, the resulting precipitate was filtered, and dried under vacuum to obtain 4-([1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (1068). MS: m / z: 328.19 (MH) + ).

[0266] The following compound was prepared by the same method: 4-([1,1'-biphenyl]-2-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1069): MS: m / z: 328.10 (MH + );4-([1,1'-biphenyl]-3-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1070):MS:m / z:328.10(MH) + );6-mercapto-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyridine-3,5-dicarbonitrile(1071):MS:m / z:396.22(MH + );4-(2'-chloro-[1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1072):MS:m / z:363.25(MH + );6-mercapto-4-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1073):MS:m / z:358.10(MH + );4-(4'-chloro-[1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1074):MS:m / z:362.11(MH +);4-(4-iodophenyl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1075):MS:m / z:379.96(M+H - );4-(4'-chloro-[1,1'-biphenyl]-3-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1076):MS:m / z:362.11(MH + );6-mercapto-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-1,2-dihydropyridine-3,5-dicarbonitrile(1077);6-mercapto-4-(4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1078):MS:m / z:360.14(M+H + );4-(4-(1H-pyrazole-1-yl)phenyl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1079):MS:m / z:320.23(M+H + );6-mercapto-2-oxo-4-(4-(pyridine-3-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitrili(1080):MS:m / z:329.05(MH + );4'-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)-[1,1'-biphenyl]-4-carboxylic acid(1081):MS:m / z:386.17(MH + );6-mercapto-2-oxo-4-(4-(pyrimidine-2-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitrile(1082):MS:m / z:330.15(MH + );4-(4'-cyano-[1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1083):MS:m / z:354.79(M+H + );6-mercapto-4-(4'-nitro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1084):MS:m / z:374.77(M+H+ );4-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(1085):MS:m / z:372.86(M+H + );6-mercapto-2-oxo-4-(4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyridine-3,5-dicarbonitrile(1086):MS:m / z:399.26(M+H + );6-mercapto-2-oxo-4-(4'-(pyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyridine-3,5-dicarbonitrile(1087):MS:m / z:399.26(M+H + );4'-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (1088) was obtained as a light brown solid. MS:m / z:401.28(M+H + ).

[0267] Preparation of 4-([1,1'-biphenyl]-3-yl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1089) [ka] Ethyl 3-([1,1'-biphenyl]-3-yl)-3-oxopropionate (1005) (2 g, 7.4 mmol) and 2-cyanoethanethioamide (740 mg, 7.45 mmol) were dissolved in EtOH (12 mL) and stirred. KOH (417 mg, 7.45 mmol) was added to the mixture, and the reaction mixture was heated at 90°C for 16 hours. The reaction mixture was cooled to RT, the resulting precipitate was filtered, and dried under vacuum to obtain 4-([1,1'-biphenyl]-3-yl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (188). MS: m / z: 305.17 (M+H + ).

[0268] The following compound was prepared by the same method: 4-(3-cyclopropylphenyl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1090): MS: m / z: 269.18 (M+H + ).

[0269] Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1091) [ka] 4-(4-iodophenyl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1075) (1.8 g, 3.9 mmol) was dissolved in CH3CN (18 mL) and stirred. K2CO3 (1.6 g, 12 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (552 mg, 4.68 mmol) under RT. The reaction mixture was stirred under RT for 16 hours, and completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was acidified with 1N HCl and extracted by DCM. The organic layer was separated, dried, and the solvent was removed under reduced pressure (Na2SO4). The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (1091). 1 H NMR (400MHz, DMSO-d6): δ7.88 (d, J = 8.40 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.59 (s, 2H). MS:m / z:462.09(M+H + ).

[0270] Preparation of 3-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidine-4-yl)-N-phenylbenzamide (1092) [ka] 3-Formyl-N-phenylbenzamide (1008) (1 g, 4.4 mmol) and 2-ethyl cyanoethyl (0.47 mL, 4.4 mmol) were dissolved in ethanol (20 mL) and stirred. Piperidine (0.87 mL, 8.9 mmol) and thiourea (338 mg, 4.4 mmol) were added to this mixture. The mixture was heated at 80°C for 2 hours and monitored by TLC. The reaction mixture was then cooled to RT, the resulting precipitate was filtered, dried under vacuum, and 3-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidine-4-yl)-N-phenylbenzamide (1092) was obtained. MS: m / z: 349.17 (MH) + ).

[0271] Preparation of 2,4-dihydroxy-6-phenylpyrimidine-5-carbonitride (1093) [ka] Benzaldehyde (10 g, 94 mmol) and ethyl 2-cyanoethyl acetate (10 mL, 94 mmol) were dissolved in EtOH (94 mL) and a stirred solution was prepared. K2CO3 (13 g, 94 mmol) and urea (5.6 g, 94.23 mmol) were added to this solution. The reaction mixture was stirred at 70°C for 16 hours and monitored by TLC. Volatile substances were removed under vacuum, and the residue was acidified with 1N HCl. The resulting solid was recovered by filtration and dried under vacuum to obtain 2,4-dihydroxy-6-phenylpyrimidine-5-carbonitrile (1093). MS: m / z: 214.03 (M+H + ).

[0272] Preparation of 2,4-dichloro-6-phenylpyrimidine-5-carbonitrile (1094) [ka] 2,4-dihydroxy-6-phenylpyrimidine-5-carbonitrile (1093) (6 g, 28 mmol) was dissolved in N,N-diethylaniline (9 mL, 56) and stirred. POCl3 (42 mL) was added to the mixture by RT. The resulting mixture was heated at 120°C for 3 hours and monitored by TLC. After cooling to RT, saturated aqueous solution of NaHCO3 was slowly added, and the resulting solution was extracted with ELISA. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 2,4-dichloro-6-phenylpyrimidine-5-carbonitrile (1094).

[0273] Preparation of 4-chloro-2-methoxy-6-phenylpyrimidine-5-carbonitrile (1095) [ka] 2,4-Dichloro-6-phenylpyrimidine-5-carbonitrile (1094) (400 mg, 1.6 mmol) was dissolved in MeOH (4 mL) and stirred. Et3N (0.2 mL, 1.6 mmol) was added to the solution. After stirring at RT for 16 hours, the solvent was removed under vacuum, and the residue was purified by column chromatography to obtain 4-chloro-2-methoxy-6-phenylpyrimidine-5-carbonitrile (1095). MS: m / z: 246.05 (M+H + ).

[0274] Preparation of 6-mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096) [ka] 4-Chloro-2-methoxy-6-phenylpyrimidine-5-carbonitrile (1095) (300 mg, 1.22 mmol) was dissolved in DMF (3.0 mL) and stirred. NaSH (102 mg, 1.836 mmol) was added to the mixture. The reaction mixture was heated at 120 °C for 6 hours, then cooled to RT. The resulting precipitate was filtered and dried under vacuum to obtain 6-mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096). MS: m / z: 230.04 (M+H + ).

[0275] Preparation of 2-chloro-4-methoxy-6-phenyl-1,3,5-triazine (1097) [ka] 2,4-Dichloro-6-phenyl-1,3,5-triazine (500 mg, 2.2 mmol) was dissolved in THF (12 mL) and stirred. NaOMe (119 mg, 2.21 mmol) and NaH (63 mg, 2.65 mmol) were added at -30°C. The mixture was stirred at -30°C for 1 hour, and the reaction was confirmed to be complete by TLC. The reaction product was then acidified with 1N HCl and extracted with ethyl acetate. The mixed organic layer was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 2-chloro-4-methoxy-6-phenyl-1,3,5-triazine (1097). MS: m / z: 222.05 (M+H + ).

[0276] Preparation of 4-mercapto-6-phenyl-1,3,5-triazine-2-ol (1098) [ka] 2-Chloro-4-methoxy-6-phenyl-1,3,5-triazine (1097) (100 mg, 0.45 mmol) was dissolved in DMF (2 mL) and stirred. NaSH (38 mg, 0.76 mmol) was added to the solution. The mixture was heated at 120 °C for 16 hours, and the reaction was confirmed to be complete by TLC. The reaction product was then diluted with water (20 mL), acidified with 1 N HCl (pH approximately 1), and extracted by DCM. The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 4-mercapto-6-phenyl-1,3,5-triazine-2-ol (197). MS: m / z: 206.10 (M+H + ).

[0277] Preparation of 4-(4-chlorophenyl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl(1099) [ka] 3-(4-chlorophenyl)-2-cyanoprop-2-enthioamide (1043) (2 g, 9.0 mmol) was dissolved in EtOH (20 mL) and stirred. Diethyl malonate (1.37 mL, 9.01 mmol) and KOH (504 mg, 9.0 mmol) were added at RT. The resulting mixture was stirred at 90°C for 16 hours and monitored by TLC. After cooling to RT, the resulting precipitate was filtered and dried under vacuum to obtain 4-(4-chlorophenyl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (198). MS: m / z: 333.08 (MH) - ).

[0278] Preparation of 1-(4-acetylphenyl)pyrrolidine-2-one (1100) [ka] To a stirred solution of 1-(4-bromophenyl)ethanone (4 g, 20 mmol) and pyrrolidine-2-one (2.29 mL, 30.2 mmol) dissolved in 1,4-dioxane (40 mL), Cs2CO3 (19.6 g, 60.301 mmol) dissolved in H2O (4.5 mL) was added. After degassing, Pd2(dba)3 (913 mg, 1.005 mmol) and X-Phos (956 mg, 2.010 mmol) were added. The mixture was heated at 110°C for 6 hours and monitored by TLC. The reaction mixture was then diluted with water, extracted with ELISA, and the organic layer was separated. The mixture was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 1-(4-acetylphenyl)pyrrolidine-2-one (1100). MS: m / z: 204.26 (M+H + ).

[0279] The following compounds were prepared by the same method.

[0280] 4-(2-oxopyrrolidine-1-yl)benzaldehyde (1101). MS: m / z: 190.25 (M+H + ).

[0281] 1-(3-(pyrrolidine-1-yl)phenyl)ethenone(1102). MS:m / z:190.14(M+H + ).

[0282] t-Butyl-4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid (1103). MS: m / z: 221.21 (M+H + ).

[0283] Preparation of 1-(3-acetylphenyl)pyrrolidine-2-one (1104) [ka] 1-(3-bromophenyl)ethanone (4 g, 20 mmol) and pyrrolidine-2-one (1.83 mL, 24.1 mmol) were dissolved in DMF (9.6 mL). K2CO3 (5.5 g, 40 mmol), N,N-dimethylglycine (414 mg, 4.02 mmol), and CuI (381 mg, 2.01 mmol) were added by RT. After heating at 100 °C for 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 1-(3-acetylphenyl)pyrrolidine-2-one (1104). MS: m / z: 204.09 (M+H + ).

[0284] Preparation of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carbaldehyde (1105) [ka] 2-bromobenzaldehyde (5 g, 27 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (7.6 g, 40 mmol) were dissolved in 1,4-dioxane (45 mL) and stirred. Na2CO3 (8.5 g, 81 mmol) dissolved in H2O (5 mL) was added to the mixture. After degassing the reaction mixture with N2, Pd(dppf)Cl2 (1.9 g, 2.7 mmol) was added by RT. After heating at 110 °C for 16 hours, the reaction mixture was diluted with water and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carbaldehyde (1105). MS: m / z: 251.25 (M+H + ).

[0285] Preparation of methyl 3-(piperidine-1-yl)benzoate (1106) [ka] To a stirred solution of methyl 3-bromobenzoate (5 g, 23 mmol) and piperidine (3.4 mL, 35 mmol) dissolved in toluene (50 mL), Cs2CO3 (22.6 g, 69.8 mmol) was added. After degassing with N2, Pd(dba)3 (1.06 g, 1.16 mmol) and BINAP (723 mg, 1.16 mmol) were added. After stirring at 100°C for 16 hours, the reaction mixture was diluted with water and extracted with butyl. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain methyl 3-(piperidine-1-yl)benzoate (1106). MS: m / z: 220.18 (M+H + ).

[0286] Preparation of 4'-methoxy-[1,1'-biphenyl]-2-carbaldehyde (1107) [ka] 2-bromobenzaldehyde (1 g, 5.4 mmol) and (4-methoxyphenyl)boronic acid (1.2 g, 8.1 mmol) were dissolved in 1,4-dioxane (8 mL) and stirred. Na2CO3 (1.7 g, 16 mmol) dissolved in H2O (2 mL) was added to the mixture. After degassing the reaction mixture with N2, Pd(PPh3)4 (624 mg, 0.540 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours, then the reaction mixture was diluted with water and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4'-methoxy-[1,1'-biphenyl]-2-carbaldehyde (1107). MS: m / z: 213.46 (M+H + ).

[0287] The following compounds were prepared by the same method.

[0288] 4'-Chloro-[1,1'-biphenyl]-2-carbaldehyde (1108). MS: m / z: 217.43 (M+H + ).

[0289] Preparation of 2-(3-cyclopropylphenyl)-1,3-dioxolane (1109) [ka] To a stirred solution of 2-(3-bromophenyl)-1,3-dioxolane (5 g, 22 mmol) dissolved in toluene (40 mL), cyclopropylboronic acid (2.2 g, 26 mmol) and K3PO4 (13.8 g, 65 mmol) dissolved in H2O (10 mL) were added. After purging under N2 for 10 minutes, PCy3 (280 mg, 2.8 mmol) and Pd(OAc)2 (733 mg, 3 mmol) were added. After stirring at 100°C for 16 hours, the reaction mixture was diluted with water and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 2-(3-cyclopropylphenyl)-1,3-dioxolane (1109). MS: m / z: 191.24 (M+H + ).

[0290] Preparation of 3-cyclopropylbenzaldehyde (1110) [ka] 2-(3-cyclopropylphenyl)-1,3-dioxolane (1109) (6 g, 0.0315 mol) was dissolved in THF (150 mL) and stirred. 1N HCl (90 mL) was added at 0°C. After stirring at RT for 4 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na₂SO₄, and the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 3-cyclopropylbenzaldehyde (1110). MS: m / z: 147.18 (M+H + ).

[0291] Preparation of 3-(3,4-dihydroquinoline-1(2H)-yl)methyl benzoate (1111) [ka] To a stirred solution of methyl 3-bromobenzoate (5 g, 23 mmol) and 1,2,3,4-tetrahydroquinoline (4.3 mL, 34 mmol) dissolved in 1,4-dioxane (50 mL), Cs2CO3 (22.7 g, 70 mmol) was added. After degassing with N2, Pd2(dba)3 (1 g, 1.1 mmol) and X-Phos (1.1 g, 2.3 mmol) were added. After heating at 100°C for 16 hours, the reaction mixture was diluted with water and extracted with phenylethylamine. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain methyl 3-(3,4-dihydroquinoline-1(2H)-yl)benzoate (1111). MS: m / z: 268.52 (M+H + ).

[0292] The following compounds were prepared by the same method.

[0293] 3-(4-phenylpiperazine-1-yl)benzoic acid (1112). MS: m / z: 297.65 (M+H + ).

[0294] Preparation of methyl 3-(4-acetylpiperazine-1-yl)benzoate (1113) [ka] To a stirred solution of methyl 3-bromobenzoate (5 g, 23.250 mmol) and 1-(piperazin-1-yl)ethanone (2.78 mL, 23.2 mmol) dissolved in toluene (90 mL), Cs2CO3 (11.3 g, 34.9 mmol) was added. After degassing under an N2 atmosphere, Pd(OAc)2 (521 mg, 2.32 mmol) and XantPhos (2.69 g, 4.65 mmol) were added. After heating at 110°C for 16 hours, the reaction mixture was diluted with water and extracted with butyl. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain methyl 3-(4-acetylpiperazin-1-yl)benzoate (1113). MS: m / z: 263.67 (M+H + ).

[0295] Preparation of methyl(methyl(phenyl)carbamoyl)benzoate (1114) [ka] 3-(methoxycarbonyl)benzoic acid (10 g, 55 mmol) was dissolved in DMF (100 mL) and stirred. HATU (42 g, 110 mmol) and DIPEA (21.2 mL, 166 mmol) were added under RT. After stirring under RT for 30 minutes, N-methylaniline (6 mL, 56 mmol) was added. After stirring under RT for 16 hours, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was separated, dried over Na₂SO₄, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain methyl 3-(methyl(phenyl)carbamoyl)benzoate (1114). MS: m / z: 270.50 (M+H + ).

[0296] Preparation of 3-(3,4-dihydroquinoline-1(2H)-yl)benzoic acid (1115) [ka] 3,4-Dihydroquinoline-1(2H)-yl)methyl benzoate (3g, 11 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (30 mL) and a stirred solution was prepared. LiOH·H2O (1.4 g, 33 mmol) was added to the solution. After stirring at RT for 2 hours, volatile matter was removed under reduced pressure. The residue was diluted with H2O and acidified with 1H HCl (pH=1). The precipitate was filtered and dried under vacuum to obtain 3-(3,4-Dihydroquinoline-1(2H)-yl)benzoic acid (1115). MS: m / z: 254.29 (M+H + ).

[0297] The following compounds were prepared by the same method.

[0298] 3-(4-phenylpiperazine-1-yl)benzoic acid (1116). MS: m / z: 281.34 (MH) + ).

[0299] Preparation of 3-(4-acetylpiperazine-1-yl)benzoic acid (1117) [ka] Methyl 3-(4-acetylpiperazin-1-yl)benzoate (2 g, 7.6 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (15 mL) and a stirred solution was prepared. LiOH·H2O (959 mg, 22.9 mmol) was added to this solution. After stirring at RT for 2 hours, volatile matter was removed under reduced pressure, the residue was diluted with water, acidified with 1N HCl (pH=1), and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to obtain 3-(4-acetylpiperazin-1-yl)benzoic acid (1117). MS: m / z: 249.22 (MH) + ).

[0300] The following compounds were prepared by the same method.

[0301] 3-(piperidine-1-yl)benzoic acid (1118). MS: m / z: 206.20 (M+H + ).

[0302] 2-(4-methylpiperazine-1-yl)benzoic acid (1119). MS:m / z:221.25(M+H + ).

[0303] 3-(methyl(phenyl)carbamoyl)benzoic acid (1120). MS:m / z:256.24(M+H + ).

[0304] Preparation of 3-(4-(t-butoxycarbonyl)piperazin-1-yl)benzoic acid (1121) [ka] t-butyl-4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid (9 g, 28 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (90 mL) and stirred. LiOH·H2O (2.36 g, 84.4 mmol) was added to the solution. After stirring at RT for 4 hours, the volatiles were evaporated under reduced pressure. The residue was acidified with citric acid solution. The precipitate was filtered and dried under reduced pressure to obtain 3-(4-(t-butoxycarbonyl)piperazine-1-yl)benzoic acid (1121). MS: m / z: 305.39 (MH) + ).

[0305] Preparation of 3-oxo-3-(4-(2-oxopyrrolidine-1-yl)phenyl)propionate ethyl (1122) [ka] Diethyl carbonate (3.59 mL, 29.52 mmol) was added to a stirred solution of NaH (1.18 g, 29.52 mmol) dissolved in anhydrous THF (36 mL). After stirring at 70°C for 1 hour, 1-(4-acetylphenyl)pyrrolidine-2-one (3 g, 14.708 mmol) dissolved in anhydrous THF (10 mL) was added dropwise. After stirring at 70°C for 3 hours, the reaction mixture was acidified with 1N HCl (pH=1) and extracted with ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl hydroxyl (2-oxopyrrolidine-1-yl)phenyl) (1122) (MS: m / z: 276.26). + ).

[0306] The following compounds were prepared by the same method.

[0307] 3-Oxo-3-(3-(2-oxopyrrolidine-1-yl)phenyl)propionate ethyl (1123). MS: m / z: 276.25 (M+H + ).

[0308] 3-Oxo-3-(3-(pyrrolidine-1-yl)phenyl)propionate ethyl (1124). MS: m / z: 262.29 (M+H + ).

[0309] Preparation of 3-(1-methyl-1H-benzo[d]imidazole-2-yl)-3-oxopropionate ethyl (1125) [ka] Potassium 3-ethoxy-3-oxopropionate (5.2 g, 30.7 mmol) was dissolved in anhydrous ACN (42 mL) and Et3N (1.6 mL, 11.4 mmol) and MgCl2 (971 mg, 10.2 mmol) were added to a stirred solution. In a separate flask, 1-methyl-1H-benzo[d]imidazole-2-carboxylic acid (1.8 g, 10.2 mmol) was dissolved in anhydrous ACN (21 mL) and CDI (16.5 g, 102 mmol) was added to a stirred solution. The second solution was stirred at 80°C for 16 hours, then cooled to RT, and the first solution was added. After stirring for 6 hours, the reaction mixture was acidified with 1H HCl (pH=1) and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by RP C18 chromatography to obtain ethyl 3-(1-methyl-1H-benzo[d]imidazole-2-yl)-3-oxopropionate (1125). MS: m / z: 247.24 (M+H + ).

[0310] The following compounds were prepared by the same method.

[0311] 3-(3-(4-methylpiperazine-1-yl)phenyl)-3-oxopropionate ethyl(1126). MS:m / z:291.31(M+H + ).

[0312] 3-(3-(3,4-dihydroquinoline-1(2H)-yl)phenyl)-3-oxopropionate ethyl(1127). MS:m / z:324.33(M+H + ).

[0313] 3-Oxo-3-(3-(4-phenylpiperazin-1-yl)phenyl)propionate ethyl (1128). MS:m / z:353.37(M+H + ).

[0314] 3-(3-(4-acetylpiperazine-1-yl)phenyl)-3-oxopropionate ethyl(1129). MS:m / z:319.37(M+H + ).

[0315] Ethyl 3-oxo-3-(3-(piperidine-1-yl)phenyl)propionate (1130) as a yellow oil. MS:m / z:276.27(M+H + ).

[0316] 3-(2-(4-methylpiperazine-1-yl)phenyl)-3-oxopropionate ethyl(1131). MS:m / z:291.39(M+H + ).

[0317] t-Butyl-4-(3-(3-ethoxy-3-oxopropanoyl)phenyl)piperazine-1-carboxylic acid (1132). MS: m / z: 377.36 (M+H + ).

[0318] 3-(3-(methyl(phenyl)carbamoyl)phenyl)-3-oxopropionate ethyl (1133). MS:m / z:326.47(M+H + ).

[0319] Preparation of ethyl 3-(3-cyclopropylphenyl)-2-methyl-3-oxopropionate (1134) [ka] Ethyl 3-(3-cyclopropylphenyl)-3-oxopropionate (2.5 g, 10.8 mmol) was dissolved in DMF (25 mL) and stirred. Cs2CO3 (3.5 g, 10.8 mmol) was added to the mixture. After stirring for 10 minutes, MeI (0.6 mL, 10.8 mmol) was added. After stirring for 1 hour, the reaction mixture was diluted with cold water and extracted with ethyl phosphate. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain ethyl 3-(3-cyclopropylphenyl)-2-methyl-3-oxopropionate (1134). MS: m / z: 247.27 (M+H + ).

[0320] The following compounds were prepared by the same method.

[0321] 2-Methyl-3-(3-(methyl(phenyl)carbamoyl)phenyl)-3-oxopropionate ethyl (1135). MS:m / z:338.28(MH) + ).

[0322] Preparation of 3-([1,1'-biphenyl]-3-yl)-2-cyanoprop-2-enthioamide (1136) [ka] [1,1'-biphenyl]-3-carbaldehyde (5 g, 36 mmol) was dissolved in EtOH (50 mL) and stirred. 2-cyanoethanethioamide (714 mg, 7.14 mmol) and Et3N (0.99 mL, 7.14 mmol) were added by RT. After stirring at 60°C for 2 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 3-([1,1'-biphenyl]-3-yl)-2-cyanoprop-2-enthioamide (1136). MS: m / z: 223.07 (M+H + ).

[0323] The following compounds were prepared by the same method.

[0324] 2-Cyano-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)prop-2-enthioamide (1137). MS:m / z:333.25(M+H + ).

[0325] Preparation of 2-cyano-3-(4'-methoxy-[1,1'-biphenyl]-2-yl)prop-2-enthioamide (1138) [ka] 4'-methoxy-[1,1'-biphenyl]-2-carbaldehyde (700 mg, 3.3 mmol) was dissolved in EtOH (7 mL) and stirred. 2-cyanoethanethioamide (396 mg, 3.96 mmol) and piperidine (30 μL, 0.33 mmol) were added to this solution. The resulting mixture was heated at 50°C for 15 minutes. After cooling to RT and stirring for 16 hours, volatiles were removed under reduced pressure, and the residue was purified by column chromatography to obtain 2-cyano-3-(4'-methoxy-[1,1'-biphenyl]-2-yl)prop-2-enthioamide (1138). MS: m / z: 295.25 (M+H + ).

[0326] The following compounds were prepared by the same method.

[0327] 3-(4'-chloro-[1,1'-biphenyl]-2-yl)-2-cyanoprop-2-enthioamide (1139). MS:m / z:299.19(M+H + ).

[0328] 3-(3-amino-2-cyano-3-thioxoprop-1-en-1-yl)-N-methyl-N-phenylbenzamide (1140). MS:m / z:322.26(M+H + ).

[0329] Preparation of 2-cyano-3-(3-cyclopropylphenyl)prop-2-enthioamide (1141) [ka] 3-Cyanoethylbenzaldehyde (3 g, 20 mmol) was dissolved in toluene (30 mL) and stirred. 2-Cyanoethanethioamide (2.46 g, 25 mmol) and NH4OAc (157 mg, 20 mmol) were added to this solution. After stirring at 80°C for 2 hours, the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 2-Cyano-3-(3-cyclopropylphenyl)prop-2-enethioamide (1141). MS: m / z: 229.24 (M+H + ).

[0330] Preparation of 2-cyano-3-(4-(4-methylpiperazine-1-yl)phenyl)prop-2-enthioamide (1142) [ka] 4-(4-methylpiperazin-1-yl)benzaldehyde (2 g, 9.8 mmol) dissolved in EtOH (20 mL) was mixed with 2-cyanoethanethioamide (1.17 g, 11.8 mmol) and piperidine (0.09 mL, 0.98 mmol). The resulting mixture was heated at 50°C for 15 minutes. After stirring at RT for 16 hours, the volatiles were evaporated under reduced pressure. The mixture was ground with diethyl ether to obtain 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-enthioamide (1142). MS: m / z: 287.25 (M+H + ).

[0331] The following compounds were prepared by the same method.

[0332] 2-Cyano-3-(4-(2-oxopyrrolidine-1-yl)phenyl)prop-2-enthioamide (1143). MS:m / z:272.22(M+H + ).

[0333] 2-Cyano-3-(4-(pyrrolidine-1-yl)phenyl)prop-2-enthioamide (1144). MS: m / z: 258.23 (M+H + ).

[0334] Preparation of 6-mercapto-4-(4-(4-methylpiperazine-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1145) [ka] 2-Cyano-3-(4-(4-methylpiperazine-1-yl)phenyl)prop-2-enthioamide (1142) (1.3 g, 4.5 mmol) and 2-ethyl cyanoethyl (0.58 mL, 5.4 mmol) were dissolved in EtOH (13 mL) and KOH (305 mg, 4.54 mmol) was added to the stirred solution. After heating at 70°C for 2 hours, the reaction mixture was cooled to RT, the resulting precipitate was filtered, dried under vacuum, and 6-mercapto-4-(4-(4-methylpiperazine-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1145) was obtained. MS: m / z: 287.25 (M+H + ).

[0335] The following compounds were prepared by the same method.

[0336] 6-Mercapto-2-oxo-4-(4-(2-oxopyrrolidine-1-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitric acid (1146). MS:m / z:335.34(M+H + ).

[0337] 6-Mercapto-2-oxo-4-(4-(pyrrolidine-1-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitric acid (1147). MS:m / z:323.21(M+H + ).

[0338] 6-Mercapto-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1,2-dihydropyridine-3,5-dicarbonitride (1148). MS:398.26(M+H + ).

[0339] Preparation of 2-mercapto-6-oxo-4-(4-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1149) [ka] Ethyl 3-oxo-3-(4-(2-oxopyrrolidine-1-yl)phenyl)propionate (1122) (1 g, 3.6 mmol) and 2-cyanoethanethioamide (362 mg, 3.63 mmol) were dissolved in EtOH (6 mL) and stirred. NaOEt (494 mg, 7.27 mmol) was added at RT. After heating at 90°C for 16 hours, the reaction mixture was cooled to RT, the resulting precipitate was filtered, and dried under vacuum to obtain 2-mercapto-6-oxo-4-(4-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1149). MS: m / z: 310.22 (MH) + ).

[0340] The following compounds were prepared by the same method.

[0341] 4-(3-cyclopropylphenyl)-2-mercapto-5-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (1150). MS:m / z:281.29(MH) + ).

[0342] 2-Mercapto-4-(3-(4-methylpiperazine-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (1151). MS:m / z:325.21(MH) + ).

[0343] 3-(5-cyano-6-mercapto-3-methyl-2-oxo-1,2-dihydropyridine-4-yl)-N-methyl-N-phenylbenzamide (1152). MS:m / z:376.35(M+H + ).

[0344] Preparation of 2-mercapto-6-oxo-4-(3-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1153) [ka] Ethyl 3-oxo-3-(3-(2-oxopyrrolidine-1-yl)phenyl)propionate (1123) (800 mg, 2.9 mmol) and ethyl 2-cyanoethyl (290 mg, 2.9 mmol) were dissolved in EtOH (4.8 mL) and stirred. KOH (162 mg, 2.91 mmol) was added to the mixture. After heating at 80 °C for 16 hours, the reaction mixture was cooled to RT, the resulting precipitate was filtered, dried under vacuum, and 2-mercapto-6-oxo-4-(3-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1153) was obtained. MS: m / z: 310.25 (MH) + ).

[0345] The following compounds were prepared by the same method.

[0346] 2-Mercapto-6-oxo-4-(3-(pyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1154). MS:m / z:298.22(M+H + ).

[0347] 2-Mercapto-4-(1-methyl-1H-benzo[d]imidazole-2-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (1155). MS:m / z:283.21(M+H + ).

[0348] 2-Mercapto-6-oxo-4-(3-(4-phenylpiperazine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1156). MS:m / z:389.36(M+H + ).

[0349] 2-Mercapto-6-oxo-4-(3-(piperidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (1157). MS:m / z:312.29(M+H + ).

[0350] Preparation of t-butyl-4-(3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (1158) [ka] t-butyl-4-(3-(3-ethoxy-3-oxopropanoyl)phenyl)piperazine-1-carboxylic acid (1121) (1.5 g, 4.0 mmol) and 2-cyanoethanethioamide (1.19 g, 12.0 mmol) were dissolved in EtOH (6 mL) and KOH (595 mg, 16.0 mmol) was added to the stirred solution. After stirring at 80 °C for 16 hours, volatile matter was removed under reduced pressure. The residue was pulverized with diethyl ether, the precipitate was filtered, and dried under reduced pressure to obtain t-butyl-4-(3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (1158). MS: m / z: 411.42 (MH) - ).

[0351] Preparation of 4-(3-(3,4-dihydroquinoline-1(2H)-yl)phenyl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1159) [ka] Ethyl 3-(3-(3,4-dihydroquinoline-1(2H)-yl)phenyl)-3-oxopropionate (900 mg, 2.8 mmol) and 2-cyanoethanethioamide (334 mg, 3.3 mmol) were dissolved in EtOH (9 mL) and stirred. DBU (0.8 mL, 5.6 mmol) was added to this solution. After heating at 80 °C for 16 hours, the reaction mixture was cooled to RT, the resulting precipitate was filtered, and dried under vacuum to obtain 4-(3-(3,4-dihydroquinoline-1(2H)-yl)phenyl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1159). MS: m / z: 360.29 (M+H + ).

[0352] The following compounds were prepared by the same method.

[0353] 6-Mercapto-4-(4'-Methoxy-[1,1'-biphenyl]-2-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (1160). MS:m / z:360.30(M+H + ).

[0354] 4-(4'-chloro-[1,1'-biphenyl]-2-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitric acid (1161). MS: m / z: 364.21 (M+H + ).

[0355] 4-(3-(4-acetylpiperazine-1-yl)phenyl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1162). MS:m / z:353.26(MH) + ).

[0356] 2-Mercapto-4-(2-(4-methylpiperazine-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (1163). MS:m / z:327.28(M+H) + .

[0357] Preparation of 4-([1,1'-biphenyl]-3-yl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (1164) [ka] 3-([1,1'-biphenyl]-3-yl)-2-cyanoprop-2-enthioamide (500 mg, 1.9 mmol) was dissolved in EtOH (5 mL) and stirred. Diethyl malonate (0.2 mL, 2.3 mmol) and KOH (158 mg, 2.8 mmol) were added to this solution. After stirring at 90°C for 16 hours, the reaction mixture was cooled to RT, the resulting precipitate was filtered, dried under vacuum, and a mixture of 4-([1,1'-biphenyl]-3-yl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl and 4-([1,1'-biphenyl]-3-yl)-5-cyano-6-mercapto-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate ethyl (1164) was obtained. MS:m / z:377.28, 375.23(MH) + ).

[0358] The following compounds were prepared by the same method.

[0359] A mixture of 5-cyano-6-mercapto-4-(3-(methyl(phenyl)carbamoyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl and 5-cyano-6-mercapto-4-(3-(methyl(phenyl)carbamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate ethyl (1165). MS data?

[0360] 5-Cyano-4-(3-cyclopropylphenyl)-6-mercapto-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate ethyl(1166). MS:m / z:341.38(MH) + ).

[0361] Preparation of 4'-formyl-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1167) [ka] 4'-Formyl-[1,1'-biphenyl]-4-carboxylic acid (1025) (3.2 g, 0.014 mol) was dissolved in DMF (32 mL) and stirred. HATU (8 g, 0.012 mol) and DIPEA (7.56 mL, 0.042 mol) were added to this solution. After stirring for 15 minutes, aniline (1.68 mL, 0.015 mol) was added. The mixture was stirred at 50°C for 16 hours and monitored by TLC. The reaction mixture was then acidified with 1N HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4'-Formyl-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1167) as a yellow liquid. MS: m / z: 302.27 (M+H + ).

[0362] Preparation of 4'-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1168) [ka] 4'-Formyl-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1167) (50 mg, 1.7 mmol) was dissolved in EtOH (10 mL) and stirred. To this solution, 2-ethyl cyanoethyl (0.17 mL, 1.7 mmol), 2-cyanoethanethioamide (166 mg, 1.66 mmol), and piperidine (0.32 mL, 3.3 mmol) were added. The mixture was heated at 90°C for 4 hours and monitored by LC-MS. The reaction mixture was then cooled to RT and volatiles were evaporated under reduced pressure. The residue was ground with diethyl ether and dried in vacuum to obtain 4'-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1168). MS:m / z:447.16(MH + ).

[0363] Preparation of 4-(4-chlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1169) [ka] 4-chlorobenzaldehyde (5 g, 0.035 mol) and 2-ethyl cyanoethyl (3.8 mL, 0.035 mol) were dissolved in EtOH (100 mL), to which urea (2.1 g, 0.035 mol) and K2CO3 (9.7 g, 0.07 mol) were added. After heating at 90 °C for 16 hours, the reaction mixture was cooled to RT, volatiles were evaporated under reduced pressure, the residue was diluted with water, and neutralized with AcOH (pH=4). The precipitate was collected and dried to obtain 4-(4-chlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1169). MS: m / z: 248.22 (M+H + ).

[0364] The following compounds were prepared by the same method.

[0365] 6-Hydroxy-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyrimidine-5-carbonitrile (1170). MS:m / z:280.23(MH) + ).

[0366] 6-Hydroxy-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1171). MS:m / z:244.19(M+H + ).

[0367] 4-(t-butyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1172). MS:m / z:194.22(M+H + ).

[0368] 4-(3,4-dichlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1173). MS: m / z: 280.20 (M+ ), 282.24(M+2H + ).

[0369] 4-(4-fluorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1174). MS: m / z: 230.17 (MH) + ).

[0370] 4-Cyclopropyl-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1175). MS:m / z:176.19(MH) + ).

[0371] 6-Hydroxy-2-oxo-4-(pyridine-3-yl)-1,2-dihydropyrimidine-5-carbonitrile (1176). MS:m / z:215.23(M+H + ).

[0372] 6-Hydroxy-2-oxo-4-(pyridine-4-yl)-1,2-dihydropyrimidine-5-carbonitrile (1177). MS:m / z:215.17(M+H + ).

[0373] 4-Cyclohexyl-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1178). MS: m / z: 220.25 (M+H + ).

[0374] 4-(3-chlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1179). MS:m / z:248.20(M+H + ).

[0375] Preparation of 4-(2,4-dichlorophenyl)-6-hydroxy-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile (1180) [ka] 2,4-Dichlorobenzaldehyde (2 g, 11.427 mmol) and 2-ethyl cyanoethyl (1.2 mL, 11.427 mmol) were dissolved in EtOH (50 mL) and stirred. Thiourea (869 mg, 11.427 mmol) and piperidine (2.1 mL) were added to this stirred solution. After stirring at 100°C for 16 hours, the reaction mixture was cooled to RT and volatiles were removed under reduced pressure. The residue was diluted with water and neutralized with AcOH (pH=4). The precipitate was filtered and dried to obtain 4-(2,4-dichlorophenyl)-6-hydroxy-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile (1180). MS: m / z: 298.07 (M + ), 300.07 (M+2H + ).

[0376] The following compounds were prepared by the same method.

[0377] 4-benzyl-6-hydroxy-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile (1181). MS:m / z:244.11(M+H + ).

[0378] 4-(2-chlorophenyl)-6-hydroxy-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile (1182). MS:m / z:264.16(M+H + ).

[0379] Preparation of 4-(2,4-dichlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1183) [ka] 4-(2,4-dichlorophenyl)-6-hydroxy-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile (1 g, 3.354 mmol) was dissolved in ACN (30 mL) and stirred. 1 M NaHCO3 (20 mL) and hydrogen peroxide (30%, 3 mL) were added. After stirring at RT for 16 hours, volatile matter was removed under reduced pressure. The residue was diluted with water and neutralized with 1 N HCl (pH=4). The precipitate was filtered and dried to obtain 4-(2,4-dichlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1183). MS: m / z: 282.16 (M + ), 284.16 (M+2H + ).

[0380] The following compounds were prepared by the same method.

[0381] 4-benzyl-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1184). MS:m / z:228.14(M+H + ).

[0382] 4-(2-chlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1185). MS:m / z:248.23(M+H + ).

[0383] Preparation of 4-(4-chlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1186) [ka] 4-(4-chlorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1 g, 4.0 mmol) was dissolved in 1,4-dioxane (10 mL) and stirred. To this stirred solution, phosphorus pentasulfide (2.7 g, 12 mmol) was added. After stirring at 110 °C for 3 hours, the reaction mixture was cooled to RT and filtered. The residue was purified by column chromatography to obtain 4-(4-chlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1186). MS: m / z: 262.13 (MH) + ).

[0384] The following compounds were prepared by the same method.

[0385] 6-Mercapto-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyrimidine-5-carbonitrile (1187). MS: m / z: 296.15 (MH) + ).

[0386] 6-Mercapto-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1188). MS:m / z:260.12(M+H + ).

[0387] 4-(t-butyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1189). MS:m / z:210.26(M+H + ).

[0388] 4-(3,4-dichlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1190). MS: m / z: 296.14 (M + ), 298.14 (M+2H + ).

[0389] 4-(4-fluorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1191). MS: m / z: 248.08 (M+H + ).

[0390] 4-(2,4-dichlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1192). MS:m / z:298.07(M + ), 300.12 (M+2H + ).

[0391] 4-Cyclopropyl-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1193). MS:m / z:194.13(M+H + ).

[0392] 6-Mercapto-2-oxo-4-(pyridine-3-yl)-1,2-dihydropyrimidine-5-carbonitrile (1194). MS:m / z:231.18(M+H + ).

[0393] 6-Mercapto-2-oxo-4-(pyridine-4-yl)-1,2-dihydropyrimidine-5-carbonitrile (1195). MS:m / z:231.20(M+H + ).

[0394] 4-Cyclohexyl-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1196). MS:m / z:236.28(M+H + ).

[0395] 4-(3-chlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1197). MS: m / z: 264.16 (M+H + ).

[0396] 4-Benzyl-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1198). MS: m / z: 244.19 (M+H + ).

[0397] 4-(2-chlorophenyl)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (1199). MS: m / z: 264.15 (M+H + ).

[0398] Preparation of 4,6-dichloro-2-methoxypyrimidine-5-carbonitrile (1200) [ka] 2,4,6-Trichloro-1,3,5-triazine (5 g, 24 mmol) was dissolved in MeOH (50 mL) and a stirred solution was prepared. Et3N (3.3 mL, 24 mmol) was added at 0°C. After stirring at RT for 6 hours, the reaction mixture was diluted with H2O and extracted with RINKAN. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography and 4,6-dichloro-2-methoxypyrimidine-5-carbonitride (MS: m / z: 204.13 (M+H) was obtained. + )) and 4,6-dichloro-2-methoxypyrimidine-5-carbonitrile (1200) were obtained as white solids. MS: m / z: 204.13 (M+H + ).

[0399] Preparation of 4-chloro-2-methoxy-6-(4-phenylpiperazin-1-yl)pyrimidine-5-carbonitrile (1201) [ka] 4,6-Dichloro-2-methoxypyrimidine-5-carbonitrile (100 mg, 0.49 mmol) was dissolved in THF (2.5 mL) and stirred. DIPEA (0.1 mL, 0.5 mmol) was added at -70°C. After stirring at -70°C for 15 minutes, 1-phenylpiperazine (0.07 mL, 0.5 mmol) was added. After heating to RT, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4-chloro-2-methoxy-6-(4-phenylpiperazine-1-yl)pyrimidine-5-carbonitrile (1201).1 H NMR (400MHz, DMSO-d6): δ7.24(t,J=8.0Hz,2H), 6.96(d,J=8.0Hz,2H), 6.81(t,J=7.6Hz,1H), 4.09-4.07(m,4H), 3.92(s,3H), 3.33-3.31(m,4H). MS:m / z:330.27(M+H + ).

[0400] The following compounds were prepared by the same method.

[0401] 4-Chloro-6-(3,4-dihydroquinoline-1(2H)-yl)-2-methoxypyrimidine-5-carbonitrile(1202). MS:m / z:301.23(M+H + ).

[0402] 4-(benzyl(methyl)amino)-6-chloro-2-methoxypyrimidine-5-carbonitrile(1203).

[0403] Preparation of 2-chloro-4-(3,4-dihydroquinoline-1(2H)-yl)-6-methoxypyrimidine-5-carbonitrile (1204) [ka] 2,4-Dichloro-6-methoxypyrimidine-5-carbonitrile (1 g, 4.9 mmol) was dissolved in THF (25 mL) and stirred. DIPEA (0.9 mL, 5.4 mmol) and 1,2,3,4-tetrahydroquinoline (0.61 mL, 4.9 mmol) were added at -70°C. After stirring at -70°C for 1 hour, the reaction mixture was diluted with H2O and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 2-chloro-4-(3,4-dihydroquinoline-1(2H)-yl)-6-methoxypyrimidine-5-carbonitrile (1204). MS: m / z: 301.22 (M+H + ).

[0404] The following compounds were prepared by the same method.

[0405] 2-Chloro-4-methoxy-6-(4-phenylpiperazin-1-yl)pyrimidine-5-carbonitrile (1205). MS: m / z: 330.27 (M+H + ).

[0406] 4-(4-acetylpiperazine-1-yl)-2-chloro-6-methoxypyrimidine-5-carbonitrile (1206). MS:m / z:296.21(M+H + ).

[0407] Preparation of 2-hydroxy-4-mercapto-6-(4-phenylpiperazin-1-yl)pyrimidine-5-carbonitrile (1207) [ka] 4-Chloro-2-methoxy-6-(4-phenylpiperazin-1-yl)pyrimidine-5-carbonitrile (120 mg, 0.364 mmol) was dissolved in DMF (1.2 mL) and stirred. NaSH (30 mg, 0.547 mmol) was added to the solution. After heating at 120 °C for 2 hours, the reaction product was diluted with water, acidified with 1 N HCl, and extracted with DCM. The organic layer was separated, dried over Na₂SO₄, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 2-hydroxy-4-mercapto-6-(4-phenylpiperazin-1-yl)pyrimidine-5-carbonitrile (1207). MS: m / z: 314.29 (M+H + ).

[0408] The following compounds were prepared by the same method.

[0409] 4-(3,4-dihydroquinoline-1(2H)-yl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile(1208). MS:m / z:285.24(M+H + ).

[0410] 2-Mercapto-6-oxo-4-(4-phenylpiperazin-1-yl)-1,6-dihydropyrimidine-5-carbonitrile (1209). MS:m / z:314.29(M+H + ).

[0411] 4-(3,4-dihydroquinoline-1(2H)-yl)-2-hydroxy-6-mercaptopyrimidine-5-carbonitrile(1210). MS:m / z:285.21(M+H + ).

[0412] 4-(4-acetylpiperazine-1-yl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile(1211). MS:m / z:280.21(M+H + ).

[0413] 4-(benzyl(methyl)amino)-6-mercapto-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(1212). MS:m / z:273.25(M+H + ).

[0414] Preparation of 6-hydroxy-4-(perfluoroethyl)pyrimidine-2(1H)-thion(1213) [ka] To a stirred solution of 4,4,5,5,5-ethyl pentafluoro-3-oxopentanate (10 g, 43 mmol) dissolved in EtOH (100 mL), 1 M NaOEt dissolved in EtOH (80 mL) and thiourea (6.4 g, 85 mmol) were added. After stirring at 90°C for 16 hours, the solvent was removed under vacuum. The residue was diluted with H2O and extracted with ELISA. The organic layer was dried over Na2SO4 and the solvent was removed under vacuum. The residue containing 6-hydroxy-4-(perfluoroethyl)pyrimidine-2(1H)-thion (1213) was used in the next step without further purification. MS: m / z: 247.08 (M+H + ).

[0415] Preparation of 6-hydroxy-4-(perfluoroethyl)pyrimidine-2(1H)-one (1214) [ka] 6-hydroxy-4-(perfluoroethyl)pyrimidine-2(1H)-thione (1213) (16 g, 65 mmol) was dissolved in H2O (160 mL) and stirred. Chloroacetic acid (7.7 mL, 130 mmol) was added to the solution. After stirring at 100 °C for 4 hours, the reaction mixture was cooled to 0 °C and concentrated hydrochloric acid (56 mL) was added. After stirring at 100 °C for 4 hours, the solvent was removed under vacuum to obtain 6-hydroxy-4-(perfluoroethyl)pyrimidine-2(1H)-one (1214), which was used without further purification. MS: m / z: 231.14 (M+H + ).

[0416] Preparation of 6-mercapto-4-(trifluoromethyl)pyrimidine-2(1H)-one (1215) [ka] 6-hydroxy-4-(trifluoromethyl)pyrimidine-2(1H)-one (5 g, 28 mmol) was dissolved in 1,4-dioxane (150 mL) and a stirred solution was prepared. P2S5 (18.49 g, 83.33 mmol) was added to this solution. After stirring at 110 °C for 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 6-mercapto-4-(trifluoromethyl)pyrimidine-2(1H)-one (1216). MS: m / z: 195.07 (MH) - ).

[0417] The following compounds were prepared by the same method.

[0418] 6-Mercapto-4-(perfluoroethyl)pyrimidine-2(1H)-one (1216). MS:m / z:247.15(M+H + ).

[0419] Preparation of 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one (1217) [ka] 6-mercapto-4-(trifluoromethyl)pyrimidine-2(1H)-one (2.3 g, 9.9 mmol) and 5-(chloromethyl)-1-(4-methoxybenzyl)-1H-tetrazole (2.79 g, 9.9 mmol) were dissolved in ACN (46 mL) and stirred. K2CO3 (3.23 g, 19.9 mmol) was added to the mixture. After stirring at RT for 16 hours, the reaction mixture was diluted with H2O and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one. 1 H NMR (400MHz, DMSO-d6): δ12.92(s,1H), 7.49(s,1H), 7.29(d,J=8.40Hz,2H), 6.92(t,J=8.80Hz,2H), 5.81(s,2H), 4.77(s,2H), 3.74(s,3H). MS:m / z:399.20(M+H + ).

[0420] The following compounds were prepared by the same method.

[0421] 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(perfluoroethyl)pyrimidine-2(1H)-one(1218). MS:m / z:449.27(M+H + ).

[0422] Preparation of 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one(1219) [ka] 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one (1217) (1 g, 2.5 mmol) was dissolved in ACN (30 mL) and stirred. NIS (565 mg, 2.5 mmol) and AIBN (82 mg, 0.50 mmol) were added to the mixture. After stirring at 80°C for 16 hours, the reaction mixture was diluted with H2O and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one (1219). 1 H NMR (400MHz, DMSO-d6): δ13.08(s,1H), 7.30(d,J=8.40Hz,2H), 6.92(t,J=8.40Hz,2H), 5.82(s,2H), 4.68(s,2H), 3.74(s,3H). MS:m / z:525.6(M+H + ).

[0423] The following compounds were prepared by the same method.

[0424] 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(perfluoroethyl)pyrimidine-2(1H)-one(1220). MS:m / z:575.15(M+H + ).

[0425] Preparation of 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(perfluoroethyl)-1,2-dihydropyrimidine-5-carbonitrile (1221) [ka] To a stirred solution of 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazol-5-yl)methyl)thio)-4-(perfluoroethyl)pyrimidin-2(1H)-one (500 mg, 0.871 mmol) dissolved in NMP (5 mL), CuI (82 mg, 0.355 mmol) was added. After stirring for 10 minutes, KCN (169 mg, 2.6132 mmol) was added. After stirring at 140°C for 16 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by column chromatography to afford 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazol-5-yl)methyl)thio)-4-(perfluoroethyl)pyrimidin-2(1H)-one (1221). MS: m / z: 474.30 (M+H + ) (1221).

[0426] Preparation of N-(carbamoylcarbamothioyl)-4-chlorobenzamide (1222)

Chemical formula

[0427] Preparation of 4-(4-chlorophenyl)-6-mercapto-1,3,5-triazin-2-ol (1223)

Chemical formula

[0428] Preparation of 3-(((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)methyl)methyl benzoate (1224) [ka] 4-Mercapto-6-phenyl-1,3,5-triazine-2-ol (1098) (250 mg, 1.2 mmol) was dissolved in CH3CN (5 mL) and stirred. K2CO3 (334 mg, 2.43 mmol) was added, followed by methyl 3-(bromomethyl)benzoate (111 mg, 0.485 mmol). After stirring for 16 hours, the reaction mixture was acidified with 1N HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was ground with diethyl ether (2 × 10 mL) to obtain methyl 3-(((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)methyl)benzoate. MS: m / z: 352.27 (MH) + ).

[0429] The following compounds were prepared by the same method.

[0430] 2-((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)methyl acetate (1225). MS:m / z:278.13(M+H + ).

[0431] Preparation of 2,4-dichloro-6-phenoxy-1,3,5-triazine (1226) [ka] 2,4,6-trichloro-1,3,5-triazine (10 g, 54 mmol) was dissolved in DCM (10 mL) and stirred. DIPEA (9.4 mL, 54 mmol) was added to the solution. After cooling to 0°C, phenol (5 g, 0.054 mol) was added. After stirring at 0°C for 1 hour, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 2,4-dichloro-6-phenoxy-1,3,5-triazine (1226). 1 H NMR (400MHz, CDCl3): δ7.47(t,J=8.00Hz,2H), 7.38(t,J=8.00Hz,2H), 7.19-7.17(m,1H).

[0432] The following compounds were prepared by the same method.

[0433] 2-(benzyloxy)-4,6-dichloro-1,3,5-triazine (1227). ¹H NMR (400 MHz, DMSO-d6): δ 7.42-7.38 (m, 5H), 5.52 (s, 2H).

[0434] Preparation of 2,4-dichloro-6-isopropoxy-1,3,5-triazine (1228) [ka] To a stirred solution of NaHCO3 (464 mg, 5.54 mmol) dissolved in iPA (20 mL), 2,4,6-trichloro-1,3,5-triazine (1 g, 5.4 mmol) was added at 0°C. After stirring at RT for 1 hour, the mixture was diluted with water (50 mL) and extracted with ₹ (2 × 50 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 2,4-dichloro-6-isopropoxy-1,3,5-triazine (1228).

[0435] Preparation of 2-chloro-4-methoxy-6-phenoxy-1,3,5-triazine (1229) [ka] 2,4-Dichloro-6-phenoxy-1,3,5-triazine (6 g, 24.89 mmol) was dissolved in THF (156 mL) and stirred. NaOMe (1.4 g, 27 mmol) and NaH (1.1 g, 28 mmol) were added at -30°C. After stirring at -30°C for 1 hour, the reaction mixture was diluted with H2O and extracted with ELISA. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 2-chloro-4-methoxy-6-phenoxy-1,3,5-triazine (1229). MS: m / z: 238.37 (M+H + ).

[0436] Preparation of 2-chloro-4-isopropoxy-6-methoxy-1,3,5-triazine (1230) [ka] To a stirred solution of NaOMe (286 mg, 5.3 mmol) dissolved in MeOH (1 mL), NaH (212 mg, 5.3 mmol) was added at -30°C. 2,4-Dichloro-6-isopropoxy-1,3,5-triazine (1 g, 4.8 mmol) dissolved in THF (26 mL) was added at -30°C. After stirring at -30°C for 45 minutes, the reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to give 2-chloro-4-isopropoxy-6-methoxy-1,3,5-triazine (1230). MS: m / z: 204.24 (M+H + ).

[0437] Preparation of 2-(benzyloxy)-4-chloro-6-methoxy-1,3,5-triazine (1231) [Chemical Formula] To a stirred solution of 2-(benzyloxy)-4,6-dichloro-1,3,5-triazine (1.7 g, 0.0066 mol) dissolved in MeOH (17 mL), 1,10-phenanthroline (1.32 g, 0.0073 mol) was added at RT. After stirring at 50°C for 1 hour, volatile matters were removed under reduced pressure. The residue was purified by column chromatography to give 2-(benzyloxy)-4-chloro-6-methoxy-1,3,5-triazine (1231). MS: m / z: 252.26 (M+H + ).

[0438] Preparation of N-benzyl-4-chloro-6-methoxy-N-methyl-1,3,5-triazin-2-amine (1232) [Chemical Formula] 2,4-Dichloro-6-methoxy-1,3,5-triazine (1.5 g, 8.3 mmol) was dissolved in acetone (30 mL) and stirred. N-methyl-1-phenylmethaneamine (1.18 mL, 9.2 mmol) was added at 0°C. After stirring at 0°C for 2 hours, the reaction mixture was diluted with water and extracted with siRNA. The organic layer was separated, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 4N-benzyl-4-chloro-6-methoxy-N-methyl-1,3,5-triazine-2-amine (1232). MS: m / z: 265.38 (M+H + ).

[0439] The following compounds were prepared by the same method.

[0440] 4-Chloro-6-methoxy-N-methyl-N-phenyl-1,3,5-triazine-2-amine(1233). MS:m / z:251.15(M+H + ).

[0441] 2-Chloro-4-methoxy-6-(pyrrolidine-1-yl)-1,3,5-triazine(1234). MS:m / z:215.14(M+H + ).

[0442] 4-Chloro-N-(4-chlorobenzyl)-6-methoxy-N-methyl-1,3,5-triazine-2-amine(1235). MS:m / z:299.36(M+H + ).

[0443] Preparation of 6-mercapto-4-phenoxy-1,3,5-triazine-2(1H)-one (1236) [ka] 2-Chloro-4-methoxy-6-phenoxy-1,3,5-triazine (1 g, 4.2 mmol) was dissolved in DMF (10 mL) and stirred. NaSH (354 mg, 6.3 mmol) was added to the solution. After heating at 120 °C for 2 hours, the reaction mixture was diluted with water (20 mL), acidified with 1 N HCl (pH=1), and extracted by DCM. The organic layer was separated, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain 6-mercapto-4-phenoxy-1,3,5-triazine-2(1H)-one (1236). MS: m / z: 220.24 (MH) + ).

[0444] The following compounds were prepared by the same method.

[0445] 4-Isopropoxy-6-mercapto-1,3,5-triazine-2-ol (1237). MS:m / z:188.17(M+H + ).

[0446] 4-(benzyloxy)-6-mercapto-1,3,5-triazine-2-ol (1238). MS:m / z:236.18(M+H + ).

[0447] 4-(benzyl(methyl)amino)-6-mercapto-1,3,5-triazine-2(1H)-one(1239). MS:m / z:249.43(M+H + ).

[0448] 6-Mercapto-4-(methyl(phenyl)amino)-1,3,5-triazine-2(1H)-one (1240). MS:m / z:235.22(M+H + ).

[0449] 6-Mercapto-4-(pyrrolidine-1-yl)-1,3,5-triazine-2(1H)-one(1241). MS:m / z:199.17(M+H + ).

[0450] 4-((4-chlorobenzyl)(methyl)amino)-6-mercapto-1,3,5-triazine-2(1H)-one(1242). MS:m / z:283.13(M+H + ).

[0451] Preparation of 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonitrile (1237) [ka] 5-iodo-6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-4-(trifluoromethyl)pyrimidine-2(1H)-one (1219) (1.1 g, 2.099 mmol) was dissolved in DMF (44 mL) and stirred. CuI (165 mg, 0.4198 mmol), CuCN (561 mg, 6.297 mmol), and PPh3 (165 mg, 0.4198 mmol) were added by RT. After stirring at 140 °C for 24 hours, the reaction mixture was diluted with H2O (50 mL) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonitrile (1237). MS:m / z:424.14(M+H + ).

[0452] Example 1: 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide(1) [ka] 3-(6-(((1H-tetrazole-5-yl)-methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1061) (60 mg, 0.169 mmol) was dissolved in DMF (2 mL) and stirred. Aniline (23 μL, 0.254 mmol), DIPEA (62 μL, 0.338 mmol), and HATU (96 mg, 0.254 mmol) were added by RT. After monitoring the reaction by TLC for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain compound 1. 1 H NMR (400MHz, DMSO-d6): δ10.35(s,1H), 8.13(s,1H), 8.08(d,J=7.60Hz,1H), 7.77-7.79(m,3H), 7 .69(t,J=8.00Hz,1H), 7.37(t,J=7.60Hz,2H), 7.12(t,J=6.80Hz,3H), 6.56(s,1H), 4.72(s,2H). MS:m / z:428.20(MH + ).

[0453] The following compounds were prepared by the same method.

[0454] 4-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide(2). 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H), 8.08(d,J=8.40Hz,2H), 7.80(d,J=8.40Hz,2H), 7.74 (d,J=8.40Hz,2H), 7.37(t,J=7.60Hz,2H), 7.12(t,J=7.60Hz,1H), 6.57(s,1H), 4.79(s,2H). MS:m / z:430.21(M+H + ).

[0455] 2-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide(3). 1 H NMR (400MHz, DMSO-d6): δ10.53(s,1H), 7.81-7.79(m,1H), 7.67-7.64(m,2H), 7.59(d,J=7.6Hz,2 H), 7.48-7.46(m,1H), 7.31(t,J=7.60Hz,2H), 7.08(t,J=7.20Hz,1H), 6.42(s,1H), 4.79(s,2H). MS:m / z:430.18(M+H + ).

[0456] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(pyrrolidine-1-carbonyl)phenyl)-1,6-dihydropyridine-3-carbonitrile(4). 1 H NMR (400MHz, DMSO-d6): δ7.65-7.56(m,4H), 6.39(s,1H), 4.66(s,2H), 3.49-3.41(m,4H), 1.89-1.80(m,4H). MS:m / z:408.20(M+H + ).

[0457] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(4-methoxyphenyl)benzamide(5). 1 H NMR (400MHz, DMSO-d6): δ10.23(s,1H), 8.12(s,1H), 8.06(d,J=8.0Hz,1H), 7.78(d,J=8.0 Hz,1H), 7.69-7.65(m,3H), 6.94(d,J=8.80Hz,1H), 6.50(s,1H), 4.68(s,2H), 3.75(s,3H). MS:m / z:460.21(M+H + ).

[0458] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(4-chlorophenyl)benzamide(6).1 H NMR (400MHz, DMSO-d6): δ10.47(s,1H), 8.13-8.09(m,2H), 7.86-7.80(m,3H), 7.74-7.65(m,1H), 7.44(d,J=9.2Hz,2H), 6.69(s,1H), 4.86(s,2H). MS:m / z:462.18(MH + ).

[0459] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(pyridine-3-yl)benzamide(7). 1 H NMR (400MHz, DMSO-d6): δ10.55(s,1H), 8.93(s,1H), 8.34-8.33(m,1H), 8.21-8.12(m,3H) ), 7.86-7.84(m,1H), 7.73(t,J=8.0Hz,1H), 7.44-7.40(m,1H), 6.68(s,1H), 7.84(s,2H). MS:m / z:431.25(M+H + ).

[0460] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(2-methoxyethyl)benzamide(8). 1 H NMR (400MHz, DMSO-d6): δ8.68(m,1H), 8.04-7.99(m,2H), 7.76(d,J=7.60Hz,1H), 7.64(d,J=8.0Hz,1H), 6.66(s,1H), 4.86(s,2H), 3.46-.344(m,4H), 3.27(s,3H). MS:m / z:412.20(M+H + ).

[0461] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-cyclopropylbenzamide(9). 1H NMR(400MHz,DMSO-d6):δ12.37(br s,1H), 8.57-8.56(m,1H), 8.10-8.08(m,1H), 7.74(d,J=7.60Hz,1H), 7.62(t,J=7.20Hz, 1H), 6.65(s,1H), 4.86(s,2H), 2.88-2.85(m,1H), 0.74-0.69(m,2H), 0.59-0.55(m,2H). MS:m / z:394.25(M+H + ).

[0462] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(4-(trifluoromethyl)phenyl)benzamide(10). 1 H NMR (400MHz, DMSO-d6): δ8.12-8.08(m,2H), 7.99(d,J=8.40Hz,2H), 7.82-7.69(m,4H), 6.51(s,1H), 4.68(s,2H). MS:m / z:498.08(M+H + ).

[0463] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(2,2,2-trifluoroethyl)benzamide(11). 1 H NMR (400MHz, DMSO-d6): δ9.24(t,J=6.00Hz,2H), 8.09-8.04(m,2H), 7.82(d,J=7 .60Hz,1H), 7.68(t,J=8.00Hz,1H), 6.67(s,1H), 4.86(s,2H), 4.18-4.09(m,2H). MS:m / z:436.15(M+H + ).

[0464] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-methyl-N-phenylbenzamide(12). 1H NMR (400MHz, DMSO-d6): δ7.48-7.47(m,1H), 7.41(br s,1H), 7.36-7.35(m,2H), 7.29-7.25(m,2H), 7.22-7.15(m,3H), 6.13(s,1H), 4.71(s,2H), 3.40(s,3H). MS:m / z:444.27(M+H + ).

[0465] 3-(6-((3-(1H-tetrazole-5-yl)benzyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide (13). 1 H NMR (400MHz, DMSO-d6): δ10.32(s,1H), 8.18-8.08(m,3H), 7.93-7.91(m,1H), 7.82-7.69(m,5 H), 7.58(t,J=7.6Hz,1H), 7.38(t,J=8.0Hz,2H), 7.14-7.10(m,1H), 6.67(s,1H), 4.68(s,2H). MS:m / z:506.14(M+H + ).

[0466] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide (14). 1 H NMR (400MHz, DMSO-d6): δ10.33(s,1H), 8.08(d,J=7.20Hz,1H), 8.03(s,1H), 7.79(d,J=8.0Hz,2H), 7.70-7.64(m,2H), 7.36(t,J=8.0Hz,2H), 7.21(s,1H), 7.13-7.10(m,2H), 6.95(s,1H), 4.71(s,2H). MS:m / z:455.25(M+H + ).

[0467] Example 2: 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-(4-methylpiperazine-1-carbonyl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(15) [ka] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1061) (100 mg, 0.28 mmol) was dissolved in DMF (1.0 mL), to which EDC:HCl (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), and DIPEA (0.10 mL, 0.56 mmol) were added. After stirring for 15 minutes, 1-methylpiperazine (37 μL, 0.34 mmol) was added. After stirring for 16 hours and monitoring by TLC, the reaction mixture was diluted with H2O, acidified with 1N HCl (pH approximately 1), and extracted with DCM. The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by prep HPLC, the appropriate fractions were mixed, and the mixture was freeze-dried to obtain compound 15. 1 H NMR (400MHz, DMSO-d6): δ7.72-7.61(m,4H), 6.63(s,1H), 4.86(s,2H), 3.41(br s,4H), 3.28(br s,4H), 2.83(s,3H). MS:m / z:437.46(M+H + ).

[0468] The following compounds were prepared by the same method.

[0469] 2-((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl acetate (59). MS:m / z:418.32(MH) + ).

[0470] Example 3: 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-(2-(dimethylamino)ethyl)benzamide(16) [ka] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (1061) (100 mg, 0.28 mmol) dissolved in ethyl acetate (1.0 mL) was mixed with T3P (16 μL, 0.85 mmol) and DIPEA (0.15 mL, 0.85 mmol). After stirring for 15 minutes, N 1 ,N 1 -Dimethylethane-1,2-diamine (34 mg, 0.34 mmol) was added. The mixture was stirred at RT for 16 hours, and the progress was monitored by TLC. The reaction mixture was then diluted with H2O, acidified with 1N HCl (pH approximately 1), and extracted with DCM. The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain compound 16. 1 H NMR(400MHz,DMSO-d6):δ9.35(br s,1H), 8.83(m,1H), 8.03-8.02(m,2H), 7.80(d,J=8.0Hz,1H), 7.68(t,J=8.0Hz,1 H), 6.63(s,1H), 4.86(s,2H), 3.64-3.63(m,2H), 3.29-3.28(m,2H), 2.85(s,6H). MS:m / z:425.30(M+H + ).

[0471] Example 4: 3-(2-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-6-oxo-1,6-dihydropyrimidine-4-yl)-N-phenylbenzamide(17) [ka] 3-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidine-4-yl)-N-phenylbenzamide (1092) (300 mg, 0.86 mmol) was dissolved in DMSO (6 mL) and stirred. DIPEA (0.4 mL, 2.6 mmol) was added, followed by 5-(chloromethyl)-1H-tetrazole (81.3 mg, 0.689 mmol). After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, appropriate fractions were mixed, and freeze-dried to obtain compound (17). 1 H NMR (400MHz, DMSO-d6): δ10.34(s,1H), 8.31-8.29(m,1H), 8.04(d,J=7.6Hz,1H), 7.93(d,J=7.6Hz,1H), 7.79(d,J=8.0Hz,2H), 7.62(t,J=7.6Hz,1H), 7.36(t,J=7.6Hz,2H), 7.11(t,J=7.2Hz,1H), 4.57(s,2H). MS:m / z:431.35(M+H + ).

[0472] The following compounds were prepared by the same method.

[0473] 4'-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide(18). 1 H NMR (400MHz, DMSO-d6): δ7.89(d,J=8.4Hz,2H), 7.85(d,J=8.0Hz,2H), 7.67(d,J=8.0Hz,2H), 7.54(d,J=8.4Hz,2H), 5.15(s,2H), 3.01-2.97(m,6H). MS:m / z:483.22(M+H + ).

[0474] Example 5: 2-(3-(((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl)phenyl)acetic acid (19) [ka] 2-(3-(((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl)phenyl)methyl acetate (60) (150 mg, 0.295 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (4 mL) and a stirred solution was prepared. LiOH·H2O (37 mg, 0.88 mmol) was added by RT. The mixture was stirred for 2 hours, and the progress was monitored by TLC. After removing volatiles under reduced pressure, the residue was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and volatiles were evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain compound 19. 1 H NMR (400MHz, DMSO-d6): δ10.32(s,1H), 8.08(s,1H), 8.02(d,J=7.6Hz,1H), 7.76-7.72(m,3H), 7.63(t,J=7.6 Hz,1H), 7.38-7.34(m,4H), 7.25(t,J=7.2Hz,1H), 7.15-7.09(m,2H), 6.23(s,1H), 4.46(s,2H), 3.54(s,2H). MS:m / z:496.29(M+H + ).

[0475] The following compounds were prepared by the same method.

[0476] 2-((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)acetic acid (20). 1H NMR(400MHz,DMSO-d6):δ12.58(br s,2H), 10.35(s,1H), 8.14-8.09(m,2H), 7.84-7.69(m,4H), 7.37(t,J=7.6Hz,2H), 7.12(t,J=7.2Hz,1H), 6.64(s,1H), 4.15(s,2H). MS:m / z:406.27(M+H + ).

[0477] 3-(((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl)benzoic acid (21). 1 H NMR(400MHz,DMSO-d6):δ12.78(br s,2H), 10.33(s,1H), 8.14-8.06(m,3H), 7.85-7.76(m,5H), 7.68(t,J=8.0Hz,1H), 7.46( t,J=8.0Hz,1H), 7.37(t,J=8.0Hz,2H), 7.12(t,J=7.2Hz,1H), 6.61(s,1H), 4.63(s,2H). MS:m / z:482.28(M+H + ).

[0478] 2-(3-(((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl)phenyl)methyl acetate (60):MS:m / z:510.24(M+H + ).

[0479] 3-(((3-cyano-6-oxo-4-(3-(phenylcarbamoyl)phenyl)-1,6-dihydropyridine-2-yl)thio)methyl)ethyl benzoate (61).

[0480] Example 6: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(22) [ka] To a stirred solution of 4-([1,1'-biphenyl]-4-yl)-6-mercapto-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1068) (300 mg, 0.911 mmol) dissolved in CH3CN (6 mL), K2CO3 (251 mg, 1.82 mmol) was added, followed by 5-(chloromethyl)-1H-tetrazole (65 mg, 0.546 mmol) at RT, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was acidified with 1N HCl (pH approx. 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were combined and lyophilized to give the target compound. 1 1H NMR (400 MHz, DMSO-d6): δ 7.9 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.6 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.52 (t, J=7.6 Hz, 2H), 7.43 (t, J=6.4 Hz, 1H), 4.88 (s, 2H). MS: m / z: 410.24 (M-H + ).

[0481] The following compounds were prepared in a similar manner.

[0482] 6-(((1H-tetrazol-5-yl)methyl)thio)-4-([1,1'-biphenyl]-2-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (23). 1 1H NMR (400 MHz, DMSO-d6): δ 7.52 (t, J=10.80 Hz, 1H), 1.00 (t, J=7.20 Hz, 1H), 7.42 (d, J=7.60 Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (d, J=7.20 Hz, 2H), 4.67 (d, J=15.20 Hz, 1H), 4.53 (d, J=14.80 Hz, 1H). MS: m / z: 410.20 (M-H + ).

[0483] 6-(((1H-tetrazol-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (24). 1H NMR (400MHz, DMSO-d6): δ7.79-7.71(m,4H), 7.59(t,J=7.6Hz,1H), 7.51-7.38(m,4H), 4.61(s,2H). MS:m / z:411.77(M+H + ).

[0484] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydropyridine-3,5-dicarbonitride(25). 1 H NMR (400MHz, DMSO-d6): δ7.99 (d, J = 8.0 Hz, 2H), 7.89-7.84 (m, 4H), 7.56 (d, J = 8.4Hz, 2H), 4.41 (s, 2H). MS:m / z:478.20(MH + ).

[0485] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(26). 1 H NMR (400MHz, DMSO-d6): δ7.75(d,J=8.4Hz,2H), 7.71(d,J=8.8Hz,2H), 7.48(d,J=8.4Hz,2H), 7.06(d,J=8.8Hz,2H), 4.62(s,2H), 3.81(s,3H). MS:m / z:442.18(M+H + ).

[0486] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (27). 1 H NMR (400MHz, DMSO-d6): δ7.82-7.79(m,4H), 7.56-7.51(m,4H), 4.41(s,2H). MS:m / z:444.20(MH + ).

[0487] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (28). 1 H NMR (400MHz, DMSO-d6): δ7.61-7.42 (m, 8H), 4.60 (s, 2H). MS:m / z:446.08(M+H + ).

[0488] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-nitro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (29). 1 H NMR (400MHz, DMSO-d6): δ8.33(d,J=8.8Hz,2H), 8.07(d,J=8.4Hz,2H), 7.94(d,J=8.0Hz,2H), 7.59(d,J=8.0Hz,2H), 4.56(s,2H). MS:m / z:457.19(M+H + ).

[0489] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-chloro-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(30). 1 H NMR (400MHz, DMSO-d6): δ8.51(s,1H), 7.76-7.73(m,4H), 7.59-7.53(m,3H), 7.45(m,1H), 4.41(s,2H). MS:m / z:444.16(MH + ).

[0490] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(31). 1H NMR (400MHz, DMSO-d6): δ7.71(d,J=8.4Hz,4H), 7.62(d,J=8.8Hz,2H), 6.83(d,J=8.4Hz,2H), 4.66(s,2H), 2.96(s,6H). MS:m / z:455.29(M+H + ).

[0491] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(32). 1 H NMR (400MHz, DMSO-d6): δ7.70(d,J=8.0Hz,2H), 7.61(d,J=8.4Hz,2H), 7.42(d,J =8.4Hz,2H), 6.64(d,J=8.8Hz,2H), 4.59(s,2H), 3.34-3.29(m,4H), 1.97(m,4H). MS:m / z:481.25(M+H + ).

[0492] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-1,2-dihydropyridine-3,5-dicarbonitride(33). 1 H NMR (400MHz, DMSO-d6): δ7.95-7.81(m,5H), 7.67(t,J=8.0Hz,1H), 7.51(d,J=8.0Hz,1H), 4.66(s,2H). MS:m / z:480.23(M+H + ).

[0493] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(34). 1H NMR (400MHz, DMSO-d6): δ7.73(d,J=8.0Hz,1H), 7.67-7.65(m,3H), 7.55(t,J=7. 6Hz,1H), 7.37(d,J=8.0Hz,1H), 7.05(d,J=8.8Hz,2H), 4.65(s,2H), 3.81(s,3H). MS:m / z:442.01(M+H + ).

[0494] 4-(4-(1H-pyrazole-1-yl)phenyl)-6-(((1H-tetrazol-5-yl)methyl)thio)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(35). 1 H NMR (400MHz, DMSO-d6): δ8.56-8.55(m,1H), 7.95(d,J=8.0Hz,2H), 7.79(s,1H), 7.55(d,J=8.8Hz,2H), 6.58(s,1H), 4.59(s,2H). MS:m / z:402.20(M+H + ).

[0495] 4'-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)-[1,1'-biphenyl]-4-carboxylate methyl(36). 1 H NMR (400MHz, DMSO-d6): δ8.07(d,J=8.0Hz,2H), 7.95-7.89(m,4H), 7.56(d,J=7.6Hz,2H), 4.66(s,2H), 3.89(s,3H). MS:m / z:470.22(M+H + ).

[0496] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4-(pyridine-3-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitrile (37). 1H NMR (400MHz, DMSO-d6): δ8.99-8.98(m,1H), 8.61-8.60(m,1H), 8.18(d,J=8.0Hz ,1H), 7.88(d,J=8.4Hz,2H), 7.56-7.51(m,3H0,4.41(s,2H).MS:m / z:413.18(M+H + ).

[0497] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4-(pyrimidine-2-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitride(38). 1 H NMR (400MHz, DMSO-d6): δ8.96(d,J=4.8Hz,2H), 8.48(d,J=8.4Hz,2H), 7.58(d,J=7.6Hz,2H), 7.50(t,J=4.8Hz,1H), 4.66(s ,2H), 8.61-8.60(m,1H), 8.18(d,J=8.0Hz,1H), 7.88(d,J=8.4Hz,2H), 7.56-7.51(m,3H0,4.41(s,2H).MS:m / z:414.21(M+H) + ).

[0498] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (39). 1 H NMR (400MHz, DMSO-d6): δ8.00-7.95(m,4H), 7.90(d,J=8.4Hz,2H), 7.56(d,J=8.4Hz,2H), 4.59(s,2H). MS:m / z:437.19(M+H + ).

[0499] 2'-(((1H-tetrazole-5-yl)methyl)thio)-6'-oxo-6-phenyl-1',6'-dihydro-[3,4'-bipyridine]-3'-carbonitrile(40). 1H NMR (400MHz, DMSO-d6): δ8.88(s,1H), 8.19-8.15(m,4H), 7.56-7.49(m,3H), 6.72(s,1H), 4.85(s,2H). MS:m / z:388.32(M+H + ).

[0500] Example 7: 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (41) [ka] 4-([1,1'-biphenyl]-3-yl)-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile (1089) (200 mg, 0.66 mmol) was dissolved in DMSO (1 mL) and stirred. DIPEA (0.2 mL, 1.31 mmol) was added, followed by 5-(chloromethyl)-1H-tetrazole (62 mg, 0.525 mmol) by RT. The reaction mixture was stirred by RT for 16 hours and monitored by TLC. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, appropriate fractions were mixed, and freeze-dried to obtain compound 41. 1 H NMR (400MHz, DMSO-d6): δ7.88(s,1H), 7.84(d,J=7.2Hz,1H), 7.48(d,J=7.6Hz,2H), 7 .66-7.58(m,2H), 7.50(t,J=7.6Hz,2H), 7.43-7.39(m,1H), 6.71(s,1H), 4.86(s,2H). MS:m / z:387.19(M+H + ).

[0501] The following compounds were prepared by the same method.

[0502] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-cyclopropylphenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(42). 1H NMR (400MHz, DMSO-d6): δ7.40(t,J=8.0Hz,1H), 7.33-7.24(m,3H), 6.57(s, 1H), 4.84(s,2H), 2.00-1.98(m,1H), 1.00-0.97(m,2H), 0.77-0.75(m,2H). MS:m / z:351.25(M+H + ).

[0503] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (43). 1 H NMR(400MHz,DMSO-d6):δ12.2(br s,1H), 7.80(d,J=7.6Hz,1H), 7.72(d,J=7.2Hz,2H), 7.64-7.60(m,2H), 7.49(t,J=7.2Hz,2H), 7.41-7.33(m,2H), 4.85(s,2H), 1.92(s,3H). MS:m / z:401.21(M+H + ).

[0504] Example 8: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride (44) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1091) (150 mg, 0.325 mmol) and (4-methylphenyl)boronic acid (53 mg, 0.390 mmol) were dissolved in THF (1.5 mL) and K2CO3 (131 mg, 0.971 mmol) was added to the stirred solution. The reaction mixture was degassed under an N2 atmosphere and Pd(dtbpf)Cl2 (21 mg, 0.032 mmol) was added by RT. The reaction mixture was stirred at 90°C for 2 hours, and completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain compound 44. 1 H NMR (400MHz, DMSO-d6): δ7.79 (d, J = 8.40 Hz, 2H), 7.68-7.64 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H). 4.66(s,2H), 2.36(s,3H). MS:m / z:424.21(MH + ).

[0505] The following compounds were prepared by the same method.

[0506] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(3'-cyclopropyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(45). 1 H NMR (400MHz, DMSO-d6): δ7.80(d,J=8.40Hz,2H), 7.53-7.49(m,3H), 7.41-7.39(m,2H), 7.12(d,J=7.6Hz,2H), 4.60(s,2H), 2.02(m,1H), 1.02-0.99(m,2H), 0.79-0.77(m,2H). MS:m / z:452.27(M+H + ).

[0507] Example 9: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-amino-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (46) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-nitro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (29) (100 mg, 0.22 mmol) was dissolved in MeOH (2 mL) and THF (0.5 mL) and stirred. 10% Pd-C (100 mg) was added to this solution. After stirring under an H2 atmosphere for 16 hours, the reaction mixture was filtered through Celite, washed with MeOH (30 mL), and the solvent was evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain compound 46. 1 H NMR (400MHz, DMSO-d6): δ7.65 (d, J = 8.0 Hz, 2H), 7.46-7.40 (m, 4H), 6.66 (d, J = 8.4Hz, 2H), 4.66 (s, 2H). MS:m / z:427.24(M+H + ).

[0508] Example 10: N-(4'-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide(47) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-amino-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (46) (130 mg, 0.305 mmol) was dissolved in DCM (1.3 mL) and stirred. Et3N (0.1, 1.58 mmol) and acetyl chloride (149 mg, 1.264 mmol) were added to the mixture. After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain compound 47. 1 H NMR (400MHz, DMSO-d6): δ10.1(s,1H), 8.16(s,1H), 7.78-7.70(m,6H), 7.49-7.48(m,2H), 4.50(s,2H), 2.08(s,3H). MS:m / z:469.29(M+H + ).

[0509] Example 11: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-bromo-6-oxo-1,6-dihydropyridine-3-carbonitrile (48) [ka] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (41) (150 mg, 0.388 mmol) was dissolved in DMF (1.5 mL) and stirred. NBS (171 mg, 0.971 mmol) was added to this solution. The mixture was stirred at 50 °C for 16 hours, and the reaction progress was monitored by TLC. The reaction product was then diluted with water (50 mL), acidified with 1N HCl (pH approximately 1), and extracted with 10% MeOH:DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC and freeze-dried to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-bromo-6-oxo-1,6-dihydropyridine-3-carbonitrile (48). 1 H NMR (400MHz, DMSO-d6): δ7.83(d,J=8.0Hz,1H), 7.72(d,J=7.6Hz,3H), 7.64(t,J=8.0Hz,1H), 7.50(t,J=7.2Hz,2H), 7.40(t,J=7.2Hz,2H), 4.88(s,2H). MS:m / z:465.17(M + ), 467.18 (M+2) + .

[0510] Example 12: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carbonitrile (49) [ka] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (41) (150 mg, 0.388 mmol) was dissolved in AcCN (3 mL) and stirred. NCS (56 mg, 0.423 mmol) and AIBN (13 mg, 0.077 mmol) were added to this solution. The mixture was stirred at 50 °C for 16 hours, and the progress was monitored by TLC. The reaction product was then diluted with water, acidified with 1 N HCl (pH=1), and extracted with 10% MeOH:DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC and freeze-dried to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carbonitrile (49). 1 H NMR (400MHz, DMSO-d6): δ7.71(t,J=7.6Hz,3H), 7.58-7.54(m,2H), 7.48(t,J=7.6Hz,2H), 7.39(d,J=7.2Hz,1H), 7.31(d,J=7.6Hz,1H), 4.66(s,2H). MS:m / z:421.17(M+H + ).

[0511] Example 13: 4-(((1H-tetrazole-5-yl)methyl)thio)-6-phenyl-1,3,5-triazine-2(1H)-one(50) [ka] 4-Mercapto-6-phenyl-1,3,5-triazine-2-ol (1098) (100 mg, 0.48 mmol) was dissolved in ACN (5 mL) and stirred. 5-(chloromethyl)-1H-tetrazole (28 mg, 0.24 mmol) and K2CO3 (134 mg, 0.97 mmol) were added to this solution. The mixture was stirred for 2 hours, and the reaction was confirmed complete by TLC. The reaction product was then diluted with water (20 mL), acidified with 1 N HCl (pH approximately 1), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain compound 50. 1 H NMR (400MHz, DMSO-d6): δ8.17 (d, J = 7.20 Hz, 2H), 7.70 (t, J = 7.60 Hz, 1H), 7.57 (t, J = 7.60 Hz, 2H), 4.73 (s, 2H). MS:m / z:288.15(M+H + ). Example 14: 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile(51) [ka] 6-Mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096) (180 mg, 0.79 mmol) was dissolved in CH3CN (1.8 mL) and stirred. K2CO3 (325 mg, 2.35 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (111 mg, 0.943 mmol). After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, appropriate fractions were mixed, and freeze-dried to obtain the target compound. 1 H NMR (400MHz, DMSO-d6): δ7.74(d,J=7.2Hz,2H), 7.70-7.59(m,3H), 4.79(s,2H). MS:m / z:312.13(M+H + ).

[0512] The following compounds were prepared by the same method.

[0513] 6-((3-(1H-tetrazole-5-yl)benzyl)thio)-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile(52). 1 H NMR (400MHz, DMSO-d6): δ8.14 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.74-7.57 (m, 7H), 4.62 (s, 2H). MS:m / z:388.20(M+H + ).

[0514] Example 15: 3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)methyl benzoate (62) [ka] 6-mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096) (250 mg, 1.09 mmol) was dissolved in CH3CN (2.5 mL) and stirred. K2CO3 (301 mg, 2.18 mmol) was added, followed by methyl 3-(bromomethyl)benzoate (125 mg, 0.546 mmol). After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH approximately 1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain methyl 3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)benzoate (62). MS: m / z: 376.30 (M+H + ).

[0515] Example 16: 3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)benzoic acid (53) [ka] 3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)methyl benzoate (62) (300 mg, 0.767 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (6 mL) and LiOH·H2O (96 mg, 2.301 mmol) was added to the stirred solution. The mixture was stirred at RT for 2 hours, and the progress was monitored by TLC. After removing volatiles under reduced pressure, the residue was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain compound 53. 1 H NMR (400MHz, DMSO-d6): δ8.01(s,1H), 7.83(d,J=8.0Hz,1H), 7.72-7.70(m,3H), 7.54-7.46(m,4H), 4.53(s,2H). MS:m / z:364.22(M+H + ).

[0516] Example 17: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl(54) [ka] 4-(4-chlorophenyl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (1099) (320 mg, 0.95 mmol) was dissolved in DMSO (6.4 mL) and 5-(chloromethyl)-1H-tetrazole (56 mg, 0.47 mmol) and DIPEA (0.2 mL, 1.14 mmol) were added to the stirred solution. The mixture was stirred at RT for 4 hours and monitored by TLC. The reaction mixture was then diluted with water (50 mL), acidified with 1N HCl (pH approximately 1), and extracted with ethyl The residue was purified by prep HPLC and freeze-dried to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (54). 1 H NMR 400MHz, DMSO-d6: δ7.60(d,J=8.40Hz,2H), 7.41(d,J=8.00Hz,2H), 4.88(s,2H), 3.99(q,J=6.80Hz,2H), 0.90(t,J=7.20Hz,3H). MS:m / z:417.12(M+H + ).

[0517] Example 18: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (54) (200 mg, 0.48 mmol) was dissolved in 4 mL of THF:MeOH (1:1) and 2 M NaOH (4.8 mL, 9.65 mmol) was added to the stirred solution. The reaction mixture was stirred at 50°C for 36 hours and monitored by TLC. The solvent was removed under vacuum, the residue was diluted with water (50 mL), acidified with 1 N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC and freeze-dried to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55). 1 H NMR 400MHz, DMSO-d6: δ7.55(d,J=8.40Hz,2H), 7.37(d,J=8.40Hz,2H), 4.85(s,2H). MS:m / z:388.72(M+H + ).

[0518] Example 19: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-N,N-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide (56) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55) (200 mg, 0.51 mmol) was dissolved in DMF (3.5 mL) and stirred. EDC:HCl (148 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol), and DIPEA (0.26 mL, 1.5 mmol) were added by RT. After stirring for 30 minutes, dimethylamine (2 M in THF, 0.33 mL, 0.62 mmol) was added. The mixture was stirred for 16 hours and monitored by TLC. The reaction product was then diluted with water (20 mL), acidified with 1N HCl (pH approximately 1), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep HPLC and freeze-dried to obtain the target compound (56). 1 H NMR 400MHz, DMSO-d6: δ7.56(d,J=8.40Hz,2H), 7.39(d,J=8.40Hz,2H), 4.91-4.81(m,2H), 2.75(m,6H). MS:m / z:416.15(M+H + ).

[0519] Example 20: 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(57) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (54) (300 mg, 0.72 mmol) was dissolved in THF (4 mL) and LiAlH4 (1 M in THF, 1.44 mL, 1.44 mmol) was added at 0°C. The mixture was heated to ambient temperature, stirred for 2 hours, monitored by TLC, and then cooled to 0°C and quenched with aqueous Na2SO4 paste. The solid was removed by filtration, the organic layer was separated and dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by prep HPLC and lyophilized to obtain compound 57. 1 H NMR 400MHz, DMSO-d6: δ7.59(d,J=8.40Hz,2H), 7.46(d,J=8.0Hz,2H), 4.86(s,2H), 4.09(s,2H). MS:m / z:375.04(M+H + ).

[0520] Example 21: 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxamide (58) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55) (200 mg, 0.514 mmol) was dissolved in DMF (2 mL) and stirred. HATU (587 mg, 1.546 mmol), NH4Cl (40 mg, 0.773 mmol), and DIPEA (0.53 mL, 3.09 mmol) were added to the solution. The mixture was stirred at RT for 16 hours and monitored by TLC. The reaction product was then diluted with water (20 mL), acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by prep HPLC and lyophilized to obtain compound 58. 1H NMR 400MHz, DMSO-d6: δ7.43(d,J=8.4Hz,2H), 7.25(d,J=8.4Hz,2H), 4.60(m,2H). MS:m / z:386.23(MH + ).

[0521] Example 22: Preparation of tert-butyl-4-(3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (63) [ka] t-butyl-4-(3-(5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (1158) (1.5 g, 3.6 mmol) and 5-(chloromethyl)-1H-tetrazole (214 mg, 1.82 mmol) were dissolved in ACN (30 mL) and K2CO3 (1 g, 17 mmol) was added to the stirred solution. After stirring at RT for 16 hours, volatile matter was removed under reduced pressure. The residue was acidified with citric acid and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4-(3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (63). MS: m / z: 495.37 (M+H + ).

[0522] Example 23: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(piperazin-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (64) [ka] t-butyl-4-(3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylic acid (63) (500 mg, 1.0 mmol) was dissolved in DCM (5 mL) and stirred. 4N HCl dissolved in 1,4-dioxane (2.5 mL) was added at 0°C. After stirring at RT for 16 hours, volatile matter was removed under reduced pressure. The residue was washed with diethyl ether and dried under reduced pressure to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(piperazine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (64). MS: m / z: 395.58 (M+H + ).

[0523] Example 24: Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)ethyl benzoate (65) [ka] Ethyl 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoate (1057,700 mg, 1.9 mmol) was dissolved in ACN (21 mL) and stirred. NCS (276 mg, 2.07 mmol) and AIBN (62 mg, 0.38 mmol) were added to this solution. The mixture was stirred at 50°C for 16 hours and monitored by TLC. The reaction mixture was then diluted with water, acidified with 1N HCl (pH=1), and extracted with 10% MeOH:DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and lyophilized to obtain 2-ethyl 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (65). MS:m / z:417.35(M+H + ).

[0524] Example 25: Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (130) [ka] 500 mg, 1.25 mmol of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)ethyl benzoate (64) (64) was dissolved in 15 mL of MeOH:THF:H2O (1:1:1), to which LiOH·H2O (157 mg, 1.25 mmol) was added. The mixture was stirred for 2 hours, monitored by TLC, and then volatile matter was removed under reduced pressure. The residue was diluted with H2O, acidified with 1N HCl (pH=1), and extracted by DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (130). MS: m / z: 387.22 (M+H + ).

[0525] Example 26: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-(4-methylpiperazine-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (66) [ka] 6-mercapto-4-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1145) (300 mg, 0.86 mmol) was dissolved in DMSO (3 mL) and stirred. K2CO3 (235 mg, 1.71 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (60 mg, 0.51 mmol). After stirring at RT for 16 hours, the reaction mixture was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (66). 1 H NMR (400MHz, DMSO-d6): δ7.35(d,J=8.8Hz,2H), 7.09(d,J=8.4Hz,2H), 4.87(s,2H), 3.84-3.80(m,2H), 3.65-3.51(m,6H), 3.05(s,3H). MS:m / z:434.29(M+H + ).

[0526] The following compounds were prepared by the same method.

[0527] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(4-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile(67). 1 H NMR (400MHz, DMSO-d6): δ7.82(d,J=8.8Hz,2H), 7.61(d,J=8.4Hz,2H), 6.46(s, 1H), 4.72(s,2H), 3.89(t,J=6.8Hz,2H), 2.55-2.53(m,2H), 2.10-2.07(m,2H). MS:m / z:394.27(M+H + ).

[0528] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4-(2-oxopyrrolidine-1-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitride(68). 1H NMR (400MHz, DMSO-d6): δ7.78(d,J=8.4Hz,2H), 7.42(d,J=8.4Hz,2H), 6.64(d,J=8. 8Hz,2H), 4.51(s,2H), 3.89(t,J=6.8Hz,2H), 2.55-2.53(m,2H), 2.11-2.06(m,2H). MS:m / z:419.39(M+H + ).

[0529] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4-(pyrrolidine-1-yl)phenyl)-1,2-dihydropyridine-3,5-dicarbonitride (69). 1 H NMR (400MHz, DMSO-d6): δ7.44(d,J=8.8Hz,2H), 6.68(d,J=8.8Hz,2H), 4.88(s,2H), 3.32(m,4H), 1.98(m,4H). MS:m / z:405.38(M+H + ).

[0530] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(2-oxopyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile(70). 1 H NMR (400MHz, DMSO-d6): δ7.87-7.85(m,2H), 7.54(t,J=7.6Hz,1H), 7.33(d,J=7.6Hz,1H) , 6.58(s,1H), 4.85(s,2H), 3.89(t,J=6.8Hz,2H), 2.55-2.53(m,2H), 2.12-2.04(m,2H). MS:m / z:392.20(MH + ).

[0531] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(pyrrolidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (71). 1H NMR (400MHz, DMSO-d6): δ7.29(t,J=8.4Hz,1H), 6.74-6.66(m,3H), 6.56(br s,1H), 4.84(s,2H), 3.26(m,4H), 1.96(m,4H). MS:m / z:380.26(M+H + ).

[0532] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-phenoxy-1,3,5-triazine-2(1H)-one(72). 1 H NMR (400MHz, DMSO-d6): δ7.33(t,J=7.60Hz,2H), 7.16(t,J=7.20Hz,1H), 7.07-7.05(m,2H), 4.32(s,2H). MS:m / z:304.16(M+H + ).

[0533] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(1-methyl-1H-benzo[d]imidazole-2-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(73). 1 H NMR(400MHz,DMSO-d6):δ12.6(br s,1H), 7.76(d,J=8.0Hz,1H), 7.7(d,J=8.0Hz,1H), 7.40(t,J=7.6Hz,1H), 7.32(t,J=8.0Hz,1H), 6.90(s,1H), 4.88(s,2H), 3.88(s,3H). MS:m / z:365.27(M+H + ).

[0534] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-phenoxy-1,3,5-triazine-2(1H)-one(74). 1 H NMR (400MHz, DMSO-d6): δ7.23(t,J=7.60Hz,2H), 6.96(d,J=8.0Hz,2H), 6.81(t,J=7.2Hz,1H), 4.71(s,2H), 3.93(m,4H), 3.28(m,4H). MS:m / z:396.30(M+H + ).

[0535] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3,4-dihydroquinoline-1(2H)-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile(75). 1 H NMR (400MHz, DMSO-d6): δ7.19-7.08(m,4H), 4.74(s,2H), 3.81(m,2H), 2.73(t,J=5.60Hz,2H), 1.94(t,J=6.00Hz,2H). MS:m / z:367.28(M+H + ).

[0536] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(4-phenylpiperazine-1-yl)-1,6-dihydropyrimidine-5-carbonitrile(76). 1 H NMR 400MHz, DMSO-d6: δ7.23(t,J=8.40Hz,2H), 6.95(d,J=7.6Hz,2H), 6.80(t,J=8.40Hz,1H), 4.73(s,2H), 3.93-3.73(m,4H)3.48(m,4H). MS:m / z:396.30(M+H + ).

[0537] 4-(((1H-tetrazole-5-yl)methyl)thio)-6-(3,4-dihydroquinoline-1(2H)-yl)-2-hydroxypyrimidine-5-carbonitrile(77). 1 H NMR (400MHz, DMSO-d6): δ12.24(s,1H), 7.22-7.08(m,4H), 4.74(s,2H), 3.81(m,2H), 2.73(t,J=6.80Hz,2H), 1.94(t,J=6.80Hz,2H). MS:m / z:367.29(M+H + ).

[0538] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-acetylpiperazine-1-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (78). 1H NMR 400MHz, DMSO-d6: δ4.72(s,2H), 3.73-3.64(m,4H), 3.46-3.34(m,4H), 2.02(s,3H). MS:m / z:362.25(M+H + ).

[0539] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-(4-methylpiperazine-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (79). 1 H NMR (400MHz, DMSO-d6): δ7.36-7.34(m,1H), 7.11(m,2H), 6.97(d,J=7.6Hz,1H), 6.42(s,1H), 4.67(s,2H), 3.32(m,4H), 2.83(m,4H). MS:m / z:408.81(M+H + ).

[0540] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1,2-dihydropyridine-3,5-dicarbonitride(80). 1 H NMR (400MHz, DMSO-d6): δ7.74(d,J=8.4Hz,2H), 7.61-7.53(m,3H), 7.48-7.36(m,3H), 4.65(d,J=14.8Hz,1H), 4.49(d,J=14.8Hz,1H). MS:m / z:478.30(MH + ).

[0541] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-(3,4-dihydroquinoline-1(2H)-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(81). 1H NMR(400MHz,DMSO-d6):δ12.40(br s,1H), 7.49(t,J=8.4Hz,1H), 7.38(m,2H), 7.22(d,J=7.2Hz,1H), 7.06(d,J=7.2Hz,1H), 6.96-6.86(m,2H), 6. 73(t,J=7.6Hz,1H), 6.59(s,1H), 4.88(s,2H), 3.66-3.64(m,2H), 2.77(t,J=6.4Hz,2H), 1.95(t,J=5.6Hz,2H). MS:m / z:442.32(M+H + ).

[0542] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-methoxy-[1,1'-biphenyl]-2-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(82). 1 H NMR (400MHz, DMSO-d6): δ7.51(t,J=7.2Hz,1H), 7.45-7.37(m,2H), 7.26(d,J=7.6Hz,1H), 7.09(d, J=8.0Hz,2H), 6.87(d,J=8.4Hz,2H), 4.59(d,J=14.8Hz,1H), 4.46(d,J=14.8Hz,1H), 3.72(s,3H). MS:m / z:442.32(M+H + ).

[0543] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4'-chloro-[1,1'-biphenyl]-2-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitride(83). 1 H NMR (400MHz, DMSO-d6): δ7.58-7.48(m,2H), 7.43-7.37(m,3H), 7.31(d,J=7.6 Hz,1H), 7.17(d,J=8.4Hz,2H), 4.63(d,J=14.8Hz,1H), 4.47(d,J=14.8Hz,1H). MS:m / z:446.22(M+H + ).

[0544] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(2-(4-methylpiperazine-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(84). 1 H-NMR 400MHz, DMSO-d6: δ7.37(t,J=8.0Hz,1H), 7.18(d,J=8.0Hz,1H), 7.13-7.07(m,2 H), 6.16(s,1H), 4.52(s,2H), 2.78-2.67(m,4H), 2.32-2.24(m,4H), 2.07(s,3H). MS:m / z:409.27(M+H + ).

[0545] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(pyrrolidine-1-yl)-1,3,5-triazine-2(1H)-one(85). NMR (400MHz, DMSO-d6): 4.58(s,2H), 3.38-3.34(m,4H), 1.91-1.80(m,4H). MS: m / z: 281.20(M+H + ).

[0546] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-((4-chlorobenzyl)(methyl)amino)-1,3,5-triazine-2(1H)-one(86). 1 H NMR 400MHz, DMSO-d6: δ7.41-7.39(m,2H), 7.27(d,J=8.00Hz,2H), 4.80-4.74(m,2H), 4.55-4.45(m,2H), 3.05-2.97(m,3H). MS:m / z:365.21(M+H + ).

[0547] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(pyridine-3-yl)-1,2-dihydropyrimidine-5-carbonitrile (87). 1 H NMR 400MHz, DMSO-d6: δ8.88(s,1H), 8.78-8.77(m,1H), 8.15(d,J=8.00Hz,1H), 7.63-7.60(m,1H), 4.72(s,2H). MS:m / z:313.29(M+H + ).

[0548] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-3-methyl-2-oxo-1,2-dihydropyridine-4-yl)-N-methyl-N-phenylbenzamide (88). 1 H NMR (400MHz, DMSO-d6): δ7.41-7.40(m,2H), 7.26-7.07(m,7H), 4.67(s,2H), 3.38(s,4H), 1.42(s,3H). MS:m / z:458.38(M+H + ).

[0549] Example 27: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-cyclopropylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (89) [ka] 5-Cyano-4-(3-cyclopropylphenyl)-6-mercapto-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid ethyl (1166) (400 mg, 1.2 mmol) was dissolved in DMSO (4 mL) and stirred. K2CO3 (322 mg, 2.33 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (82 mg, 0.70 mmol). After stirring at RT for 16 hours, the reaction mixture was diluted with water, acidified with 1H HCl, and extracted with DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-cyclopropylphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid (1243). MS:m / z:425.25(M+H +) 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-cyclopropylphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid (1243) (350 mg, 0.82 mmol) dissolved in 1,4-dioxane (3.5 mL) was mixed with DDQ (224 mg, 0.99 mmol) and K2CO3 (227 mg, 1.65 mmol). After stirring at 90°C for 2 hours, the reaction mixture was cooled to RT, diluted with water, acidified with 1H HCl, and extracted with DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by prep HPLC, the pure fraction was recovered and freeze-dried to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-cyclopropylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (89). 1 H NMR (400MHz, DMSO-d6): δ7.29(t,J=7.2Hz,1H), 7.17-7.16(m,1H), 7.07-7.05(m,1H), 6.96(s,1H), 4.7 8(s,2H), 3.92-3.89(m,2H), 1.98(s,1H), 0.95-0.93(m,2H), 0.82(t,J=7.2Hz,3H), 0.64-0.63(m,2H). MS:m / z:423.22(M+H + ).

[0550] Example 28: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-cyclopropylphenyl)-5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (90) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-cyclopropylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (89) (200 mg, 0.47 mmol) was dissolved in THF (4 mL) and stirred. 2 M LiAlH4 (1.1 mL) was added to this mixture at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was quenched with NH4Cl (20 mL) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by prep HPLC, the pure fraction was recovered, and lyophilized to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-cyclopropylphenyl)-5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (90). 1 H NMR (400MHz, DMSO-d6): δ7.36(t,J=7.6Hz,1H), 7.22-7.16(m,2H), 7.08(s,1H), 4.81(s,2H), 4.07-4.02(m,2H), 1.97(m,1H), 1.17(t,J=7.2Hz,1H), 0.99-0.97(m,2H), 0.85-0.73(m,2H). MS:m / z:381.22(M+H + ).

[0551] Example 29: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyrimidine-5-carbonitrile (91) [ka] 6-Mercapto-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydropyrimidine-5-carbonitrile (1187) (400 mg, 1.3 mmol) was dissolved in DMSO (8 mL) and stirred. 5-(chloromethyl)-1H-tetrazole (95 mg, 0.81 mmol) and DIPEA (0.48 mL, 2.7 mmol) were added to this mixture. After stirring at RT for 16 hours, the reaction mixture was diluted with water, acidified with 1N HCl (pH=1), and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC and lyophilized to obtain the desired compound (91). 1 H NMR 400MHz, DMSO-d6: δ7.98(d,J=8.0Hz,2H), 7.93(d,J=8.4Hz,2H), 4.78(s,2H). MS:m / z:380.15(M+H + ).

[0552] The following compounds were prepared by the same method.

[0553] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(92). 1 H NMR 400MHz, DMSO-d6: δ7.73(d,J=8.8Hz,2H), 7.16(d,J=8.8Hz,2H), 4.78(s,2H), 3.86(s,3H). MS:m / z:342.24(M+H + ).

[0554] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(4-phenylpiperazine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (93). 1H NMR (400MHz, DMSO-d6): δ7.39(t,J=7.6Hz,1H), 7.24(t,J=8.0Hz,2H), 7.18-7.16(m,2H), 7.00(t,J=8.8Hz,3H), 6.81(t,J=8.4Hz,1H), 6.58(s,1H), 4.83(s,2H), 3.37-3.29(m,8H). MS:m / z:471.29(M+H + ).

[0555] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-(4-acetylpiperazine-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(94). 1 H NMR (400MHz, DMSO-d6): δ7.37(t,J=8.4Hz,1H), 7.12(m,2H), 6.97(d,J=7.6Hz,1H ), 6.53(s,1H), 4.78(s,2H), 3.75(m,4H), 3.24(m,2H), 3.17(m,2H), 2.04(s,3H). MS:m / z:437.26(M+H + ).

[0556] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(piperidine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (95). 1 H NMR (400MHz, DMSO-d6): δ7.22(t,J=8.0Hz,1H), 6.96-6.91(m,2H), 6.77(d,J =7.6Hz,1H), 5.63(s,1H), 4.36(s,2H), 3.16-3.14(m,4H), 1.61-1.52(m,6H). MS:m / z:394.30(M+H + ).

[0557] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(benzyloxy)-4,5-dihydro-1,3,5-triazine-2-ol(96). 1 H NMR (400MHz, DMSO-d6): δ7.45-7.35(m,5H), 5.33(s,2H), 4.42(s,2H). MS:m / z:318.22(M+H+ ).

[0558] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(benzyl(methyl)amino)-1,3,5-triazine-2(1H)-one(97). 1 H NMR 400MHz, DMSO-d6: δ7.31-7.17(m,5H), 4.72-4.59(m,4H), 2.94(s,3H). MS:m / z:331.27(M+H + ).

[0559] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(methyl(phenyl)amino)-1,3,5-triazine-2(1H)-one(98). 1 H NMR (400MHz, DMSO-d6): 7.33 (d, J = 7.6 Hz, 2H), 7.25-7.24 (m, 3H), 4.46 (s, 2H), 3.37 (s, 3H). MS:m / z:317.22(M+H + ).

[0560] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(tert-butyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (99). 1 H NMR 400MHz, DMSO-d6: δ4.37(s,2H), 1.26(s,9H). MS:m / z:292.21(M+H + ).

[0561] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(3,4-dichlorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile (100). 1 H NMR 400MHz, DMSO-d6: δ8.05(s,1H), 7.91(d,J=8.4Hz,1H), 7.74(d,J=8.4Hz,1H), 4.79(s,2H). MS:m / z:380.04(M+), 381.97(M+2H + ).

[0562] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-fluorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(101). 1 H NMR 400MHz, DMSO-d6: δ7.84-7.81(m,2H), 7.48(t,J=8.8Hz,2H), 4.79(s,2H). MS:m / z:330.36(M+H + ).

[0563] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(2,4-dichlorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(102). 1 H NMR 400MHz, DMSO-d6: δ7.98(s,1H), 7.77-7.70(m,2H), 4.81(s,2H). MS:m / z:378.18(M + ), 380.15 (M+2H + ).

[0564] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-cyclopropyl-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(103). 1 H NMR 400MHz, DMSO-d6: δ4.73(s,2H), 2.12-2.07(m,1H), 1.35-1.23(m,4H). MS:m / z:276.22(M+H + ).

[0565] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(pyridine-4-yl)-1,2-dihydropyrimidine-5-carbonitrile(104). 1 H NMR (400MHz, DMSO-d6): δ8.84 (d, J = 5.6 Hz, 2H), 7.72 (d, J = 6.0 Hz, 2H), 4.80 (s, 2H). MS:m / z:313.24(M+H + ).

[0566] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-cyclohexyl-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(105). 1 H NMR (400MHz, DMSO-d6): δ4.73(s,2H), 2.73-2.67(m,1H), 1.77-1.65(m,7H), 1.30-1.17(m,4H). MS:m / z:318.30(M+H + ).

[0567] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-chlorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(106). 1 H NMR 400MHz, DMSO-d6: δ7.84(s,1H), 7.56-7.62(m,3H), 4.79(s,2H). MS:m / z:346.17(M+H + ).

[0568] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(benzyl(methyl)amino)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(107). 1 H NMR (400MHz, DMSO-d6): δ7.37(t,J=7.6Hz,2H), 7.31-7.24(m,3H), 4.93(s,2H), 4.74(s,2H), 3.22(s,3H). MS:m / z:355.31(M+H + ).

[0569] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-benzyl-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(108). 1 H NMR 400MHz, DMSO-d6: δ7.38-7.31(m,5H), 4.73(s,2H), 3.99(s,2H). MS:m / z:326.28(M+H + ).

[0570] Example 30: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(4-pivaloylpiperazin-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (109) [ka] 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(piperazin-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (64) (100 mg, 0.25 mmol) was dissolved in DMF (1 mL) and stirred. Et3N (0.03 mL, 0.38 mmol) was added to the mixture. After stirring for 15 minutes, pivaloyl chloride (0.03 mL, 0.25 mmol) was added. After stirring at RT for 16 hours, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The crude residue was purified by prep HPLC and lyophilized to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-6-oxo-4-(3-(4-pivaloylpiperazine-1-yl)phenyl)-1,6-dihydropyridine-3-carbonitrile (109). 1 H NMR (400MHz, DMSO-d6): δ7.38(t,J=7.6Hz,1H), 7.12-7.10(m,2H), 6.83(d,J=7. 2Hz,1H), 6.56(s,1H), 4.82(s,2H), 3.70(m,4H), 3.21-3.20(m,4H), 1.22(s,9H). MS:m / z:479.36(M+H + ).

[0571] The following compounds were prepared by the same method.

[0572] 4-(3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)phenyl)piperazine-1-carboxylate methyl(110). 1H NMR (400MHz, DMSO-d6): δ7.35(t,J=8.8Hz,1H), 7.09-7.08(m,2H), 6.96(d,J=7.6Hz ,1H), 6.35(s,1H), 4.62(s,2H), 3.63(s,3H), 3.51-3.50(m,4H), 3.21-3.19(m,4H). MS:m / z:453.29(M+H + ).

[0573] Example 31: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl (111) [ka] 4-([1,1'-biphenyl]-3-yl)-5-cyano-6-mercapto-2-oxo-1,2-dihydropyridine-3-carboxylate ethyl and 4-([1,1'-biphenyl]-3-yl)-5-cyano-6-mercapto-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate ethyl (420 mg, 1.1 mmol) were dissolved in CH3CN (8.4 mL), to which 5-(chloromethyl)-1H-tetrazole (66 mg, 0.56 mmol) and K2CO3 (308 mg, 2.24 mmol) were added. After stirring at RT for 4 hours, the reaction mixture was diluted with water (50 mL), acidified with 1N HCl (pH=1), and extracted with ethyl phosphate. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was dissolved in 1,4-dioxane (2 mL), and K2CO3 (120 mg, 0.869 mmol) and DDQ (98 mg, 0.65 mmol) were added. After heating at 100°C for 2 hours, the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The crude residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (111). 1H-NMR 400MHz, DMSO-d6: δ7.69-7.64(m,3H), 7.52-7.46(m,4H), 7.38(t,J=7.60Hz,1H), 7.26(d,J=7.2 0Hz,1H), 4.52(s,2H), 3.81(q,J=6.80,14.0Hz,2H), 0.76(t,J=6.80Hz,3H).MS:m / z:459.31(M+H + ).

[0574] The following compounds were prepared by the same method.

[0575] 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-(methyl(phenyl)carbamoyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (112). 1 H NMR 400MHz, DMSO-d6: δ7.27-7.15(m,9H), 4.60(s,2H), 3.82(q,J=6.8Hz,2H), 3.41(s,3H), 0.83(t,J=7.20Hz,3H). MS:m / z:516.43(M+H + ).

[0576] Example 32: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-4-(3-(methyl(phenyl)carbamoyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (113) [ka] Ethyl 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (54) (330 mg, 0.64 mmol) was dissolved in EtOH (3.3 mL) and stirred. 2 M KOH (1.6 mL, 3.2 mmol) was added to the mixture. After stirring at 50 °C for 24 hours, the solvent was removed under vacuum. The residue was diluted with water, acidified with 1 N HCl (pH=1), and extracted with ELISA. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by column chromatography to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (113). MS:m / z:488.27(M+H + ).

[0577] Example 33: Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-5-cyano-2-oxo-3-(pyrrolidine-1-carbonyl)-1,2-dihydropyridine-4-yl)-N-methyl-N-phenylbenzamide (114) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (113) (130 mg, 0.266 mmol) was dissolved in DMF (1.3 mL) and stirred. HATU (202 mg, 0.534 mmol) and DIPEA (0.14 mL, 0.801 mmol) were added to the mixture. After stirring for 30 minutes, pyrrolidine (0.04 mL, 0.53 mmol) was added. After stirring at RT for 16 hours, the reaction mixture was diluted with water, acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by prep HPLC. The pure fraction was collected and freeze-dried to obtain the target compound (114). 1H-NMR 400MHz, DMSO-d6: δ7.35(s,1H), 7.23-7.09(m,8H), 4.64(s,2H), 3.37(s,3 H), 3.25-3.17(m,2H), 2.99-2.91(m,2H), 1.73-1.71(m,2H), 1.58(m,2H). MS:m / z:541.29(M+H + ).

[0578] Example 34: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-1,3,5-triazine-2(1H)-one(115) [ka] 4-(4-chlorophenyl)-6-mercapto-1,3,5-triazine-2-ol (1223) (500 mg, 2.09 mmol) was dissolved in CH3CN (5 mL) and stirred. K2CO3 (577 mg, 4.18 mmol) and 5-(chloromethyl)-1H-tetrazole (148 mg, 1.26 mmol) were added to the mixture. After stirring for 16 hours, the reaction product was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (115). 1 H NMR (400MHz, DMSO-d6): δ8.20 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.74 (s, 2H). MS:m / z:322.19(M+H + ).

[0579] The following compounds were prepared by the same method.

[0580] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(116). 1H NMR 400MHz, DMSO-d6: δ7.72(d,J=8.0Hz,2H), 7.52(d,J=8.4Hz,2H), 4.41(s,2H), 2.21(s,3H). MS:m / z:344.09(MH + ).

[0581] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-cyclopropylphenyl)-5-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(117). 1 H NMR(400MHz,DMSO-d6):δ12.1(br s,1H), 7.38(t,J=8.0Hz,1H), 7.18(d,J=7.6Hz,1H), 7.07(dJ=7.6Hz,1H), 7.01(s, 1H), 4.83(s,2H), 1.99-1.94(m,1H), 1.85(s,3H), 0.99-0.98(m,2H), 0.72(m,2H). MS:m / z:363.30(MH + ).

[0582] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(2-chlorophenyl)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile(118). 1 H NMR 400MHz, DMSO-d6: δ7.64-7.50(m,4H), 4.62(s,2H). MS:m / z:346.17(M+H + ).

[0583] Example 35: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonitrile (119) [ka] 6-(((1-(4-methoxybenzyl)-1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonitrile (1237) (300 mg, 0.71 mmol) was dissolved in DCM (30 mL) and stirred. TFA (15 mL) was added at 0°C. The reaction mixture was heated to RT and stirred for 16 hours. Volatile substances were removed under reduced pressure, and the residue was purified by prep HPLC. After lyophilization, 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonitrile was obtained. 1 H NMR (400MHz, DMSO-d6): δ4.47(s, 2H). MS:m / z:304.16(M+H + ).

[0584] The following compounds were prepared by the same method.

[0585] 6-(((1H-tetrazole-5-yl)methyl)thio)-2-oxo-4-(perfluoroethyl)-1,2-dihydropyrimidine-5-carbonitrile(120). 1 H NMR (400MHz, DMSO-d6): δ4.84(s, 2H). MS:m / z:354.27(M+H + ).

[0586] Example 36: Preparation of 4'-(6-(((1H-tetrazole-5-yl)methyl)thio)-3,5-dicyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenyl-[1,1'-biphenyl]-4-carboxamide (121) [ka] 4'-(3,5-dicyano-6-mercapto-2-oxo-1,2-dihydropyridine-4-yl)-N-phenyl-[1,1'-biphenyl]-4-carboxamide (1167) (200 mg, 0.446 mmol) was dissolved in DMSO (2 mL) and stirred. K2CO3 (240 mg, 1.78 mmol) was then added, followed by 5-(chloromethyl)-1H-tetrazole (105 mg, 0.892 mmol). After stirring for 16 hours, the reaction mixture was acidified with 1N HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, appropriate fractions were mixed, and freeze-dried to obtain the target compound (121). 1 H NMR (400MHz, DMSO-d6): δ10.4(s,1H), 8.08(d,J=8.4Hz,2H), 7.93(t,J=8.4 Hz, 3H), 7.81(d,J=7.6Hz,2H), 7.57(d,J=8.4Hz,2H), 7.37(t,J=7.60Hz,2H), 7.11(t,J=7.6Hz,1H), 4.68(s,2H). MS:m / z:531.39(M+H + ).

[0587] Example 37: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-5-chloro-4-(3-cyclopropylphenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (122) [ka] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(3-cyclopropylphenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (42,150 mg, 0.43 mmol) was dissolved in ACN (4.5 mL) and stirred. NCS (62 mg, 0.47 mmol) and AIBN (14 mg, 0.086 mmol) were added to this mixture. After stirring at 80°C for 16 hours, the reaction mixture was diluted with water, acidified with 1N HCl (pH=1), and extracted with 10% MeOH:DCM. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by prep HPLC to obtain 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carbonitrile (122). 1 H NMR (400MHz, DMSO-d6): δ7.37(t,J=7.2Hz,1H), 7.15(d,J=7.6Hz,1H), 7.12(d,J=7.6 Hz,1H), 7.06(s,1H), 4.79(s,2H), 2.00-1.94(m,1H), 0.99-0.97(m,2H), 0.71(m,2H). MS:m / z:383.22(MH + ).

[0588] Example 38: Preparation of 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)-N-phenylbenzamide (123) [ka] 3-(6-(((1H-tetrazole-5-yl)methyl)thio)-3-chloro-5-cyano-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid (130) (300 mg, 0.77 mmol) was dissolved in DMF (3 mL) and stirred. Aniline (70 μL, 0.77 mmol), DIPEA (0.4 mL, 2.3 mmol), and HATU (587 mg, 1.55 mmol) were added to the mixture. The mixture was stirred for 16 hours and monitored by TLC. The reaction product was then acidified with 1N HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (123). 1 H NMR (400MHz, DMSO-d6): δ10.30(s,1H), 8.03(d,J=8.0Hz,1H), 7.93(s,1H), 7.78(d,J=8.0Hz,2H), 7.64 (t,J=7.60Hz,1H), 7.54(d,J=7.60Hz,1H), 7.36(t,J=7.60Hz,2H), 7.11(t,J=7.60Hz,1H), 4.71(s,2H). MS:m / z:463.79(M+H + ).

[0589] Example 39: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-N-phenyl-1,2-dihydropyridine-3-carboxamide (124) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55) (200 mg, 0.514 mmol) was dissolved in DMF (2 mL) and stirred. HATU (391 mg, 1.03 mmol) and DIPEA (0.27 mL, 1.5 mmol) were added to the mixture. After stirring for 30 minutes, aniline (0.09 mL, 0.62 mmol) was added. The mixture was stirred at RT for 16 hours and monitored by TLC. The reaction product was then diluted with water (20 mL), acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the desired fractions were mixed, and freeze-dried to obtain the target compound (124). 1 H NMR 400MHz, DMSO-d6: δ11.83(s,1H), 7.44(t,J=8.40Hz,4H), 7.30-7.21(m,5H), 7.09(br s,1H), 6.98(t,J=7.60Hz,1H), 4.72(s,2H). MS:m / z:462.35(MH + ).

[0590] Example 40: Preparation of 2-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-6-oxo-5-(pyrrolidine-1-carbonyl)-1,6-dihydropyridine-3-carbonitrile (125) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55,200 mg, 0.514 mmol) was dissolved in DMF (2 mL) and stirred. EDC·HCl (147 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol), and DIPEA (0.26 mL, 1.5 mmol) were added to the mixture. After stirring the reaction for 30 minutes, pyrrolidine (0.06 mL, 0.773 mmol) was added. The mixture was stirred for 16 hours and monitored by TLC. The reaction was then diluted with water (20 mL), acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried over Na₂SO₄, and evaporated under reduced pressure. The residue was purified by prep HPLC and freeze-dried to obtain the target compound (125). 1 H-NMR 400MHz, DMSO-d6: δ7.52(d,J=8.40Hz,2H), 7.36(d,J=8.40Hz,2H), 4.74(m,2H) ), 3.26-3.17(m,2H), 3.08-2.96(m,2H), 1.73-1.69(m,2H), 1.63-1.58(m,2H). MS:m / z:442.32(M+H + ).

[0591] The following compounds were prepared by the same method.

[0592] 2-(((1H-tetrazole-5-yl)methyl)thio)-4-([1,1'-biphenyl]-3-yl)-6-oxo-5-(pyrrolidine-1-carbonyl)-1,6-dihydropyridine-3-carbonitrile (126). 1 H NMR 400MHz, DMSO-d6:δ7.72(d,J=8.00Hz,1H), 7.65(t,J=7.6 Hz, 3H), 7.55-7.47(m,3H), 7.41-7.34(m,2H), 4.69(s,2H), 3.26-3.14(m,2H), 3.11-2.94(m,2H), 1.72-1.69(m,2H), 1.54-1.51(m,2H). MS:m / z:484.43(M+H + ).

[0593] Example 41: Preparation of 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (127) [ka] 6-(((1H-tetrazole-5-yl)methyl)thio)-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylic acid (55) (200 mg, 0.51 mmol) was dissolved in DMF (2 mL) and stirred. EDC·HCl (147 mg, 0.773 mmol), HOBt (104 mg, 0.773 mmol), and DIPEA (0.27 mL, 1.546 mmol) were added to the mixture. After stirring at RT for 30 minutes, methylamine (2 M in THF, 1.28 mL, 2.578 mmol) was added. After stirring at RT for 16 hours, the reaction mixture was diluted with water, acidified with 1N HCl (pH=1), and extracted with SiO2. The organic layer was separated, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by prep HPLC, the pure fraction was recovered, and freeze-dried to obtain the target compound (127). 1 H NMR 400MHz, DMSO-d6: δ9.46(br s,1H), 7.38(d,J=8.40Hz,2H), 7.15(d,J=8.4Hz,2H), 4.55(s,2H), 2.50(s,3H). MS:m / z:400.30(MH + ).

[0594] Example 42: Preparation of 3-(((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)methyl)benzoic acid (128) [ka] 3-(((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)methyl)methyl benzoate (380 mg, 1.1 mmol) was dissolved in MeOH:THF:H2O (1:1:1) (11.4 mL) and LiOH·H2O (132 mg, 3.23 mmol) was added by RT. The mixture was stirred for 2 hours, monitored by TLC, and then volatile matter was removed under reduced pressure. The reaction product was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (128). 1 H NMR (400MHz, DMSO-d6): δ13.01 (br s, 1H), 8.20 (br s,2H), 8.05(s,1H), 7.84(d,J=7.6Hz,1H), 7.73-7.67(m,2H), 7.57(t,J=7.6Hz,2H), 7.47(t,J=7.6Hz,1H), 4.51(s,2H). MS:m / z:340.20(M+H + ).

[0595] The following compounds were prepared by the same method.

[0596] 2-((6-oxo-4-phenyl-1,6-dihydro-1,3,5-triazine-2-yl)thio)acetic acid (129). 1 H NMR (400MHz, DMSO-d6): δ8.22 (d, J=8.0Hz, 2H), 7.49-7.40 (m, 3H), 3.63 (s, 2H). MS:m / z:264.12(M+H + ).

[0597] Example 43: Preparation of 2-(3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)phenyl)acetic acid (130) [ka] 6-mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096,250 mg, 1.09 mmol) was dissolved in CH3CN (2.5 mL) and stirred. K2CO3 (301 mg, 2.18 mmol) was then added, followed by methyl 3-(bromomethyl)benzoate (211 mg, 0.873 mmol). After stirring for 16 hours, the reaction mixture was acidified with 1N HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to obtain methyl 2-(3-(((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)methyl)phenyl)acetate. This was dissolved in MeOH:THF:H2O (1:1:1) (12 mL), and LiOH·H2O (125 mg, 2.962 mmol) was added. The mixture was stirred for 2 hours, monitored by TLC, and then volatile matter was removed under reduced pressure. The residue was acidified with 1N HCl (pH=1) and extracted by DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (130). 1 H NMR (400MHz, DMSO-d6): δ7.73-7.57(m,5H), 7.45-7.29(m,3H), 7.20-7.18(m,1H), 4.42(s,2H), 3.61(s,2H). MS:m / z:378.18(M+H + ).

[0598] Example 44: Preparation of 2-((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)acetic acid (131) [ka] 6-Mercapto-2-oxo-4-phenyl-1,2-dihydropyrimidine-5-carbonitrile (1096,270 mg, 2.8 mmol) was dissolved in CH3CN (2.7 mL) and stirred solution was prepared. K2CO3 (767 mg, 5.56 mmol) and 2-methyl bromoacetate (382 mg, 1.67 mmol) were added to this solution. After stirring for 16 hours, the reaction mixture was acidified with 1H HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography and 2-((5-cyano-2-oxo-6-phenyl-2,3-dihydropyrimidine-4-yl)thio)ethyl acetate (MS: m / z: 316.23 (M+H)) was obtained. + The following compound (131) was obtained. This was dissolved in MeOH:THF:H2O (1:1:1) (2.7 mL), and LiOH·H2O (108 mg, 2.571 mmol) was added. After stirring, the solvent was removed under reduced pressure. The residue was acidified with 1H HCl (pH=1) and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (131). 1 H NMR (400MHz, DMSO-d6): δ13.1 (br s, 1H), 7.75-7.58 (m, 5H), 4.03 (s, 2H). MS:m / z:288.17(M+H + ).

[0599] Example 45: Preparation of 6-((3-(1H-tetrazole-5-yl)benzyl)thio)-4-phenyl-1,3,5-triazine-2(1H)-one(132) [ka] 4-Mercapto-6-phenyl-1,3,5-triazine-2-ol (1098) (250 mg, 1.2 mmol) was dissolved in ACN (5 mL) and stirred. To this stirred solution, 5-(3-(bromomethyl)phenyl)-1H-tetrazole (232 mg, 0.9078 mmol) and K2CO3 (334 mg, 2.427 mmol) were added. After stirring for 2 hours, the reaction mixture was diluted with water, acidified with 1N HCl (pH=1), and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC, the appropriate fractions were mixed, and freeze-dried to obtain the target compound (132). 1 H NMR (400MHz, DMSO-d6): δ8.21-8.14(m,3H), 7.92(d,J=7.60Hz,1H), 7.68-7.51(m,5H), 4.55(s,2H). MS:m / z:364.28(M+H + ).

[0600] Example 466: Preparation of (((1H-tetrazole-5-yl)methyl)thio)-4-isopropoxy-1,3,5-triazine-2(1H)-one(133) [ka] 4-Isopropoxy-6-mercapto-1,3,5-triazine-2-ol (160 mg, 0.86 mmol) was dissolved in DMSO (3.2 mL) and stirred. This solution was then added to DIPEA (0.3 mL, 1.7 mmol) and 5-(chloromethyl)-1H-tetrazole (50 mg, 0.43 mmol). After stirring at RT for 16 hours, the reaction mixture was diluted with H2O, acidified with 1N HCl, and extracted with DCM. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by prep HPLC and lyophilized to obtain 6-(((1H-tetrazole-5-yl)methyl)thio)-4-isopropoxy-1,3,5-triazine-2(1H)-one (133). 1 H NMR(400MHz,DMSO-d6):δ5.25-5.18(m,1H), 4.37(s,2H), 1.29(d,J=6.00Hz,6H).MS:m / z:270.20(M+H +).

[0601] Example 47: Biological Assay Mouse frozen primary hepatocytes were thawed according to the manufacturer's instructions and seeded in 6-well plates at a density of 300,000 cells / well. After standing for several hours, 3 μM of the compound, resuspended in DMSO, was added to serum-free William E medium supplemented with 500 μM tryptophan, and the cells were incubated for 6 hours. After 6 hours, the cells were washed with phosphate-buffered saline (PBS) and collected in a pre-cooled protein precipitation solution (crashing solution) containing an internal standard (telmisartan and / or verapamil) (acetonitrile:methanol:water (40%:40%:20% w / w)). Ammonium bicarbonate (15%; 30 μL) was added to the lysate, and the mixture was incubated on dry ice for 10 minutes. The mixture was then centrifuged at 14,000 rpm for 10 minutes, and the QA concentration was quantified using an optimized LC-MS / MS method. In this study, an Atlantis, T3 3μm, 150×4.6mm column was used, and 0.1% formic acid dissolved in water and 0.2% formic acid dissolved in methanol were used as mobile phases A and B, respectively. The results are shown in Table 1 as the ratio of the amount of QA generated in the wells with the compound added to the amount of QA in the wells without the compound (DMSO). ACMSD is located at a branching point in the tryptophan metabolic pathway. Both an increase in QA concentration and a decrease in PA concentration indicate inhibition of ACMSD. When mouse hepatocytes were treated with the compounds of the present invention, an increase in QA concentration was observed, indicating that these are inhibitors of ACMSD. [Table 1] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25

Claims

1. Compounds with structural formula (I): 【Chemistry 1】 Or a pharmaceutically acceptable salt, hydrate, or solvate thereof: X is R ３ It is C- or -N-; Y is CN-C- or -N-; R １ is (C ２ ~C ２０ ) alkyl, substituted alkyl, alkenyl, substituted alkenyl, -OR １２ , -NR １３ R １４ aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkenyl; R ２ is -(CR ４ R ５ ) ｎ -A-B; R ３ -H, -CN, -CH ２ OH, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, -C(O)NR ６ R ７ , -CO ２ R ８ , -NR １５ R １６ , -OR １７ And; A is an aryldiyl, a substituted aryldiyl, a heteroaryldiyl, a substituted heteroaryldiyl, or is absent; B is - (CR ９ R １０ ) ｒ CO ２ R １１ , 【Chemistry 2】 , or their prodrugs; n is either 1 or 2; r is either 0 or 1; Each R ４ These are independently -H, -F, alkyl, or alkenyl; Each R ５ These are independently -H, -F, alkyl, or alkenyl; R ６ , R ７ , R １３ ~R １６ These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, or together with the atom to which they are bonded, they form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring; R ８ and R １１ These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl; Each R ９ These are independently -H, -F, alkyl, or alkenyl; Each R １０ These are independently -H, -F, alkyl, or alkenyl; and R １２ and R １７ These are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, or substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl; However, R is only valid if X is -N-. １ is (C ２ ~C ２０ ) is alkyl, substituted alkyl, or cycloalkyl; however, R is only considered if X and Y are -N-. １ ha-OR １２ And; however, Y is CN-C- and R ３ When R is -H or -CN, １ is phenyl, (C １ ~C ５ ) alkyl, (C １ ~C ５ ) Haloalkyl, halo, -CN, or -NO ２ Phenyl, monocyclic heteroaryl, (C) substituted with １ ~C ５ ) Alkyl (C １ ~C ５ ) Haloalkyl, halo, -CN, or -NO ２ Not a monocyclic heteroaryl substituted with; provided that Y is -CN-C- and R ３ -F, Cl, CH ３ , or -CO ２ When H, R １ is not phenyl; however, Y is -CN-C- and R ３ ga-CO ２ Et and R ２ ga-CH ２ CO ２ Me or -CH(CH ３ ) CO ２ When Me is, R １ is not p-chlorophenyl; however, Y is -CN-C- and R ３ ga-CO ２ Et and R ２ ga-CH ２ CO ２ Me, -CH ２ CO ２ Et, or -CH(CH ３ ) CO ２ When Me is, R １ is not 2-furanyl; however, Y is -N- and R ３ is -CN and R ２ but 【Transformation 3】 When R １ is not 2-thiophenyl; and provided that X and Y are -N- and R ２ ga-CH ２ CO ２ When Et, R １ teeth 【Chemistry 4】 Not a compound.

2. Structural formula (II): 【Transformation 5】 The compound according to claim 1.

3. R １ The compound according to claim 2, wherein is an aryl or substituted aryl.

4. A does not exist, n is 1, and R ４ and R ５ The compound according to claim 2 or 3, wherein is -H.

5. R １ The compound according to claim 2, wherein is a biphenyl or a substituted biphenyl.

6. R １ teeth 【Transformation 6】 and, and R １８ , R １９ , R ２０ , and R ２１ are each independently -H, alkyl, substituted alkyl, halo, -CN, -NO ２ , -OR ２２ , -NR ２３ R ２４ , -NR ２５ COR ２６ , -CO ２ R ２７ , -CONR ２８ R ２９ , or cycloalkyl; R ２２ is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl; R ２５ to R ２７ are each independently -H, alkyl, or alkenyl; and R ２３ , R ２４ , R ２８ , and R ２９ are -H, alkyl, alkenyl, aryl, substituted aryl, or together with the atoms to which they are attached form a cycloheteroalkyl ring or substituted cycloheteroalkyl ring, the compound according to claim 5.

7. R ２１ is -H, and R ２２ , R ２３ , and R ２４ One of them is H, alkyl, substituted alkyl, halo, -CN, -NO ２ , -OCR ２２ , -NR ２３ R ２４ , -NR ２５ COR ２６ , -CO ２ R ２７ , -CONR ２８ R ２９ The compound according to claim 6, which is either , or cycloalkyl.

8. A does not exist, n is 1, and R ４ and R ５ The compound according to any one of claims 5 to 7, wherein is -H.

9. R １ The compound according to claim 2, wherein is an aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, or substituted heteroaryl.

10. R １ The compound according to claim 9, wherein is a substituted phenyl.

11. R １ teeth 【Transformation 7】 And R ３０ is -H or alkyl, R ３１ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or cycloalkyl, or R ３０ and R ３１ The compound according to claim 10, wherein the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

12. R ３０ is -H or methyl, R ３１ is alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl, or cyclopropyl, or R ３０ and R ３１ The compound according to claim 11, wherein the atoms to which they are bonded form a pyrrolidine, substituted pyrrolidine, piperazine, or substituted piperazine ring.

13. A does not exist, n is 1, and R ４ and R ５ The compound according to any one of claims 9 to 12, wherein is -H.

14. R ３ is -H, and R ２７ is -H or methyl, and R ２８ The compound according to claim 12, wherein is phenyl or substituted phenyl.

15. structure: 【Transformation 8】 The compound according to claim 14, having the following characteristics.

16. R ３ is -H, and R ３０ is -H or methyl, R ３１ is alkyl, substituted alkyl, cycloheteroalkyl, or cycloalkyl, or R ２７ and R ２８ The compound according to claim 12, wherein the atoms to which they are bonded form a pyrrolidine, substituted pyrrolidine, piperazine, or substituted piperazine ring.

17. structure: 【Chemistry 9】 The compound according to claim 16, having the following characteristics.

18. A is aryl zyle, n is 1, and R ４ and R ５ The compound according to claim 11 or 12, wherein is -H.

19. R ３ is -H, and R ３０ is -H or methyl, and R ３１ The compound according to claim 18, wherein is phenyl or substituted phenyl.

20. structure: 【Chemistry 10】 The compound according to claim 19, having the following characteristics.

21. R ３ is -CN, n is 1, and R ４ and R ５ The compound according to claim 10, wherein is -H.

22. structure: 【Chemistry 11】 The compound according to claim 21, having the following characteristics.

23. R １ is a heteroaryl or substituted heteroaryl, A is absent, n is 1, and R ４ and R ５ The compound according to claim 9, wherein is -H.

24. R ３ The compound according to claim 23, wherein is -H.

25. structure: 【Chemistry 12】 The compound according to claim 24, having the following characteristics.

26. R １ is an aryl or substituted aryl, A is absent, n is 1, and R ４ and R ５ The compound according to claim 9, wherein is -H.

27. R ３ The compound according to claim 26, wherein is -H.

28. structure: 【Chemistry 13-1】 【Chemistry 13-2】 The compound according to claim 27, having the following characteristics.

29. R ３ is, -CH ２ OH, halo, alkyl, substituted alkyl, -C(O)NR ６ R ７ , or -CO ２ R ８ The compound according to claim 26.

30. structure: 【Chemistry 14-1】 【Chemistry 14-2】 The compound according to claim 29, having the following characteristics.

31. R ３ The compound according to claim 8, wherein is -CN.

32. structure: 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 The compound according to claim 31, having the following characteristics.

33. R １ is a cycloheteroalkyl or substituted cycloheteroalkyl, A is absent, n is 1, and R ４ and R ５ The compound according to claim 9, wherein is -H.

34. R ３ The compound according to claim 33, wherein is -CN.

35. structure: 【Chemistry 16】 The compound according to claim 34, having the following characteristics.

36. Structural formula (III): 【Chemistry 17】 The compound according to claim 1.

37. R １ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, or -NR １３ R １４ The compound according to claim 36.

38. A does not exist, n is 1, and R ４ and R ５ The compound according to claim 36 or 37, wherein is -H.

39. structure: 【Chemistry 18-1】 【Chemistry 18-2】 The compound according to claim 38, having the following characteristics.

40. A is an aryldiyl, a substituted aryldiyl, n is 1, and R ４ and R ５ The compound according to claim 36 or 37, wherein is -H.

41. structure: 【Chemistry 19】 The compound according to claim 40, having the following characteristics.

42. Structural formula (IV): 【Chemistry 20】 The compound according to claim 1.

43. R １ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, -OR １２ , or -NR １３ R １４ The compound according to claim 42.

44. C does not exist, n is 1, and R ４ and R ５ The compound according to claim 42 or 43, wherein is -H.

45. structure: 【Chemistry 21】 The compound according to claim 44, having the following characteristics.

46. A is an aryldiyl, a substituted aryldiyl, n is 1, and R ４ and R ５ The compound according to claim 42 or 43, wherein is -H.

47. structure: 【Chemistry 22】 The compound according to claim 46, having the following characteristics.

48. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable vehicle.

49. A method for treating or preventing a disease or disorder by inhibiting α-amino-β-carboxy-muconate-ε-semialdehyde decarboxylase, comprising administering to a subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

50. NAD ＋ A method for treating or preventing a disease or disorder associated with a decrease in concentration, comprising administering to a subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

51. A method for treating or preventing a disease or disorder related to mitochondrial dysfunction, comprising administering to a subject in need of such treatment an effective amount of the compound described in claim 1, or an effective amount of the pharmaceutical composition described in claim 48.

52. The subjects had a history of muscle structural disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, β-oxidation disorders, metabolic disorders, cancer, vascular diseases, ocular vascular diseases, ocular muscle diseases, or kidney diseases, hereditary lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne and Becker muscular dystrophy, diabetes mellitus (type I or II), obesity, and sarcopenia, Alper's disease, CPEO - chronic progressive extraocular muscle palsy, Kearns-Sayre syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, and breast milk disease. A method for treating or preventing acidosis and stroke-like seizures, MERRF-myoclonus epilepsy with red rag fibers, NARP-neurogenic muscle weakness, ataxia and retinitis pigmentosa, Pearson syndrome, chemotherapy-induced ototoxicity by platinum-based agents, Cockayne syndrome, xeroderma pigmentosum A, Waller degeneration, alcoholic steatohepatitis, autosomal dominant polycystic kidney disease (ADPKD), inflammatory diseases, or HIV-induced lipodystrophy, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

53. A method for treating a subject having acute kidney injury, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

54. A method for treating a subject having cancer, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

55. A method for preventing acute kidney injury in a subject, comprising administering to a subject in need of such injury a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

56. A method for treating a subject having chronic kidney disease, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

57. A method for treating a subject having ADPKD, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

58. A method for preventing ADPKD in a subject, comprising administering to a subject in need of such prevention a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

59. A method for treating a subject having ADPKD, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48, and a therapeutically effective amount of tolvapatan.

60. A method for preventing ADPKD in a subject, comprising administering to a subject in need of such prevention a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48, and a therapeutically effective amount of tolvapatan.

61. A method for treating a subject having a chronic liver disease, comprising administering to the subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 46.

62. Hepatorenal syndrome - A method for treating a subject having acute kidney injury, comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

63. A method for preventing hepatorenal syndrome-acute kidney injury (HRS-AKI) in a subject, comprising administering to a subject in need of such prevention a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

64. A method for treating a subject having compensated or decompensated cirrhosis of the liver, comprising administering to a subject in need a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

65. A method for preventing compensatory and decompensated cirrhosis in a subject, comprising administering to a subject in need of such prevention a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

66. A method for regenerating liver tissue in a subject, comprising administering to a subject in need of such regeneration a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

67. A method for regenerating kidney tissue in a subject, comprising administering to a subject in need of such regeneration a therapeutically effective amount of the compound described in claim 1, or a therapeutically effective amount of the pharmaceutical composition described in claim 48.

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