α-Amino-β-carboxymuconic acid semialdehyde decarboxylase inhibitors

Abstract

This disclosure relates to NAD + Disclosed are compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and / or treatment of diseases and disorders associated with biosynthetic deficiencies, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and age-related diseases. The present application also discloses pharmaceutical compositions containing the compounds and the use of such compounds as medicines.

Description

[Technical Field]

[0001] The present disclosure relates to compounds that can modulate the activity of α-amino-β-carboxymuconic semialdehyde decarboxylase (ACMSD). The compounds of the present disclosure are capable of modulating NAD + They may be used in methods for preventing and / or treating diseases and disorders associated with biosynthetic deficiencies, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with aging. [Background technology]

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 769,959, filed November 20, 2018, the contents of which are incorporated herein by reference in their entirety.

[0003] ACMSD is an important enzyme in tryptophan metabolism, converting tryptophan to NAD. + ACMSD regulates the biosynthesis of picolinic acid (PA), quinolinic acid (QA), and NAD + ACMSD is a zinc-dependent amidohydrolase involved in homeostasis. It converts tryptophan into NAD. + Located at the branching point of the biosynthetic pathway, it determines the final fate of the amino acid, i.e., conversion to PA, complete oxidation via the citric acid cycle, or NAD via QA synthesis. + Determine the conversion to

[0004] ACMSD has been purified from human liver, kidney, and brain tissues. Two isoforms, ACMSD1 and ACMSD2, exist due to differential splicing of the ACMSD gene transcript, but only ACMSD1 possesses enzymatic activity. ACMSD1 directs ACMS (α-amino-ω-carboxymuconic acid semialdehyde) into the acetyl-CoA pathway, and when ACMSD1 is inhibited, ACMS is non-enzymatically converted to quinolinic acid (QA), resulting in the conversion of NAD. + Formation of intracellular NAD + resulting in an increase in level.

[0005] NAD + Increased levels have been shown to protect against neurodegeneration, improve muscle function and oxidative metabolism in mice, and extend lifespan in earthworms. + Decreased levels are associated with a range of pathophysiological conditions, including type 2 diabetes (T2D), dyslipidemia (elevated cholesterol and TAG), mitochondrial disease, neutropenia, cancer, and renal impairment.

[0006] Therefore, inhibition of ACMSD reduces NAD + Increases levels and NAD + It represents a novel approach to correct the pathophysiology of diseases associated with biosynthetic defects. Summary of the Invention

[0007] The objective of the embodiments of the present disclosure is to + The present invention provides a series of novel compounds capable of regulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and / or treatment of diseases and disorders associated with biosynthetic defects, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and age-related diseases.

[0008] The compounds of formula (I) or (II) defined herein may be used to treat diseases or disorders involving ACMSD. + A method for treating a disease or disorder associated with abnormalities in biosynthesis, comprising: inhibiting ACMSD1 to induce intracellular NAD synthesis in a subject suffering from or susceptible to the disease or disorder. + The disclosed method includes administering a therapeutically effective amount of one or more compounds that increase NAD by inhibiting ACMSD in an amount sufficient to activate sirtuins (SIRTs) and downstream targets of SIRTs, such as PGC-1α, FoxO1, and superoxide dismutase (SOD). +Inhibition of ACMSD can be used to treat metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, age-related diseases, and other ACMSD-dependent diseases, or NAD + This may provide a novel approach to the prevention and treatment of diseases characterized by synthetic deficiencies.

[0009] The present disclosure provides a compound represented by formula (I):

[0010] [ka]

[0011] During the ceremony, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl; W is N or C; (i) When W is N, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0012] [ka]

[0013] , -(C(R 5 )2) m Y 1 (C(R 5 )2) p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and (ii) When W is C, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0014] [ka]

[0015] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R 5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2)m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and Y 1 But, O, NR 4 , or S(O) q and Y 2 are each independently O, NH, or S; R 1 But absent or C6-C 10 arylene or heteroarylene, wherein the heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, and the C6-C 10 The arylene or heteroarylene is one to two R e optionally replaced by R 2 is H or C1-C4 alkyl; R 2’ is H, C1-C4 alkyl, or C3-C7 cycloalkyl, or R 2 and R 2’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S; R 3 is H or C1-C4 alkyl; R 4 is H or C1-C4 alkyl; R 5 is each independently at each occurrence H or C1-C4 alkyl; R 6 is each independently at each occurrence H or C1-C4 alkyl; R 7 is H, A, B, or C, A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r Isoxazol-3-ol, -(CH2) r P(O)(OH)OR x , -(CH2) r S(O)2OH, -(CH2) r C(O)NHCN, or -(CH2) r C(O)NHS(O)2 alkyl, -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r isoxazol-3-ol optionally substituted with C1-C6 alkyl; B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) r S(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(CH2) r C(O)NR g R g’ , -(CH2) r S(O)NR g R g’ , -(CH2) r C(O)NHS(O)NRg R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x and C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R 6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2) rC(O)NHS(O)2C1-C4 alkyl, wherein the aryl and the heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S; R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x and R d But methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH, or -CN; R f is absent, H, or methyl; R g is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2; R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10aryl or 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and -OH; R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl, R i However, (i)-(CH2) s OC(O)C1-C6 alkyl (wherein the alkyl is substituted with one or more NH2), (ii) (CH2CH2O) n or (iii) a C1-C6 alkyl substituted with one or more substituents independently selected from OH, and a 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms each selected from O, N, or S; R j is absent, H, C1-C6 alkyl, or -CN; R x each independently at each occurrence is H, C-C alkyl, or C-C 10 is aryl, R y and R z are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; m, p, q, r, and t are each independently 0, 1, or 2; n is 0, 1, 2, or 3; s is 1 or 2, o is 0, 1, 2, 3, or 4;

[0016] [ka]

[0017] represents a single or double bond, however, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, R 7 is not -COOH, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, and R 7 is tetrazole, R c But not H, X is O and R f is H, W is C, and R j is -CN and L is -SC(R 5 )2 or -SCH2CH2-, and R 1 If absent, R 7 is not COOH or tetrazole, X is O and R f is H, W is N, and R j is absent, and R d is methyl, an optionally substituted 5- to 10-membered aryl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered cycloalkyl, L is -SCH2- or -OCH2-, and R 1 is phenylene, R 7 -COOH, -CH2COOH,

[0018] [ka]

[0019] Instead, X is O and R f is H, W is N, and R j is absent, L is -NHCH2-, -CH2NH-, or -NH-C(O)-, and R 1 is phenylene, R d is not phenyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0020] The present disclosure provides a compound represented by formula (II):

[0021] [ka]

[0022] During the ceremony, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl; W is N or C; (i) When W is N, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0023] [ka]

[0024] , -(C(R 5 )2) m Y 1 (C(R 5 )2) p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y 1CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and (ii) When W is C, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0025] [ka]

[0026] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R 5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5 )2) m NR3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and Y 1 But, O, NR 4 , or S(O) q and Y 2 are each independently O, NH, or S; R 1 But absent, C6-C 10 arylene, heteroarylene, or C3-C8 cycloalkylene, wherein the heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S; 10 The arylene, the heteroarylene, and the C3-C8 cycloalkylene are each independently selected from 1 to 2 R e optionally replaced by R 2 is H or C1-C4 alkyl; R 2’ is H, C1-C4 alkyl, or C3-C7 cycloalkyl, or R 2 and R 2’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S; R 3 is H or C1-C4 alkyl; R 4 is H or C1-C4 alkyl; R 5 is each independently at each occurrence H or C1-C4 alkyl; R 6 is each independently at each occurrence H or C1-C4 alkyl; R 7 is H, A, B, or C, A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazolone, -(C(R 6 )2) r Thiadiazolol, -(C(R 6 )2) r Isoxazol-3-ol, -(C(R 6 )2) r P(O)(OH)OR x , -(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r C(O)NHCN, or -(C(R 6 )2) r C(O)NHS(O)2 alkyl, -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazolone, -(C(R 6 )2) r Thiadiazolol, -(C(R 6 )2) r isoxazol-3-ol optionally substituted with C1-C6 alkyl; B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) rS(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NR g R g’ , -(C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NHS(O)NR g R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x and C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R6 )2) r Heteroaryl, -O(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R 6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2) r C(O)NHS(O)2C1-C4 alkyl, wherein the aryl and the heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S; R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x and R d But methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH, or -CN; R f is absent, H, or methyl; Rg is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2; R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10 aryl or 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and -OH; R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl, R i However, (i)-(CH2) s OC(O)C1-C6 alkyl (wherein the alkyl is substituted with one or more NH2), (ii) (CH2CH2O) n or (iii) a C1-C6 alkyl substituted with one or more substituents independently selected from OH, and a 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms each selected from O, N, or S; R j is absent, H, C1-C6 alkyl, or -CN; R x each independently at each occurrence is H, C-C alkyl, or C-C 10 is aryl, R y and Rz are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; m, p, q, r, and t are each independently 0, 1, or 2; n is 0, 1, 2, or 3; s is 1 or 2, o is 0, 1, 2, 3, or 4;

[0027] [ka]

[0028] represents a single or double bond, however, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, R 7 is not -COOH, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, and R 7 is tetrazole, R c But not H, X is O and R f is H, W is C, and R j is -CN and L is -SC(R 5 )2 or -SCH2CH2-, and R 1 If absent, R 7 is not COOH or tetrazole, X is O and R f is H, W is N, and R j is absent, and R d is methyl, an optionally substituted 5- to 10-membered aryl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered cycloalkyl, L is -SCH2- or -OCH2-, and R1 is phenylene, R 7 -COOH, -CH2COOH,

[0029] [ka]

[0030] Instead, X is O and R f is H, W is N, and R j is absent, L is -NHCH2-, -CH2NH-, or -NH-C(O)-, and R 1 is phenylene, R d is not phenyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0031] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0032] Another aspect of the present disclosure provides a compound of formula (I) or (II) for use as a medicament. Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or (II) for use as a medicament.

[0033] Another aspect of the present disclosure provides a method for treating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing the disease or disorder a therapeutically effective amount of one or more compounds of formula (I) or (II).Another aspect of the present disclosure provides a method for preventing a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing the disease or disorder a therapeutically effective amount of one or more compounds of formula (I) or (II). Another aspect of the disclosure provides a method for reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing the disease or disorder a therapeutically effective amount of one or more compounds of formula (I) or (II).

[0034] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + 1. A method for treating a disease or disorder associated with decreased levels of NAD, comprising: + Another aspect of the present disclosure provides a method for treating a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD), comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + 1. A method for preventing a disease or disorder associated with decreased levels of NAD, comprising: + Another aspect of the present disclosure provides a method for treating a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD), comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + 1. A method for reducing the risk of a disease or disorder associated with decreased NAD levels, comprising: +The method includes administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of one or more compounds of formula (I) or (II).

[0035] Another aspect of the present disclosure is a method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder intracellular nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure is a method for preventing a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder an amount of intracellular nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure provides a method for reducing the risk of a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II) that increases intracellular nicotinamide adenine dinucleotide (NAD + The present invention provides a method for treating a pulmonary artery disease, comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) to a patient having a pulmonary artery disease.

[0036] Another aspect of the present disclosure is a method for promoting oxidative metabolism, comprising administering intracellular nicotinamide adenine dinucleotide (NAD) to a subject suffering from or susceptible to developing a metabolic disorder. + The present invention provides a method for treating a pulmonary artery disease, comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) to a patient having a pulmonary artery disease.

[0037] Another aspect of the disclosure provides a compound of Formula (I) or (II) for use in treating a disease or disorder caused by the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the disclosure provides a compound of Formula (I) or (II) for use in preventing a disease or disorder caused by the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the disclosure provides a compound of Formula (I) or (II) for use in reducing the risk of a disease or disorder caused by the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0038] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure provides a compound of formula (I) or (II) for use in treating a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + Another aspect of the present disclosure provides a compound of formula (I) or (II) for use in the prevention of a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + The present invention provides a compound of formula (I) or (II) for use in reducing the risk of a disease or disorder associated with decreased levels of erythrocyte sedimentation factor (EGF).

[0039] Another aspect of the present disclosure is a method for treating disorders associated with mitochondrial dysfunction by administering to a subject an intracellular nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure provides compounds of formula (I) or (II) that increase intracellular nicotinamide adenine dinucleotide (NAD) levels for use in the prevention of disorders associated with mitochondrial dysfunction. + Another aspect of the present disclosure provides compounds of formula (I) or (II) that increase intracellular nicotinamide adenine dinucleotide (NAD) levels for use in reducing the risk of disorders associated with mitochondrial dysfunction. + The present invention provides a compound of formula (I) or (II) that increases the saturation potential of the compound.

[0040] Another aspect of the present disclosure is a method for the preparation of intracellular nicotinamide adenine dinucleotide (NAD) for use in promoting oxidative metabolism. + The present invention provides a compound of formula (I) or (II) that increases the saturation potential of the compound.

[0041] Another aspect of the present disclosure provides the use of a compound of Formula (I) or (II) for treating a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the present disclosure provides the use of a compound of Formula (I) or (II) for preventing a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the present disclosure provides the use of a compound of Formula (I) or (II) for reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0042] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) for treating a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) for preventing a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + The present invention provides the use of a compound of formula (I) or (II) for reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (erythropoietin).

[0043] Another aspect of the present disclosure is the use of intracellular nicotinamide adenine dinucleotide (NAD) for the treatment of disorders associated with mitochondrial dysfunction. + Another aspect of the present disclosure provides the use of compounds of formula (I) or (II) to increase intracellular nicotinamide adenine dinucleotide (NAD) levels for preventing disorders associated with mitochondrial dysfunction.+ Another aspect of the present disclosure provides the use of compounds of formula (I) or (II) to increase intracellular nicotinamide adenine dinucleotide (NAD) levels to reduce the risk of disorders associated with mitochondrial dysfunction. + The present invention provides the use of a compound of formula (I) or (II) to increase the activity of a hydroxybenzoate.

[0044] Another aspect of the present disclosure is the administration of intracellular nicotinamide adenine dinucleotide (NAD) to promote oxidative metabolism. + The present invention provides the use of a compound of formula (I) or (II) to increase the activity of a hydroxybenzoate.

[0045] Another aspect of the disclosure provides the use of a compound of Formula (I) or (II) in the manufacture of a medicament for treating a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the disclosure provides the use of a compound of Formula (I) or (II) in the manufacture of a medicament for preventing a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the disclosure provides the use of a compound of Formula (I) or (II) in the manufacture of a medicament for reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0046] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for treating a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for preventing a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD). +The present invention provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for reducing the risk of a disease or disorder associated with decreased levels of erythropoietin.

[0047] Another aspect of the present disclosure is the use of intracellular nicotinamide adenine dinucleotide (NAD) in the manufacture of a medicament for treating a disorder associated with mitochondrial dysfunction. + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) to increase intracellular nicotinamide adenine dinucleotide (NAD) levels in the manufacture of a medicament for preventing disorders associated with mitochondrial dysfunction. + Another aspect of the present disclosure provides the use of a compound of formula (I) or (II) to increase intracellular nicotinamide adenine dinucleotide (NAD) in the manufacture of a medicament for reducing the risk of disorders associated with mitochondrial dysfunction. + The present invention provides the use of a compound of formula (I) or (II) to increase the activity of a hydroxybenzoate.

[0048] Another aspect of the present disclosure is the use of intracellular nicotinamide adenine dinucleotide (NAD) in the manufacture of a medicament for promoting oxidative metabolism. + The present invention provides the use of a compound of formula (I) or (II) to increase the activity of a hydroxybenzoate.

[0049] In certain embodiments, compounds of the present disclosure may be administered alone or in combination with other compounds, including other ACMSD-modulating compounds, or other therapeutic agents.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.In this specification, the singular form can also include the plural form unless the context clearly dictates otherwise.Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.All publications, patent applications, patents, and other references mentioned herein are incorporated by reference.References cited herein are not admitted to be prior art to the claimed disclosure.In the event of a conflict, the present specification, including definitions, will control.In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0051] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0052] All references cited herein, including any patents or patent applications, are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Further, no admission is made that any prior art constitutes part of the common general knowledge in the art.

[0053] As used throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: In the event of a lack of a term, conventional terms known to those skilled in the art shall prevail.

[0054] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense. Throughout this detailed description and the claims, the words "comprise" and "contain," as well as variations of these words, such as "comprising" and "comprises," mean "including, but not limited to," and do not exclude other moieties, additives, ingredients, integers, or steps. Throughout this detailed description and the claims, the singular encompasses the plural unless the context otherwise requires. Specifically, where the indefinite article is used, it should be understood that the specification contemplates the singular as well as the plural, unless the context otherwise requires.

[0055] As used in this disclosure, the articles "a" and "an" may refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. As an example, "an element" may mean one element or more than one element.

[0056] As used in this disclosure, the term "and / or" can mean either "and" or "or," unless otherwise indicated.

[0057] In order to provide a more concise explanation, some of the quantitative expressions provided herein are not modified with the term "about". Regardless of whether the term "about" is explicitly used, all quantities provided herein are intended to refer to the actual given value, and are also intended to refer to the approximation of such given value that may be reasonably inferred based on ordinary skill in the art, including equivalent and approximate values ​​under experimental and / or measurement conditions for such given value. Whenever a yield is expressed as a percentage, such a yield refers to the mass of the entity to which the yield is given relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Concentrations expressed as percentages refer to mass ratios unless otherwise indicated.

[0058] The term "alkyl" as used herein refers to a saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains 1 to 8 carbon atoms (C), including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl, isohexyl, heptyl, and octyl. 1-8 -alkyl), more preferably 1 to 6 carbon atoms (C 1-6 -alkyl), specifically 1 to 4 carbon atoms (C 1-4 In a preferred embodiment, "alkyl" includes C 1-4 represents an -alkyl group, which may specifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Correspondingly, the term "alkylene" refers to the corresponding biradical (-alkyl-).

[0059] The term "cycloalkyl" or "carbocycle" as used herein refers to a ring system having preferably 3 to 10 carbon atoms (C), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-10 -cycloalkyl or C 3-10-carbocyclic rings), e.g., 3 to 8 carbon atoms (C 3-8 -cycloalkyl or C 3-10 -carbocyclic ring), preferably 3 to 6 carbon atoms (C 3-6 -cycloalkyl or C 3-10 "cycloalkyl" refers to cyclic alkyl groups, including bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, decalinyl, and adamantyl. Correspondingly, the term "cycloalkylene" refers to the corresponding biradical (-cycloalkyl-). Alkyl and cycloalkyl groups can be optionally substituted with one to four substituents. Examples of alkyl group substituents include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo, and -CN.

[0060] The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain or cyclic hydrocarbon containing one or more double bonds, including dienes, trienes, and polyenes. Typically, an alkenyl group contains 2 to 8 carbon atoms (C 2-8 -alkenyl), for example, 2 to 6 carbon atoms (C 2-6 -alkenyl), specifically 2 to 4 carbon atoms (C 2-4Examples of alkenyl groups include ethenyl, 1- or 2-propenyl, 1-, 2-, or 3-butenyl, or 1,3-butodienyl, 1-, 2-, 3-, 4-, or 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1,3-octadienyl, or 1,3,5-octatrienyl, or 1,3,5,7-octatetraenyl, or cyclohexene. Correspondingly, the term "alkenylene" refers to the corresponding biradical (-alkenyl-). Alkenyl groups can be optionally substituted with 1 to 4 substituents. Examples of alkenyl group substituents include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo, and -CN.

[0061] The term "alkynyl," as used herein, refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes, and poly-ynes. Typically, an alkynyl group contains 2 to 8 carbon atoms (C 2-8 -alkynyl), for example, alkynyl having 2 to 6 carbon atoms (C 2-6 -alkynyl), specifically alkynyl having 2 to 4 carbon atoms (C 2-4-alkynyl). Examples of preferred alkynyl groups include ethynyl, 1- or 2-propynyl, 1-, 2-, or 3-butynyl, or 1,3-butidinyl, 1-, 2-, 3-, 4-, or 5-hexynyl, or 1,3-hexa-diynyl, or 1,3,5-hexa-triynyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-octynyl, or 1,3-octo-diynyl, or 1,3,5-octo-triynyl, or 1,3,5,7-octo-tetraynyl. Correspondingly, the term "alkynylene" refers to the corresponding biradical (-alkynyl-). The alkynyl group may be optionally substituted with one to four substituents. Examples of substituents for alkynyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo, and -CN.

[0062] As used herein, the terms "halo" and "halogen" refer to fluoro, chloro, bromo, or iodo. Thus, a trihalomethyl group represents, for example, a trifluoromethyl group or a trichloromethyl group. Preferably, the terms "halo" and "halogen" refer to fluoro or chloro.

[0063] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, that is substituted one or more times with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0064] The term "alkoxy" as used herein refers to the group "alkyl-O-", where alkyl is defined above.

[0065] The term "hydroxyalkyl," as used herein, refers to an alkyl group (as defined above) that is substituted one or more times with hydroxy. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0066] As used herein, the term "oxy" refers to the group "-O-."

[0067] As used herein, the term "oxo" refers to a "=O" group.

[0068] The term "amine," as used herein, refers to primary amines (R-NH, where R is not H), secondary amines ((R)-NH, where (R) is not H), and tertiary amines ((R)-N, where R is not H). A substituted amine is intended to mean an amine in which at least one of the hydrogen atoms has been replaced with a substituent.

[0069] The term "carbamoyl," as used herein, refers to a "H2N(C=O)-" group.

[0070] As used herein, the term "aryl," unless otherwise indicated, includes carbocyclic aromatic ring systems derived from aromatic hydrocarbons by removal of a hydrogen atom. Aryl further includes bicyclic, tricyclic, and polycyclic ring systems. Examples of preferred aryl moieties include phenyl, naphthyl, indenyl, indanyl, fluorenyl, biphenyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, pentalenyl, azulenyl, and biphenylenyl. Preferred "aryl" is phenyl, naphthyl, or indanyl, especially phenyl, unless otherwise specified. Any aryl used can be optionally substituted. Correspondingly, the term "arylene" refers to the corresponding biradical (-aryl-). An aryl group can be optionally substituted with one to four substituents. Examples of substituents for an aryl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0071] As used herein, the term "heteroaryl" refers to an aromatic group containing one or more heteroatoms selected from O, S, and N, preferably 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms. Heteroaryl further includes bicyclic, tricyclic, and polycyclic groups in which at least one ring is aromatic and at least one of the rings contains a heteroatom selected from O, S, and N. Heteroaryl also includes ring systems substituted with one or more oxo moieties. Examples of preferred heteroaryl moieties include N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydro-benzo[b]thiophenyl, xanthenyl, isoindanyi, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzyl, benzo ... Examples of heteroaryls include azimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl, azaindolyl, pyrazolinyl, 1,2,4-oxadiazol-5(4H)-one, and pyrazolidinyl. Non-limiting examples of partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-octalin. Correspondingly, the term "heteroarylene" refers to the corresponding biradical (-heteroaryl-). Heteroaryl groups can be optionally substituted with 1 to 4 substituents.Examples of substituents on heteroaryl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0072] As used herein, the term "heterocyclyl" refers to a cyclic non-aromatic group containing one or more heteroatoms selected from O, S, and N, preferably 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms. Heterocyclyl further includes bicyclic, tricyclic, and polycyclic non-aromatic groups in which at least one of the rings contains a heteroatom selected from O, S, and N. Heterocyclyl also includes ring systems substituted with one or more oxo moieties. Examples of heterocyclic groups are oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridinyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazinanyl, pyrimidinyl, 1,3-diazinanyl, pyrazinyl, piperazinyl, 1 ,4-dioxinyl, 1,4-dioxanyl, 1,3-diazinanyl, 1,4-oxazinyl, morpholino, thiomorpholino, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromyl, isochromanyl, 4H-chromenyl, 1H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1H-pyrrolidinyl, 4H-quinolidinyl, and aza-8-bicyclo[3.2.1]octane. Correspondingly, the term "heterocyclylene" refers to the corresponding biradical (-heterocyclyl-). The heterocyclyl group may be optionally substituted with 1 to 4 substituents. Examples of heterocyclyl group substituents include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0073] The term "N-heterocyclic ring" as used herein refers to a heterocyclyl or heteroaryl as defined above having at least one nitrogen atom and bonded via a nitrogen atom. Examples of such N-heterocyclic rings include pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, piperidinyl, pyridazinyl, pyrazinyl, piperazinyl, morpholino, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, etc.

[0074] In this specification, the structural formulas of the compounds may, in some cases, conveniently represent a particular isomer; however, the present disclosure encompasses all isomers, including geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like. Therefore, the definition of a compound of formula (I) or (II) should be understood to encompass any and all individual isomers corresponding to the formula (I) or (II), including cis-trans isomers, stereoisomers, and tautomers, as well as racemic mixtures thereof and pharmaceutically acceptable salts thereof. Therefore, the definition of a compound of formula (I) or (II) is intended to encompass all R and S isomers of the chemical structure in any proportion; for example, when one of the possible isomers is enriched (i.e., enantiomeric excess or diastereomeric excess), the proportion of the corresponding other isomer will be smaller. Additionally, crystalline polymorphism may exist in the compound represented by formula (I) or (II). It should be noted that any crystalline form, mixture of crystalline forms, or anhydrates or hydrates thereof are within the scope of the present disclosure. Additionally, so-called metabolites produced by degradation of the present compounds in vivo are also within the scope of the present disclosure.

[0075] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0076] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."

[0077] "Chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center can exist as either individual diastereomers or a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the sequencing rules of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0078] Diastereoisomers, i.e., non-superimposable stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation. Optical isomers can be obtained by resolving racemic mixtures according to conventional processes, for example, by forming diastereomeric salts by treatment with an optically active acid or base. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Diastereomeric mixtures can be separated by crystallization followed by liberation of the optically active base from the salt. An alternative process for separating optical isomers involves the use of chiral chromatographic columns optimally selected to maximize the separation of the enantiomers. Yet another available method involves the synthesis of covalent diastereomeric molecules by reacting a compound of formula (I) or (II) with an activated form of an optically pure acid or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds. Optically active compounds of formula (I) can be obtained similarly by utilizing optically active starting materials and / or chiral catalysts. These isomers can be in the form of free acids, free bases, esters, or salts. Examples of chiral separation techniques are described in "Chiral Separation Techniques, A Practical Approach, 2000." nd ed. by G. Subramanian, Wiley-VCH, 2001.

[0079] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about double bonds. These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0080] Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers. An "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist due to restricted rotation caused by hindrance of rotation of large groups around a central bond. Such atropic isomers typically exist as a mixture, but recent advances in chromatographic techniques have made it possible in selected cases to separate a mixture of two atropic isomers.

[0081] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer to another. This conversion involves the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0082] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of an electron and a hydrogen atom occurs; and ring-chain tautomerism, which occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving it the cyclic (ring-shaped) form exhibited by glucose.

[0083] Common tautomeric pairs are ketone-enol, amide-nitrile, lactam-lactam, amide-imidic acid tautomers in heterocyclic rings (e.g., nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. It should be understood that the compounds of the present disclosure can be depicted as different tautomers. When a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and it should also be understood that the naming of the compound does not exclude any tautomeric form.

[0084] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0085] In addition, compounds of the present disclosure, such as salts of compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0086] "Solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one molecule of a substance, where the water retains its molecular state as HO.

[0087] As used herein, a "subject" or a "subject in need thereof" refers to a subject having a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction or inhibited by α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD). A "subject" includes a mammal. The mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, a fowl, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. Preferably, the mammal is a human.

[0088] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention.Isotopes include atoms having the same atomic number but different mass numbers.By way of general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include C-13 and C-14.

[0089] compound The present disclosure provides a compound of formula (I):

[0090] [ka]

[0091] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein.

[0092] The present disclosure provides a compound of formula (II):

[0093] [ka]

[0094] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein.

[0095] In certain embodiments of formula (I) or (II) where W is N, the present disclosure provides compounds of formula (II):

[0096] [ka]

[0097] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for Formulas (I) and (II).

[0098] In certain embodiments of formula (I) or (II) where W is C, the present disclosure provides compounds of formula (I-2):

[0099] [ka]

[0100] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for Formulas (I) and (II).

[0101] R 1 In certain embodiments of formula (I) or (II), where is phenyl, the present disclosure provides compounds of formula (I-3):

[0102] [ka]

[0103] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for Formulas (I) and (II).

[0104] R 1 In certain embodiments of formula (I) or (II) where is absent, the present disclosure provides compounds of formula (I-4):

[0105] [ka]

[0106] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for Formulas (I) and (II).

[0107] As described above, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl. In certain embodiments, X is O, OH, OR h , F, Br, or Cl. In certain embodiments, X is H, S, SR 2 , N.R. 2 , or NR 2 R 2’ In certain embodiments, X is H. In certain embodiments, X is S. In certain embodiments, X is SR. 2 In certain embodiments, X is NR 2 In certain embodiments, X is NR 2 R 2’ In certain embodiments, X is O. In certain embodiments, X is OH. In certain embodiments, X is OR h In certain embodiments, X is F. In certain embodiments, X is Br. In certain embodiments, X is Cl.

[0108] As described above, R 2 is H or C1-C4 alkyl. In certain embodiments, R 2 is H. In certain embodiments, R 2 is C1-C4 alkyl. In certain embodiments, R 2 is -CH3.

[0109] As described above, R 2’is H, C1-C4 alkyl, or C3-C7 cycloalkyl. In certain embodiments, R 2’ is H. In certain embodiments, R 2’ is C1-C4 alkyl. In certain embodiments, R 2’ is a C3-C7 cycloalkyl.

[0110] As described above, R 2 and R 2’ are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S. In certain embodiments, R 2 and R 2’ taken together with the nitrogen atom to which they are attached form a 6-membered heterocycloalkyl ring.

[0111] As described above, R h is H, C1-C4 alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein each alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and each heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl. In certain embodiments, R h is H. In certain embodiments, R h is C1-C4 alkyl, each alkyl optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2. In certain embodiments, R h is a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, each heterocycloalkyl being optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0112] As described above, R f is absent, H, or methyl. In certain embodiments, R f is absent. In certain embodiments, R f is H. In certain embodiments, R f is methyl.

[0113] As described above, W is N or C. In certain embodiments, W is N. In certain embodiments, W is C.

[0114] As described above, R j is absent, H, C1-C6 alkyl, or -CN. In certain embodiments, R j is absent. In certain embodiments, R j is H. In certain embodiments, R j is C1-C6 alkyl. In certain embodiments, R j is -CN.

[0115] In certain embodiments, W is N and R j In certain embodiments, W is C and R j is H, C1-C6 alkyl, or -CN. In certain embodiments, W is C and R j is -CN.

[0116] As described above, R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x In certain embodiments, R c is H. In certain embodiments, R c is C1-C6 alkyl. In certain embodiments, R c is C-C haloalkyl. In certain embodiments, R c is halogen. In certain embodiments, R c is -CN. In certain embodiments, Rc -OR x In certain embodiments, R c -CO2R x is.

[0117] As described above, R x is independently, at each occurrence, H, C1-C6 alkyl, or C6-C 10 In certain embodiments, R x is H. In certain embodiments, R x is C1-C6 alkyl. In certain embodiments, R x is C6-C 10 It is aryl.

[0118] As described above, R d is methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl.

[0119] In certain embodiments, R d is methyl. In certain embodiments, R d is CF. In certain embodiments, R d is CR f In certain embodiments, R d is -(C(R 6 )2) t C6-C 10 In certain embodiments, R d is -CH2C6-C 10 In certain embodiments, R dis —CH2C6 aryl. In certain embodiments, R d is -(C(R 6 )2) t -5- or 6-membered heteroaryl. In certain embodiments, R d is -(C(R 6 )2) t -5- or 6-membered cycloalkyl. In certain embodiments, R d is an optionally substituted C6-C 10 In certain embodiments, R d is an optionally substituted 5- or 6-membered heteroaryl. In certain embodiments, R d is an optionally substituted 5- or 6-membered cycloalkyl.

[0120] As described above, R f is absent, H, or methyl. In certain embodiments, R f is absent. In certain embodiments, R f is H. In certain embodiments, R f is methyl.

[0121] As described above, t is 0, 1, or 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

[0122] As described above, when W is N, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0123] [ka]

[0124] , -(C(R 5 )2) m Y 1 (C(R 5 )2)p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p -It is.

[0125] In certain embodiments, W is N and L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p In certain embodiments, W is N and L is

[0126] [ka]

[0127] In certain embodiments, W is N and L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p In certain embodiments, W is N and L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-。 In certain embodiments, W is N and L is -(C(R 5 )2) m Y 1 In certain embodiments, W is N and L is —(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p In certain embodiments, W is N and L is -(C(R 5 )2) m Phenyl (C(R 5 )2) p In certain embodiments, W is N and L is -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p In certain embodiments, W is N and L is -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p In certain embodiments, W is N and L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example, -SCH2- or -NHCH2-. In certain embodiments, W is N and L is -SCH2-. In certain embodiments, W is N and L is -NHCH2-.

[0128] As described above, when W is C, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0129] [ka]

[0130] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R 5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p -It is.

[0131] In certain embodiments, W is C and L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) o In certain embodiments, W is C and L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p In certain embodiments, W is C and L is

[0132] [ka]

[0133] In certain embodiments, W is C and L is -(C(R 5 )2) m Y 1 In certain embodiments, W is C and L is -(C(R 5 )2) m C=(O)(CH2) p In certain embodiments, W is C and L is -(C(R 5 )2) m C=(O)O(C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) m Phenyl (C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p In certain embodiments, W is C and L is -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p -It is.

[0134] As described above, Y 1 , O, NR 4, or S(O) q In certain embodiments, Y 1 is O. In certain embodiments, Y 1 is NR 4 As described above, R 4 is H or C1-C4 alkyl. In certain embodiments, R 4 is H. In certain embodiments, R 4 is C1-C4 alkyl.

[0135] In certain embodiments, Y 1 is S(O) q As described above, q is 0, 1, or 2. In certain embodiments, q is 0. In certain embodiments, Y 1 is S. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0136] As described above, R 5 is each independently at each occurrence H or C1-C4 alkyl. In certain embodiments, R 5 is H. In certain embodiments, R 5 is C1-C4 alkyl.

[0137] As described above, R 3 is H or C1-C4 alkyl. In certain embodiments, R 3 is H. In certain embodiments, R 3 is C1-C4 alkyl.

[0138] As described above, m and p are each independently 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0139] In certain embodiments, o is 0, 1, 2, 3, or 4. In certain embodiments, o is 0. In certain embodiments, o is 1. In certain embodiments, o is 2. In certain embodiments, o is 3. In certain embodiments, o is 4.

[0140] As described above, R 1 is absent or C6-C 10 arylene or heteroarylene, where heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, and is C6-C 10 An arylene or heteroarylene is a group consisting of one to two R e In certain embodiments, R 1 is absent. In certain embodiments, R 1 is 1 to 2 R e C6-C optionally substituted with 10 In certain embodiments, R 1 is heteroarylene, which contains one or two 5- to 7-membered rings and one to four heteroatoms selected from N, O, and S, and one to two R e In certain embodiments of Formula (II), R 1 is C3-C8 cycloalkylene, for example, C3 cycloalkylene, C4 cycloalkylene, C5 cycloalkylene, C6 cycloalkylene, C7 cycloalkylene, or C8 cycloalkylene.

[0141] As described above, R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , —OH, or —CN.

[0142] As described above, R 7 is H, A, B, or C. In certain embodiments, R 7is H. In certain embodiments, R 7 is A. In certain embodiments, R 7 is B. In certain embodiments, R 7 is C.

[0143] As described above for formula (I), A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r Isoxazol-3-ol, -(CH2) r P(O)(OH)OR x , -(CH2) r S(O)2OH, -(CH2) r C(O)NHCN, or -(CH2) r C(O)NHS(O)2 alkyl, -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r The isoxazol-3-ol is optionally substituted with C1-C6 alkyl.

[0144] As described above for formula (II), A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R6 )2) r Tetrazolone, -(C(R 6 )2) r Thiadiazolol, -(C(R 6 )2) r Isoxazol-3-ol, -(C(R 6 )2) r P(O)(OH)OR x , -(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r C(O)NHCN, or -(C(R 6 )2) r C(O)NHS(O)2 alkyl, -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazolone, -(C(R 6 )2) r Thiadiazolol, -(C(R 6 )2) r The isoxazol-3-ol is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r In certain embodiments, A is -(C(R 6 )2) r In certain embodiments, A is -(C(R 6 )2) r In certain embodiments, A is -(C(R 6 )2) r In certain embodiments, A is -(C(R 6 )2) r In certain embodiments, A is -(C(R 6 )2) r P(O)(OH)OR x In certain embodiments, A is -(C(R 6 )2) rS(O)OH. In certain embodiments, A is -(C(R 6 )2) r C(O)NHCN. In certain embodiments, A is -(C(R 6 )2) r C(O)NHS(O)2 alkyl.

[0145] In certain embodiments, A is -(C(R 6 )2) r CO2R x In certain embodiments, A is -Y 2 (C(R 6 )2) r CO2R x In certain embodiments, A is -(CH) r In certain embodiments, A is -(CH) r In certain embodiments, A is -(CH) r In certain embodiments, A is -(CH) r In certain embodiments, A is -(CH) r In certain embodiments, A is -(CH) r P(O)(OH)OR x In certain embodiments, A is -(CH) r S(O)OH. In certain embodiments, A is -(CH) r C(O)NHCN. In certain embodiments, A is -(CH) r C(O)NHS(O) alkyl. In certain embodiments, —(CH) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r The isoxazol-3-ol is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r CO2Rx or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, and the tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl.

[0146] As described above for formula (I), B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) r S(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(CH2) r C(O)NR g R g’ , -(CH2) r S(O)NR g R g’ , -(CH2) r C(O)NHS(O)NR g R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2)r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x is.

[0147] As described above for formula (II), is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) r S(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NR g R g’ , -(C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NHS(O)NR g R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x)2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x In certain embodiments, B is -(C(R 6 )2) r C(O)NR g R g’ In certain embodiments, B is -(C(R 6 )2) r S(O)NR g R g’ In certain embodiments, B is -(C(R 6 )2) r C(O)NHS(O)NR g R g’ is.

[0148] In certain embodiments, B is —(C(R 6 )2) r S(O)OC1-C4 alkyl. In certain embodiments, B is -O(C(R 6 )2) r S(O)2OC1-C4 alkyl. In certain embodiments, B is -Y 2 (C(R 6 )2) r C(O)NR g R g’ In certain embodiments, B is -Y 2 (C(R 6 )2) r S(O)NR g R g’ In certain embodiments, B is -(CH) r C(O)NR g R g’ In certain embodiments, B is -(CH) r S(O)NR g R g’In certain embodiments, B is -(CH) r C(O)NHS(O)NR g R g’ In certain embodiments, B is -(C(R 6 )2) r CO2R i In certain embodiments, B is -(C(R 6 )2) r NH2CO2R x In certain embodiments, B is -(C(R 6 )2) r P(O)(OR x )2. In certain embodiments, B is —O(C(R 6 )2) r P(O)(OR x )2. In certain embodiments, B is -(C(R 6 )2) r In certain embodiments, B is —O(C(R 6 )2) r S(O)OH. In certain embodiments, B is -(C(R 6 )2) r P(O)2OR x In certain embodiments, B is —O(C(R 6 )2) r P(O)2OR x is.

[0149] As described above, C is —(CH) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2) r C(O)NHS(O)2C1-C4 alkyl, wherein the aryl and heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S.

[0150] In certain embodiments, C is (CH) r In certain embodiments, C is -(CH) s In certain embodiments, C is -OH. In certain embodiments, C is halogen. In certain embodiments, C is -(C(R 6 )2) r C6-C 10 In certain embodiments, C is —(C(R 6 )2) r S-C6-C 10 In certain embodiments, C is —(C(R 6 )2) r In certain embodiments, C is —O(C(R 6 )2) r In certain embodiments, C is —O(C(R 6 )2) r In certain embodiments, C is —O(C(R 6 )2) r In certain embodiments, C is -OR. y In certain embodiments, C is -(C(R 6 )2) r C(O)NHCN. In certain embodiments, C is -CH=CHCOR x In certain embodiments, C is -(C(R 6 )2) rC(O)NHS(O)2C1-C4 alkyl, wherein the aryl and heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S.

[0151] As described above, R 6 is each independently at each occurrence H or C1-C4 alkyl. In certain embodiments, R 6 is H. In certain embodiments, R 6 is C1-C4 alkyl.

[0152] As described above, R x are each independently, at each occurrence, H, C-C alkyl, or C-C 10 In certain embodiments, R x is H. In certain embodiments, R x is C1-C6 alkyl. In certain embodiments, R x is C6-C 10 It is aryl.

[0153] As described above, Y 2 are each independently O, NH, or S. In certain embodiments, Y 2 is O. In certain embodiments, Y 2 is NH. In certain embodiments, Y 2 is S.

[0154] As described above, each r is independently 0, 1, or 2. In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2.

[0155] As described above, s is 1 or 2. In certain embodiments, s is 1. In certain embodiments, s is 2.

[0156] As described above, R g is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2.

[0157] As described above, R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10 aryl, or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and -OH.

[0158] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b) is CN, c)R d is a 5- or 6-membered heteroaryl, for example, thiophenyl; d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, e)R 1 is phenylene; f)R 7 is A, for example, COOH or tetrazole.

[0159] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b)R d is CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R 7 is A, for example, COOH or tetrazole.

[0160] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b) is CN, c)R d is a 5- or 6-membered heteroaryl, for example, thiophenyl; d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, e)R 1 is absent, f)R 7 is A, for example, COOH or tetrazole.

[0161] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b)R d is CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is absent, e)R 7 is A, for example, COOH or tetrazole.

[0162] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is C, b)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5- or 6-membered heteroaryl), c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R 7 is A, for example, COOH or tetrazole.

[0163] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is C, b)R d is -CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R 7 is A, for example, COOH or tetrazole.

[0164] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b) is CN, c)R d is a 5- or 6-membered heteroaryl, for example, thiophenyl; d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, e)R 1 is phenylene; f)R 7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0165] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b)R d is CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R 7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0166] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b) is CN, c)R d is a 5- or 6-membered heteroaryl, for example, thiophenyl; d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, e)R 1 is absent, f)R 7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0167] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is N; b)R d is CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is absent, e)R 7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0168] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is C, b)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5- or 6-membered heteroaryl), c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0169] In some embodiments, the present disclosure provides compounds of formula (I) having one, two, or three of the following characteristics: a) W is C, b)R d is -CF3, c) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , for example -SCH2-, d)R 1 is phenylene; e)R 7 is A, for example, -(C(R 6 )2) r CO2R x or -(CH2) r It is tetrazole.

[0170] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Ia) having at least one of the following features:

[0171] [ka]

[0172] and pharmaceutically acceptable salts and tautomers thereof, wherein: a)R d is a 5- or 6-membered heteroaryl; b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and c)R 7 is A or C, d) X, R d , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I). In certain embodiments, R d is thiophenyl. In certain embodiments, L is -SCH- or -NHCH-. In certain embodiments, R 7 is C. In certain embodiments, C is -(C(R 6 )2) r C6-C 10 aryl, each substituted with 1 to 3 substituents independently selected from C-C alkyl, C-C haloalkyl, halogen, and OH. 7 is A. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Ia) has one, two, three, or four of features (a) through (d).

[0173] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Ib) having at least one of the following features:

[0174] [ka]

[0175] and pharmaceutically acceptable salts and tautomers thereof, wherein: a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and b)R 7 is A, c) X, R c , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0176] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Ib) has one, two, or three of features (a)-(c).

[0177] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Ic) having at least one of the following features:

[0178] [ka]

[0179] and pharmaceutically acceptable salts and tautomers thereof, wherein: a)R d is a 5- or 6-membered heteroaryl; b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and c)R 7 is A, d) X, R d , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0180] In certain embodiments, R d is thiophenyl. In certain embodiments, L is -SCH- or -NHCH-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Ic) has one, two, three, or four of features (a)-(d).

[0181] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Id) having at least one of the following features:

[0182] [ka]

[0183] and pharmaceutically acceptable salts and tautomers thereof, wherein: a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and b)R 7 is A, c) X, R d , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0184] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Id) has one, two, or three of features (a)-(c).

[0185] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Ie) having at least one of the following features:

[0186] [ka]

[0187] and pharmaceutically acceptable salts and tautomers thereof, wherein: a)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5- or 6-membered heteroaryl), b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and c)R 7 is A, d) X, R d , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0188] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) rThe tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Ie) has one, two, three, or four of features (a)-(d).

[0189] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (If) having at least one of the following features:

[0190] [ka]

[0191] and pharmaceutically acceptable salts and tautomers thereof, wherein: a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and b)R 7 is A, c) X, R c , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0192] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) rTetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, and the tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, R c is CN. In certain embodiments, formula (If) has one, two, or three of features (a)-(c).

[0193] In certain embodiments, together with certain features of formula (I) above, the present disclosure provides compounds of formula (Ig) having at least one of the following features:

[0194] [ka]

[0195] and pharmaceutically acceptable salts and tautomers thereof, wherein: a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p and b)R 7 is A, c) X, R d , R f , R j , A, R 5 , Y 1 , m, and p are defined as for formula (I).

[0196] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -(C(R6 )2) r COOH or -(CH2) r Tetrazole, -(CH2) r The tetrazole is optionally substituted with C-C alkyl. In certain embodiments, A is -COOH, -CHCOOH, -tetrazole, or -(CH)tetrazole, where tetrazole and -(CH)tetrazole are optionally substituted with C-C alkyl. In certain embodiments, Formula (Ig) has one, two, or three of features (a)-(c).

[0197] In some embodiments, the compound of formula (I) is a compound selected from:

[0198] [Table 1-1]

[0199] [Table 1-2]

[0200] [Table 1-3]

[0201] [Table 1-4]

[0202] [Table 1-5]

[0203] or a pharmaceutically acceptable salt or tautomer thereof.

[0204] In some embodiments, the compound of formula (I) or (II) is a compound selected from the following:

[0205] [Table 2-1]

[0206] [Table 2-2]

[0207] [Table 2-3]

[0208] In some embodiments, the compound of formula (I) is a compound selected from the following, or a pharmaceutically acceptable salt or tautomer thereof:

[0209] [Table 3-1]

[0210] [Table 3-2]

[0211] [Table 3-3]

[0212] [Table 3-4]

[0213] [Table 3-5]

[0214] [Table 3-6]

[0215] [Table 3-7]

[0216] [Table 3-8]

[0217] [Table 3-9]

[0218] or a pharmaceutically acceptable salt or tautomer thereof.

[0219] In some embodiments, the compound of Formula (I) or (II) is a compound selected from the following, or a pharmaceutically acceptable salt or tautomer thereof:

[0220] [Table 4]

[0221] It is to be understood that such references are intended to encompass not only the general formula above, but also any and all of the embodiments discussed below, etc. Unless stated to the contrary, it is also to be understood that such references also encompass isomers, mixtures of isomers, pharmaceutically acceptable salts, solvates, and prodrugs of the compounds of formula (I) or (II).

[0222] Methods for Preparing Compounds The compounds of the present disclosure (e.g., compounds of formula (I)) can be prepared by several methods well known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The final reaction products described herein can be isolated by conventional techniques, such as extraction, crystallization, distillation, chromatography, and the like.

[0223] The compounds of the present disclosure can be synthesized according to the steps outlined in general schemes A-F, which include different sequences for constructing intermediates Ia-Ih and Ij-Io. Starting materials are either commercially available or made by known procedures in the published literature or as illustrated. Useful steps that can be used in the preparation of the compounds will be known to those skilled in the art. The following methods are provided as non-limiting examples of how the compounds can be prepared.

[0224] [ka]

[0225] In the formula, R 1 , R c , R d , and L are defined as in formula (I).

[0226] A general method for preparing compounds of formula (I) using intermediates Ia and Ib is outlined in General Scheme A. Coupling of Ia and Ib using a base, i.e., potassium carbonate (K2CO3), in a solvent, i.e., acetonitrile (CH3CN), optionally at elevated temperature, affords the desired product of formula (I). Bases that can be used include, but are not limited to, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), N,N-diisopropylethylamine (DIPEA), and triethylamine. The solvent used in the coupling reaction can be a polar or nonpolar solvent. For example, the solvent can be acetonitrile (CH3CN), acetone, or dimethyl sulfoxide (DMSO).

[0227] [ka]

[0228] where X is a good leaving group, i.e., Cl, Br, —SCH, or S(O)CH, and R 1 , R 2 , R c , R d , and p are defined as in formula (I).

[0229] Alternatively, compounds of formula (I) can be prepared using intermediates Ic and Id as outlined in general Scheme B. Amination of intermediate Ic with Ie using a base, i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc., in a solvent, i.e., methanol (MeOH), ethanol (EtOH), water (HO), etc., provides compounds of formula (I).

[0230] [ka]

[0231] where X is a good leaving group, i.e., Cl, Br, —SCH, or S(O)CH, and R 1 , R 2 , R c , R d , and p are defined as in formula (I).

[0232] Compounds of formula (I) can also be prepared using intermediates Ie and If as outlined in general Scheme C. Amination of intermediate Ie with If using a base, i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc., in a solvent, i.e., methanol (MeOH), ethanol (EtOH), water (HO), etc., provides compounds of formula (I).

[0233] [ka]

[0234] In the formula, R 1 , R c , and R dis defined as in formula (I).

[0235] Alternatively, compounds of formula (I) can be prepared using intermediates Ig, Ih, Ij, Ik, and Im, as outlined in General Scheme D. Olefination of Ig using a base, i.e., potassium carbonate (K2CO3) and diethyl (cyanomethyl)phosphonate, in a solvent, i.e., tetrahydrofuran (THF), water (HO), optionally at elevated temperature, affords intermediate Ih. Hydrogenation of Ih using a metal catalyst, i.e., palladium on carbon (Pd / C), platinum dioxide (PtO2), etc., and hydrogen (H2) gas in a solvent, i.e., ethanol (EtOH) and / or tetrahydrofuran (THF), affords intermediate Ij. Intermediate Ik can be obtained by treating intermediate Ij with an acid, i.e., hydrochloric acid (HCl), in a solvent, i.e., ethanol (EtOH), dichloromethane (CHCl), etc., followed by a base, i.e., ammonia (NH3). Cyclization of intermediates Ik and Im using a base, i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc., in a solvent, i.e., dimethylacetamide (DMA), optionally at elevated temperature, provides compounds of formula (I).

[0236] [ka]

[0237] In the formula, R 1 , R c , and R d is defined as in formula (I).

[0238] Alternatively, compounds of formula (I) can be prepared using intermediates In and Io as outlined in general Scheme D. Acylation of intermediate In with Io using a base, i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc., in a solvent, i.e., methanol (MeOH), ethanol (EtOH), water (HO), etc., provides compounds of formula (I).

[0239] [ka]

[0240] In the formula, L, R c , R d , R 1 , and R 7 is defined as in formula (I).

[0241] The general procedure for synthesizing compounds having general formula (I) (e.g., I-17 to I-30) is to react 1 equivalent of the corresponding substituted 6-mercapto-2-oxo-4,5-disubstituted-1,2-dihydro-pyridine derivative with a stoichiometric amount of LR using 2 equivalents of DIPEA as base and acetone as solvent. 1 ~LR 7 This involves carrying out a final coupling between intermediates to give the final compound.

[0242] Alternatively, certain compounds of formula (I) or (II) can be prepared using the schemes shown below, and compounds of formula (I) or (II) can generally be prepared based on the schemes shown below.

[0243] [ka]

[0244] [ka]

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] The mixtures of enantiomers, diastereomers, cis / trans isomers resulting from the above processes can be separated into their single components by chiral salt techniques, normal phase, reverse phase, or chromatography using chiral columns, depending on the nature of the separation.

[0249] In the descriptions and formulas given above, the various groups R 1 , R 2 , X, L, Y, R a , R b , R c , R d , R e , R f , R x , R y , R z It is understood that m, n, p, q, r, and other variables are as defined hereinabove unless otherwise indicated. Additionally, for synthetic purposes, the compounds of General Schemes A-E are representative only, with radicals selected to illustrate general methods of synthesis for compounds of Formula (I) as defined herein.

[0250] Pharmaceutical Composition The compounds of formula (I) or (II) may be provided in any form suitable for the intended administration, including, in particular, pharmaceutically acceptable salts, solvates, and prodrugs of the compounds of formula (I) or (II).

[0251] Pharmaceutically acceptable salts refer to salts of compounds of Formula (I) or (II) that are deemed acceptable for clinical and / or veterinary use. Typical pharmaceutically acceptable salts include salts prepared by reaction of compounds of Formula (I) or (II) with mineral or organic acids or organic or inorganic bases. Such salts are known as acid addition salts and base addition salts, respectively. It will be recognized that the particular counterion forming part of any salt is not critical, so long as the salt as a whole is pharmaceutically acceptable and the counterion does not impart undesirable qualities to the salt as a whole. These salts can be prepared by methods known to those skilled in the art. Pharmaceutically acceptable salts are those described and discussed, for example, in Remington's Pharmaceutical Sciences, 17th Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, USA, 1985 and more recent editions, and in the Encyclopedia of Pharmaceutical Technology.

[0252] Examples of pharmaceutically acceptable addition salts include those with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, hydroiodic acid, metaphosphoric acid, or phosphoric acid, and those with organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, malic acid, lactic acid, formic acid, propionic acid, glycolic acid, gluconic acid, camphorsulfonic acid, isothioic acid, mucic acid, gentisic acid, isonicotinic acid, saccharinic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), ethanethiol acid, methyl ... Examples of pharmaceutically acceptable salts include acid addition salts formed with arylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid, as well as base addition salts formed with alkali metals and alkaline earth metals and organic bases, such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine, as well as internally formed salts. All references to pharmaceutically acceptable salts should be understood to include solvent addition forms (solvates) or crystalline forms (polymorphs) of the same salt, as defined herein.

[0253] The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may be provided in dissoluble or indissoluble form together with a pharmaceutically acceptable solvent such as water, ethanol, etc. Dissoluble forms may also include hydrated forms such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc.

[0254] The compound of formula (I) or (II) or its pharmaceutically acceptable salt can be provided as a prodrug.The term "prodrug" as used herein is intended to mean a compound that, when exposed to certain physiological conditions, can release the compound of formula (I) or (II) or its pharmaceutically acceptable salt, and then exhibit the desired biological effect.A typical example is the unstable carbamate of an amine.

[0255] Because prodrugs are known to enhance many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), compounds of the present disclosure can be delivered in the form of a prodrug. Accordingly, the present disclosure is intended to encompass prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the present disclosure in vivo when such prodrug is administered to a subject. Prodrugs in the present disclosure are prepared by modifying functional groups present in the compound such that the modifications are cleaved to the parent compound either by routine manipulation or in vivo. Prodrugs include compounds of the present disclosure in which a hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy, or free carbonyl group, respectively.

[0256] Examples of prodrugs include esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds of the disclosure, esters (e.g., C 1-6 These include, but are not limited to, alkyl esters (e.g., methyl ester, ethyl ester, 2-propyl ester, phenyl ester, 2-aminoethyl ester, morpholinoethanol ester, etc.), N-acyl derivatives (e.g., N-acetyl) of amino functional groups, N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups. See Bundegaard, H., Design of Prodrugs, p. 1-92, Elesevier, New York-Oxford (1985).

[0257] The compound or its pharmaceutically acceptable salt, ester or prodrug can be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.In one embodiment, the compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0258] The dosage regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the particular compound or salt thereof being used. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0259] Techniques for formulating and administering the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th Edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0260] In one aspect of the present disclosure, there is provided a pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, diluents, and / or carriers. The compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent, or excipient, in either a single dose or multiple doses. Suitable pharmaceutically acceptable carriers, diluents, and excipients include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents.

[0261] A "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. Pharmaceutical compositions can be formulated with a pharmaceutically acceptable carrier or diluent, and any other known adjuvants and excipients, according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2000, Lippincott Williams & Wilkins.

[0262] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are suitable, within the scope of sound pharmaceutical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0263] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for both veterinary and human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and more than one such excipient.

[0264] Pharmaceutical compositions formed by combining a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as defined herein with a pharmaceutically acceptable carrier, diluent, or excipient can be readily administered in a variety of dosage forms, such as tablets, powders, lozenges, syrups, suppositories, injectable solutions, and the like. In powders, the carrier is a finely divided solid, such as talc or starch, mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0265] The pharmaceutical compositions may be specially prepared for administration by any suitable route, such as oral and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. It will be understood that the preferred route will depend on the general condition and age of the subject being treated, the nature of the condition being treated, and the active ingredient selected.

[0266] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be prepared so as to provide controlled release of the active ingredient, such as sustained or extended release, according to methods well known in the art.

[0267] For oral administration in the form of a tablet or capsule, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof as defined herein may be suitably combined with an oral, non-toxic, pharmaceutically acceptable carrier, such as ethanol, glycerol, or water. Furthermore, if necessary, suitable binders, lubricants, disintegrants, flavoring agents, and coloring agents may be added to the mixture. Suitable binders include, for example, lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, wax, etc. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, croscarmellose sodium, etc. Additional excipients for capsules include macrogels or lipids.

[0268] For the preparation of solid compositions such as tablets, an active compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof is mixed with one or more excipients, such as those described above, and other pharmaceutical diluents, such as water, to produce a solid preformulation composition comprising a homogeneous mixture of the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof. The term "homogeneous" is understood to mean that the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof is dispersed evenly throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets or capsules.

[0269] Liquid compositions of the compounds of formula (I) or (II) or their pharmaceutically acceptable salts, for either oral or parenteral administration, include, for example, aqueous solutions, syrups, elixirs, aqueous or oil suspensions, and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, or polyvinylpyrrolidone.

[0270] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions, or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions before use.

[0271] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersion, and the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0272] The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0273] For example, sterile injectable solution can be prepared by incorporating the active compound in the required amount into a suitable solvent with one or combination of the ingredients listed above, and then sterile filtering.Generally, dispersion is prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the other ingredients listed above.For the sterile powder used to prepare sterile injectable solution, the preparation method is vacuum drying and freeze-drying, thereby obtaining the powder of active ingredient plus any additional desired ingredients from the solution that has been previously sterile filtered.Depot injectable composition is also considered to be within the scope of the present disclosure.

[0274] For parenteral administration, a solution containing a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or sterile aqueous solution can be used. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should first be made isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Oily solutions are suitable for intraarticular, intramuscular, and subcutaneous injection.

[0275] In addition to the aforementioned components, the present compositions having a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof may contain one or more additional ingredients such as diluents, buffers, flavoring agents, coloring agents, surfactants, thickeners, preservatives, e.g., methyl hydroxybenzoate (including antioxidants), emulsifiers, and the like.

[0276] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent a specified disease, disorder, or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. In a preferred embodiment, the disease or disorder being treated is a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0277] For any compound, the therapeutically effective amount can be initially estimated using cell culture assays, e.g., cells, or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0278] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, sex, diet, administration time and frequency, drug combination(s), reaction sensitivity, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0279] The appropriate dosage of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof will depend on the age and condition of the patient, the severity of the disease being treated, and other factors well known to practitioners. The compound may be administered according to different dosing schedules, for example, daily or at intervals such as once a week, either orally, parenterally, or topically. Generally, a single dose will range from 0.01 to 500 mg / kg body weight, preferably from about 0.05 to 100 mg / kg body weight, more preferably from 0.1 to 50 mg / kg body weight, and most preferably from 0.1 to 25 mg / kg body weight. The compound may be administered as a bolus (i.e., the entire daily dose is administered at once) or in divided doses two or more times daily. Variations based on the foregoing dosage ranges can be made by those skilled in the art, taking into account known considerations such as the body weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration.

[0280] The compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof may also be prepared in pharmaceutical compositions containing one or more additional active agents, either alone or in combination with pharmaceutically acceptable carriers, diluents, or excipients, in either single or multiple doses. Suitable pharmaceutically acceptable carriers, diluents, and excipients are as described hereinabove, and the one or more additional active agents may be any of the active agents, or preferably those described in the "Combination Therapy" section hereinbelow.

[0281] Treatment method In another aspect, the present disclosure relates to a method for preventing, reducing the risk of, or ameliorating a disease or disorder involving α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0282] Another aspect of the present disclosure relates to a method for preventing, reducing the risk of, or ameliorating a disease or disorder involving α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0283] Another aspect of the present disclosure relates to a method of treating, preventing, reducing the risk of, or ameliorating a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing the disease or disorder a therapeutically effective amount of one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0284] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with ACMSD a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0285] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + The present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder involving modulation of ATP, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0286] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + The present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder involving modulation of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-36, IL-37, IL-38, IL-49, IL-59, IL-59, IL-59, IL-59, IL-59, IL-59, IL-60, IL-61, IL-62, IL-63, IL-64, IL-75, IL-76, IL-77, IL-78, IL-79, IL-80, IL-81, IL-82, IL-83, IL-84, IL-85, IL-86, IL-87, IL-88, IL-89, IL-90, IL-91, IL-92, IL-93, IL-94, IL-95, IL-96, IL-97, IL-98, IL-99, IL-109, IL-110, IL-120, IL-130, IL-140, IL-151, IL-162, IL-173, IL-174, IL-185, IL-196, IL-197, IL-198, IL-199, IL-

[0287] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + 2. A method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of NAD. + The present invention relates to a method for treating a pulmonary artery disease, comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of pulmonary artery disease, a therapeutically effective amount of one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof.

[0288] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + 2. A method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of NAD. +The present invention relates to a method comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0289] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction, comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof to a subject suffering from or susceptible to a metabolic disorder. In one embodiment, the disorder associated with mitochondrial dysfunction is a genetic mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease. In a preferred embodiment, the disorder associated with mitochondrial dysfunction is a common metabolic disorder, such as obesity or type 2 diabetes.

[0290] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to a metabolic disorder a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease. In a preferred embodiment, the disorder associated with mitochondrial dysfunction is a common metabolic disorder, such as obesity or type 2 diabetes.

[0291] In another aspect, the present disclosure provides a method for promoting oxidative metabolism, comprising administering intracellular nicotinamide adenine dinucleotide (NAD) to a subject suffering from or susceptible to developing a metabolic disorder.+ The present invention relates to a method for treating a disease comprising administering a therapeutically effective amount of one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof to a patient in need thereof to increase the level of serotonin in the patient.

[0292] In another aspect, the present disclosure provides a method for promoting oxidative metabolism, comprising administering intracellular nicotinamide adenine dinucleotide (NAD) to a subject suffering from or susceptible to developing a metabolic disorder. + The present invention relates to a method for increasing the activity of a steroid hormone, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, to a patient.

[0293] In yet another aspect, the present disclosure relates to a method for manufacturing a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder that can be mediated by ACMSD inhibition, wherein the medicament comprises a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0294] In another aspect, the present disclosure relates to a method for manufacturing a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder that can be mediated by ACMSD inhibition, wherein the medicament comprises a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0295] In yet another aspect, the present disclosure relates to a compound for use in a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder that can be mediated by ACMSD inhibition, wherein the compound comprises a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0296] In another aspect, the present disclosure relates to a pharmaceutical composition for use in a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder that can be mediated by ACMSD inhibition, the pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0297] Another aspect of the present disclosure relates to the use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0298] Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0299] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + The present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of erythrocyte sedimentation protein (EGF).

[0300] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD +The present invention relates to the use of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of erythrocyte sedimentation protein (EGF).

[0301] Another aspect of the present disclosure relates to the use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[0302] Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[0303] In another aspect, the disclosure relates to the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting oxidative metabolism.

[0304] In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient in the manufacture of a medicament for promoting oxidative metabolism.

[0305] Another aspect of the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0306] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient for use in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder through the inhibition of α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

[0307] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + The present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of erythrocyte sedimentation protein (EGF).

[0308] In another aspect, the present disclosure provides a method for the preparation of nicotinamide adenine dinucleotide (NAD + The present invention relates to pharmaceutical compositions comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of erythrocyte sedimentation protein (EGF).

[0309] Another aspect of the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[0310] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient for use as a medicament for treating, preventing, reducing the risk of, or ameliorating disorders associated with mitochondrial dysfunction.

[0311] In another aspect, the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use as an agent for promoting oxidative metabolism.

[0312] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, for use as an agent for promoting oxidative metabolism.

[0313] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + The present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment, prevention, reduction of the risk of, or amelioration of a disease or disorder associated with decreased levels of erythropoietin (EGF).

[0314] Another aspect of the present disclosure is a method for treating nicotinamide adenine dinucleotide (NAD + The present invention relates to pharmaceutical compositions comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient for use in treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with decreased levels of erythrocyte sedimentation protein (EGF).

[0315] In another aspect, the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[0316] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient for use in treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[0317] Another aspect of the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in promoting oxidative metabolism.

[0318] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, for use in promoting oxidative metabolism.

[0319] In some embodiments, nicotinamide adenine dinucleotide (NAD + Diseases or disorders associated with decreased levels of α-glucan (α-glucan) include, but are not limited to, chronic liver diseases, including primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency. In one embodiment, the common metabolic disorder is obesity or type 2 diabetes.

[0320] In some embodiments, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease.

[0321] In another aspect, the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutical composition comprising a compound of Formula (I) or (II).

[0322] As used herein, "treating" or "treating" describes the management and care of a patient for the purpose of reversing, preventing, or combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure (i.e., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to reverse the disease, condition, or disorder, eliminate the disease, condition, or disorder, or arrest the progression of the disease, condition, or disorder.

[0323] The compounds of the present disclosure (i.e., compounds of Formula (I) or (II)), or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, can also be used to prevent a disease, condition, or disorder, or to prevent one or more symptoms of such a disease, condition, or disorder. As used herein, "preventing" or "prevent" describes reducing or eliminating the onset of a symptom or complication of a disease, condition, or disorder.

[0324] The compounds of the present disclosure (i.e., compounds of Formula (I) or (II)), or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, can also be used to alleviate one or more symptoms of such diseases, conditions, or disorders. As used herein, the term "alleviating" is intended to describe a process in which the severity of a sign or symptom of a disorder is reduced. Importantly, signs and symptoms can be alleviated without being eliminated. Preferably, treatment is curative or ameliorative.

[0325] Clinical conditions and other uses of the compounds The compounds according to formula (I) or (II) defined herein, or pharmaceutically acceptable forms, compositions, medicaments, and compounds for use thereof, are useful for treating diseases or disorders involving α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) regulation. The compounds can be used in either human or veterinary medicine, and the patient can be any mammal, particularly a human. Treatment can involve administering a therapeutically effective amount of a compound of formula (I) or (II) defined herein, or a pharmaceutically acceptable salt thereof, to any mammal, particularly a human, suffering from a disease or disorder involving α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) regulation.

[0326] The present disclosure also relates to a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction, such as obesity, type 2 diabetes and its complications (e.g., diabetic retinopathy and nephropathy), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or chronic kidney disease.

[0327] The term "disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction" refers to the involvement of nicotinamide adenine dinucleotide (NAD) in the disease, at least in some cases. + ) any disease characterized by decreased expression and / or activity, or NAD + It refers to a condition that is improved by increasing levels.

[0328] The disclosed methods, medicaments, and compounds for use are useful for treating, alleviating symptoms of, or delaying the onset of disorders associated with abnormal mitochondrial function. Disorders associated with abnormal mitochondrial function include, for example, metabolic disorders, neurodegenerative disorders, age-related disorders, and chronic inflammatory disorders. Mitochondrial disorders also include diseases involving inherited and / or acquired mitochondrial dysfunction (i.e., Charcot-Marie-Tooth disease, type 2A2, mitochondrial encephalopathy lactic acidosis and stroke (MELAS), Leigh syndrome, Barth syndrome, and Leber optic neuropathy), fatty acid oxidation disorders, hereditary hearing loss and blindness, and metabolic disorders induced by exposure to toxic chemicals and / or drugs (e.g., cisplatin-induced hearing loss).

[0329] Metabolic disorders include, for example, type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance (i.e., hyperinsulinemia, metabolic syndrome, syndrome X), hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia (e.g., dyslipidemia), hypertriglyceridemia, cardiovascular disease, atherosclerosis, peripheral vascular disease, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer, and edema.

[0330] Neurodegenerative disorders include diseases such as photoreceptor degeneration (ie, retinitis pigmentosa), dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0331] Chronic inflammatory diseases include diseases such as celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), irritable bowel disease, atherosclerosis, arthritis, and psoriasis.

[0332] Age-related disorders include diseases such as cancer, dementia, cardiovascular disease (i.e., arteriosclerosis), hypertension, diabetes mellitus (type 1 or type 2), arthritis, cataracts, Alzheimer's disease, macular degeneration, and osteoporosis.

[0333] A subject may be suffering from or susceptible to developing a metabolic disorder. Subjects suffering from or at risk of developing a metabolic disorder can be identified by methods known in the art. For example, diabetes can be diagnosed by measuring fasting blood glucose levels or insulin or by a glucose tolerance test. A normal blood glucose level in an adult is approximately 60-126 mg / dL. A normal insulin level is approximately 7 mU / mL ± 3 mU. Hypertension can be diagnosed by measuring blood pressure consistently above approximately 140 / 90. Cardiovascular disease can be diagnosed by measuring cholesterol levels. For example, LDL cholesterol above approximately 137 or total cholesterol above approximately 200 indicates cardiovascular disease. Hyperglycemia can be diagnosed by a blood glucose level above approximately 10 mmol / L (180 mg / dL). Glucose intolerance can be diagnosed by a glucose level of 140-199 mg per deciliter (7.8-11.0 mmol) after a 75 g, 2-hour oral glucose tolerance test. Insulin resistance can be diagnosed by a fasting serum insulin level greater than approximately 60 pmol / L. Hypoglycemia can be diagnosed by a blood glucose level less than approximately 2.8-3.0 mmol / L (50-54 mg / dL). Obesity can be diagnosed, for example, by body mass index. Body mass index (BMI) is measured in kg / m 2 (or lb / in 2× 704.5). Alternatively, waist circumference (to estimate fat distribution), waist-to-hip ratio (to estimate fat distribution), skinfold thickness (to estimate fat distribution when measured at multiple sites), or bioimpedance (to estimate % fat based on the principle that lean mass conducts electrical current better than fat mass (i.e., fat mass impedes current)) can be measured. Parameters for normal, overweight, or obese individuals are as follows: underweight: BMI less than 18.5; normal: BMI between about 18.5 and about 24.9; overweight: BMI between about 25 and about 29.9. Overweight individuals are characterized by having a waist circumference greater than 94 cm for men or greater than 80 cm for women, and a waist-to-hip ratio greater than 0.95 for men or 0.80 for women. Obese individuals are characterized by having a BMI of 30-34.9, being 20% ​​or more above "normal" weight for their height, having a body fat percentage greater than 30% for women and greater than 25% for men, and having a waist circumference greater than 40 inches for men or 35 inches for women. Individuals with severe obesity or morbid obesity are characterized by having a BMI of 35 or greater.

[0334] The methods described herein can reduce or alleviate the severity of one or more symptoms of metabolic disorder.For example, symptoms of diabetes include elevated fasting blood glucose levels, blood pressure of 140 / 90 mm / Hg or higher, abnormal blood fat levels, such as high-density lipoprotein (HDL) of 35 mg / dL or lower, or triglycerides of 250 mg / dL or higher (mg / dL = milligrams of glucose per deciliter of blood).The effectiveness of treatment can be determined in association with any known method for diagnosing metabolic disorder.Alleviation of one or more symptoms of metabolic disorder indicates that the compound provides clinical benefit.

[0335] The disclosed methods are useful for treating, alleviating symptoms of, or delaying the onset of kidney damage, including acute kidney injury (AKI) and chronic kidney disease (CKD).

[0336] A subject may be suffering from or susceptible to developing acute kidney injury (AKI). Acute kidney injury can be characterized by one or more clinical criteria or conditions (i.e., a sudden decrease in the kidney's ability to excrete nitrogenous waste products from the blood, causing azotemia). Subjects suffering from or at risk of developing acute kidney injury (AKI) can be identified by methods known in the art. For example, acute kidney injury can be characterized by an increase in serum creatinine of at least 50% above baseline, an absolute increase in serum creatinine of at least 0.3 mg / dL above baseline, a decrease in glomerular filtration rate of at least 25% compared to baseline, a decrease in urine output to 0.5 mL / kilogram body weight per hour or less that lasts for at least 6 hours, or any combination thereof. Acute kidney injury can be caused by ischemia, drugs or toxic agents (i.e., radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, or chemotherapeutic agents), viruses, and obstructive diseases.

[0337] The subject may have or be susceptible to developing chronic kidney disease (CKD), defined as (1) kidney damage defined by structural or functional abnormalities of the kidney for 3 months or more, with or without a reduced glomerular filtration rate (GFR), or (2) a GFR of 60 mL / min / 1.73 m for 3 months or more, with or without kidney damage. 2 The subject with chronic kidney disease (CKD) or at risk of developing it is identified by methods known in the art.Structural or functional abnormalities are manifested by symptoms such as pathological abnormalities or markers of kidney damage, including abnormalities identified in imaging studies or blood or urine composition.

[0338] For example, CKD can be diagnosed by testing for specific markers. For example, markers of kidney damage include a plasma creatinine concentration greater than about 1.6 mg / dL and a blood urea nitrogen (BUN) concentration greater than about 20 mg / dL. Typically, both of these markers are elevated in patients with CKD. Additional markers of kidney damage may include hematuria (i.e., any detectable amount of blood in the urine), proteinuria (i.e., a urinary protein concentration greater than about 100 mg / dL), albuminuria (i.e., a urinary albumin concentration greater than about 100 mg / dL), a blood intact parathyroid hormone (PTH) concentration greater than about 150 pg / mL, or a blood phosphate level greater than about 4.5 mg / dL. One specific marker of kidney disease is a glomerular filtration rate (GFR) above normal (i.e., about 90 mL / min / 1.73 m 2 A GFR above normal is indicative of CKD, but a GFR below normal is also indicative of CKD.

[0339] The method of the present disclosure is useful for treating non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), alleviating its symptoms, or delaying its onset.Subject may be suffering from or prone to developing non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH).Subjects suffering from or at risk of developing non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) can be identified by methods known in the art.For example, NAFLD and / or NASH can be diagnosed by liver biopsy.

[0340] Nonalcoholic fatty liver disease (NAFLD), as defined herein, is a condition characterized by the deposition of fat in the liver and occurs in patients with an insufficient history of alcohol consumption to cause liver damage. NAFLD can be further classified into simple steatosis, steatohepatitis, and cirrhosis. Nonalcoholic steatohepatitis (NASH) refers to a condition associated with inflammation, hepatocellular necrosis, ballooning, and fibrosis. The development of nonalcoholic simple steatosis is triggered by fat deposition in hepatocytes, and this fat accumulation is defined by the balance between factors increasing fat (influx and synthesis of fat in hepatocytes) and factors decreasing fat (catabolism of fat and its release from hepatocytes). When hepatocyte damage occurs, in addition to this fat deposition, nonalcoholic simple steatosis progresses to nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis is progressive and can eventually progress to cirrhosis and hepatocellular carcinoma.

[0341] Combination treatment In another aspect, the present disclosure includes compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof for use in combination therapy. The compounds, compositions, agents, and compounds for use with Formula (I) or (II) or pharmaceutically acceptable salts thereof may also be advantageously used in combination with one or more other therapeutic agents.Such therapeutic agents include other ACMSD inhibitors; antidiabetic agents, such as PPARy agonists, PPARα / γ dual agonists, PPARδ agonists, biguanides, protein tyrosine phosphatase-1B (PTP-1B), dipeptidyl peptidase IV (DPP-IV) inhibitors, sulfonylureas, meglitinides, alpha-glucoside hydrolase inhibitors, alpha-amylase inhibitors, insulin secretagogues, A2 antagonists, insulin or insulin mimetics, glycogen phosphorylase inhibitors, GLP-1 agonists, non-thiazolidinediones, glycokinase, and 11 beta HSD-1 inhibitors; anti-obesity drugs, for example, uncoupling protein (UCP-1, UCP-2, and UCP-3) activators, beta-3 adrenergic receptor (β3), thyroid hormone beta agonists, fatty acid synthase (PAS) inhibitors, phosphodiesterase (PDE) inhibitors, lipase inhibitors, serotonin reuptake inhibitors, monoamine reuptake inhibitors, Mc4r agonists, 5HT2c agonists, growth hormone secretagogue (GHS) agonists, CNTF derivatives, ciliary neurotrophic factor (CNTh), cholecystokinin-A (CCK-A) agonists, opioid antagonists, orexin antagonists, and acetylcholinesterase inhibitors. estrogen, leptin, NPY5 antagonists, neuropeptide Y5 (NPY5) antagonists, neuropeptide Y2 (NPY2) agonists, melanin-concentrating hormone receptor (MCHLR) antagonists and melanin-concentrating hormone 2 receptor (MCH2R), MCH1R antagonists, neuropeptide Y1, ghrelin antagonists, cannabinoid receptor 1 (CB-1), serotonin (5HT) transport inhibitors, CCK-A agonists and histamine 3 (H3) antagonists / inverse agonists; cholesterol-lowering drugs, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors, fibric acid, bile acid-binding resin probucol and niacin (nicotinic acid); NAD. + Compounds that increase levels, e.g., NAD +precursors (i.e., nicotinamide ribose (NA), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide); and NAD + Compounds that inhibit consumption include, but are not limited to, PARP inhibitors and CD38 inhibitors.

[0342] PPARy agonists useful in the present disclosure include, but are not limited to, glitazones (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, CLX-0921, 5-BTZD, etc.), GW-0207, LG-100641, LY-300512, LY-519818, R483 (Roche), T131 (Tularik), and compounds disclosed in WO97 / 27857, 97 / 28115, 97 / 28137, and 97 / 27847, and pharmaceutically acceptable salts or esters thereof. PPARα / γ dual agonists useful in the present disclosure include, but are not limited to, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB219994, and muraglitazar, and pharmaceutically acceptable salts or esters thereof. KRP-297 is 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide, and pharmaceutically acceptable salts or esters thereof. PPARδ agonists useful in the present disclosure include, but are not limited to, GW 501516, GW 590735, and compounds disclosed in JP10237049, WO02 / 14291, and WO2018 / 125983, and pharmaceutically acceptable salts or esters thereof.

[0343] Biguanides useful in the present disclosure include, but are not limited to, buformin, metformin, and phenformin, as well as pharmaceutically acceptable salts or esters thereof. Metformin (Glucophage®) is indicated for patients with non-insulin-dependent diabetes mellitus, particularly those with refractory obesity. Physician's Desk Reference® pp. 1080-1086 (56th ed., 2002).

[0344] Protein tyrosine phosphatase-1B (PTP-1B) inhibitors useful in the present disclosure include, but are not limited to, A-401,674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, MC52453, and compounds disclosed in WO02 / 26707, WO02 / 26743, JP2002114768, and pharmaceutically acceptable salts or esters thereof.

[0345] Dipeptidyl peptidase IV (DPP-IV) inhibitors, such as isoleucine thiazolidide; NVP-DPP728; P32 / 98; and LAP 237, P 3298, TSL 225, valine pyrrolidide, TMC-2A / 2B / 2C, CD-26 inhibitors, FE 999011, P9310 / K364, VIP 0177, DPP4, SDZ 274A444; and WO03 / 00449, WO03 / 004496, EP1 258 476, WO02 / 083128, WO021062764, WO03 / 000250, WO03 / 002530, WO03 / 002531, WO03 / 002553, WO03 / 002593, WO03 / 000180, and compounds disclosed in WO03 / 000181.

[0346] Sulfonylureas useful in the present disclosure include, but are not limited to, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide, and pharmaceutically acceptable salts or esters thereof.Meglitinides useful in the present disclosure include, but are not limited to, repaglinide and nateglinide, and pharmaceutically acceptable salts or esters thereof.

[0347] Alpha-glucoside hydrolase inhibitors (or glucoside inhibitors) useful in the present disclosure include acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, CKD-711, MDL-25,637, MDL-73,945, and MOR 14, and pharmaceutically acceptable salts or esters thereof, and compounds disclosed in U.S. Pat. Nos. 4,062,950, 4,174,439, 4,254,256, 4,701,559, 4,639,436, 5,192,772, 4,634,765, 5,157,116, 5,504,078, 5,091,418, 5,217,877, and 5,091,524. Alpha-amylase inhibitors useful in the present disclosure include, but are not limited to, tendamistat, trestatin, and A1-3688, and pharmaceutically acceptable salts and esters thereof, as well as compounds disclosed in U.S. Pat. Nos. 4,451,455, 4,623,714, and 4,273,765.

[0348] Insulin secretagogues useful in the present disclosure include, but are not limited to, linoglilide and A-4166, and pharmaceutically acceptable salts and esters thereof.

[0349] Fatty acid oxidation inhibitors useful in the present disclosure include, but are not limited to, clomoxir and etomoxir, and their pharmaceutically acceptable salts and esters.A2 antagonists useful in the present disclosure include, but are not limited to, midaglizole, isaglidole, deriglidole, idazoxan, elaroxan, fluparoxan, and their pharmaceutically acceptable salts and esters.Insulin or insulin mimetics useful in the present disclosure include, but are not limited to, biopharmaceuticals, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-1(73-7) (insulin tropin), and GLP-1(7-36)-NH2), and their pharmaceutically acceptable salts or esters.

[0350] Glycogen phosphorylase inhibitors useful in the present disclosure include, but are not limited to, CP-368,296, CP-316,819, BAYR3401, and compounds disclosed in WO01 / 94300 and WO02 / 20530, and pharmaceutically acceptable salts or esters thereof.GLP-1 agonists useful in the present disclosure include, but are not limited to, exendin-3 and exendin-4, and compounds disclosed in US2003087821 and NZ504256, and pharmaceutically acceptable salts or esters thereof.

[0351] Non-thiazolidinediones useful in the present disclosure include, but are not limited to, JT-501 and farglitazar (GW-2570 / GI-262579), and pharmaceutically acceptable salts or esters thereof. Glycokinase activators useful in the present disclosure include, but are not limited to, fused heterocyclic aromatic compounds, such as those disclosed in US2002103199, and isoindolin-1-one substituted propionamide compounds, such as those disclosed in WO02 / 48106.

[0352] Serotonin (5HT) transport inhibitors useful in the present disclosure include, but are not limited to, paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine. Norepinephrine (NE) transport inhibitors useful in the present disclosure include, but are not limited to, GW 320659, despiramine, talspram, and nomifensine. Cannabinoid receptor 1 (CB-1) antagonists / inverse agonists useful in the present disclosure include those disclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, and U.S. Pat. No. 6,028,084, and PCT Application Nos. WO96 / 33159, WO98 / 33765, WO98 / 43636, WO98 / 43635, WO98 / 43636, WO98 / 43637, WO98 / 43638, WO98 / 43639, WO98 / 43640, WO98 / 43641, WO98 / 43642, WO98 / 43643, WO98 / 43644, WO98 / 43645, WO98 / 43646, WO98 / 43647, WO98 / 43648, WO98 / 43649 ... These include WO98 / 01 / 09120, WO98 / 31227, WO98 / 41519, WO98 / 37061, WO00 / 10967, WO00 / 10968, WO97 / 29079, WO99 / 02499, WO01 / 58869, WO02 / 076949, WO01 / 64632, WO01 / 64633, WO01 / 64634 and WO03 / 007887, and EPO application EP-658546. Specific CB-1 antagonists / inverse agonists useful in the present disclosure include, but are not limited to, rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY 65-2520 (Bayer), and SLY 319 (Solvay). CCK-A agonists useful in the present disclosure include GI 181771 and SR 146,131. Ghrelin antagonists useful in the present disclosure include those described in PCT Application Nos. WO01 / 87335 and WO02 / 08250.Histamine 3 (H3) antagonists / inverse agonists useful in the present disclosure include those described in PCT Application No. WO 02 / 15905, and include O-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3 receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001)), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., al., Pharmazie, 55:83-6 (2000)), and proxyfan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000)). Specific H3 antagonists / inverse agonists useful in the present disclosure include, but are not limited to, thioperamide, 3-(1H-imidazol-4-yl)propyl N-4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxyfan, GT2394 (Gliatech), and A331440.

[0353] Melanin-concentrating hormone receptor (MCHLR) antagonists and melanin-concentrating hormone 2 receptor (MCH2R) agonists / antagonists useful in the present disclosure include those described in PCT Patent Application Nos. WO01 / 82925, WO01 / 87834, WO02 / 06245, WO02 / 04433, and WO02 / 51809, and Japanese Patent Application No. JP13226269. Specific MCH1R antagonists useful in the present disclosure include, but are not limited to, T-226296 (Takeda), SB 568849, and SNAP 7941. Neuropeptide Y1 (NPY1) antagonists useful in the present disclosure include those described in U.S. Patent No. 6,001,836, and PCT Application Nos. WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 / 85690, WO01 / 85098, WO01 / 85173, and WO01 / 89528.Specific examples of NPY1 antagonists useful in the present disclosure include, but are not limited to, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A. Neuropeptide Y2 (NPY2) agonists useful in the present disclosure include, but are not limited to, peptide YY (PYY), and PYY3_36, peptide YY analogs, PYY agonists, and compounds disclosed in WO03 / 026591, WO03 / 057235, and WO03 / 027637.Neuropeptide Y5 (NPY5) antagonists useful in the present disclosure include those described in U.S. Patent Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,337,332, 6,329,395, and 6,340,683; U.S. Patent Nos. 6,326,375, 6,329,395, 6,337,333; 2, 6,335,345, European Patent Nos. EP01010691 and EP01044970, and PCT International Patent Publication Nos. WO97 / 19682, WO97 / 20820, WO97 / 20821, WO97 / 20822, WO97 / 20823, WO98 / 27063, WO00 / 107409, WO00 / 185714, WO00 / 185730, WO00 / 64880, WO00 / 68197, WO00 / 69849, WO01 / 09120, WO 01 / 85714, WO01 / 85730, WO01 / 07409, WO01 / 02379, WO01 / 02379, WO01 / 23388, WO These include, but are not limited to, compounds described in WO01 / 23389, WO01 / 44201, WO01 / 62737, WO01 / 62738, WO01 / 09120, WO02 / 20488, WO02 / 22592, WO02 / 48152, WO02 / 49648, and WO01 / 14376. Particular NPY5 antagonists useful in the combinations of the present disclosure include, but are not limited to, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR 235,208, FR 226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, JCF-104, and H409 / 22.Additional specific NPY5 antagonists useful in the combinations of the present disclosure include, but are not limited to, the compounds described in Norman et al., J. Med. Chem. 43:42884312 (2000). Leptins include, but are not limited to, recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen). Leptin derivatives (e.g., truncated forms of leptin) useful in the present disclosure include those described in Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos. WO96 / 23513, WO96 / 23514, WO96 / 23515, WO96 / 23516, WO96 / 23517, WO96 / 23518, WO96 / 23519, and WO96 / 23520.

[0354] Opioid antagonists useful in the present disclosure include those described in PCT Application No. WO00 / 21509. Specific opioid antagonists useful in the present disclosure include, but are not limited to, nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone. Orexin antagonists useful in the present disclosure include those described in PCT Patent Application Nos. WO01 / 96302, WO01 / 68609, WO02 / 51232, WO02 / 51838, and WO03 / 023561. Specific orexin antagonists useful in the present disclosure include, but are not limited to, SB-334867-A. Acyl-estrogens useful in the present disclosure include oleoyl-estrone (del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001)). Cholecystokinin-A (CCK-A) agonists useful in the present disclosure include those described in U.S. Patent No. 5,739,106. Specific CCK-A agonists include, but are not limited to, AR-R 15849, GI181771, JMv-180, A-71378, A-71623, and SR146131. ​​Specific ciliary neurotrophic factors (CNTh) useful in the present disclosure include, but are not limited to, GI-181771 (GlaxoSmithKline), SR146131 (Sanofi Synthelabo), butavindide, PD170,292, and PD 149164 (Pfizer). CNTF derivatives useful in the present disclosure include, but are not limited to, axokine (Regeneron) and PCT Application Nos. WO94 / 09134, WO98 / 22128, and WO99 / 43813. Growth hormone secretagogue (GHS) agonists useful in the present disclosure include U.S. Patent No. 6,358,951, U.S. Patent Application Nos. 2002 / 049196 and 2002 / 022637, and PCT Application Nos. WO01 / 56592 and WO02 / 32888. Specific GHS agonists include, but are not limited to, NN703, hexarelin, MK-0677, SM-130686, CP424 391, L-692,429, and L-163,255.

[0355] The 5HT2c agonist useful in the present disclosure includes U.S. Patent No. 3,914,250, and PCT application Nos. WO02 / 36596, WO02 / 48124, WO02 / 10169, WO01 / 66548, WO02 / 44152, WO02 / 51844, WO02 / 40456 and WO02 / 40457.The specific 5HT2c agonist useful in the present disclosure includes but is not limited to BVT933, DPCA37215, 1K264, PNU22394, WAY161503, R-1065 and YM348.

[0356] Mc4r agonists useful in the present disclosure include those disclosed in PCT Application Nos. WO99 / 64002, WO00 / 74679, WO01 / 991752, WO01 / 74844, WO01 / 70708, WO01 / 70337, WO01 / 91752, WO02 / 059095, WO02 / 059107, WO02 / 0 59108, WO02 / 059117, WO02 / 12166, WO02111715, WO02 / 12178, WO02 / 15909, WO02 / 068387, WO02 / 068388, WO02 / 067869, WO03 / 007949, and WO03 / 009847. Particular Mc4r agonists useful in the present disclosure include CIR86036 (Chiron), ME-10142, and ME-10145 (Melacure).

[0357] Monoamine reuptake inhibitors useful in the present disclosure include those disclosed in PCT Application Nos. WO 01 / 27068 and WO 01 / 62341. Particular monoamine reuptake inhibitors useful in the present disclosure include, but are not limited to, sibutramine (Meridia O / Reductil®), which is disclosed in U.S. Patent Nos. 4,746,680, 4,806,570, and 5,436,272, and U.S. Patent Publication No. 2002 / 0006964.

[0358] Serotonin reuptake inhibitors and releasing agents useful in the present disclosure include dexfenfluramine, fluoxetine, and other serotonin reuptake inhibitors, including, but not limited to, those described in U.S. Pat. No. 6,365,633 and PCT Patent Applications WO01 / 27060 and WO01 / 162341.

[0359] 11β HSD-1 inhibitors useful in the present disclosure include, but are not limited to, BVT 3498, BVT 2733, and the compounds disclosed in WO01 / 90091, WO01 / 90090, and WO01 / 90092. Uncoupling protein (UCP-1, UCP-2, and UCP-3) activators useful in the present disclosure include those described in PCT Patent Application No. WO99 / 00123. Specific uncoupling protein (UCP-1, UCP-2, and UCP-3) activators useful in the present disclosure include, but are not limited to, phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), and retinoic acid.

[0360] Beta3 adrenergic receptor (beta3) agonists useful in the present disclosure include those described in U.S. Patent Nos. 5,705,515 and 5,451,677, and PCT Patent Applications WO01 / 74782 and WO02 / 32897. Specific beta agonists useful in the present disclosure include, but are not limited to, AD9677 / TAK677 (Dainippon / Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecadrine, Zeneca D7114, and SR 59119A.

[0361] Thyroid hormone beta agonists useful in the present disclosure include those described in PCT Application No. WO02 / 15845 and Japanese Patent Application No. JP2000256190. Specific thyroid hormone beta agonists useful in the present disclosure include, but are not limited to, KB-2611 (KaroBioBMS). Specific fatty acid synthase (PAS) inhibitors useful in the present disclosure include, but are not limited to, cerulenin and C75. Specific phosphodiesterase (PDE) inhibitors useful in the present disclosure include, but are not limited to, theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast.

[0362] Lipase inhibitors useful in the present disclosure include, but are not limited to, those disclosed in PCT Application No. WO 01 / 77094, and U.S. Pat. Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644, 4,189,438, and 4,242,453. Specific lipase inhibitors useful in the present disclosure include, but are not limited to, tetrahydrolipstatin (orlistat / Xenical®), Triton WR1339, RHC80267, lipstatin, tea saponin, and diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, estellacin, ebelactone A, ebelactone B, and RHC 80267.

[0363] Examples of HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, and fluvastatin.Examples of HMG-CoA synthase inhibitors are the beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564, U.S. Patent No. 4,816,477, U.S. Patent No. 4,847,271, and U.S. Patent No. 4,751,237, the beta-lactam derivatives disclosed in U.S. Patent No. 4,983,597 and U.S. Patent No. 07 / 540,992 filed June 20, 1990, and the substituted oxacyclopropane analogs disclosed in European Patent Publication No. EP 0 411 703.Examples of squalene epoxidase inhibitors are disclosed in European Patent Publication No. EP 0 318 860 and Japanese Patent Publication No. J02 169-571A. Examples of LDL-receptor gene inducer molecules are disclosed in U.S. Patent No. 5,182,298, filed March 18, 1991. Other cholesterol-lowering drugs that may be administered include niacin, probucol, fibric acids (i.e., clofibrate and gemfibrozil), and LDL-receptor gene inducers.

[0364] Examples of PARP inhibitors include iodonitricoumarin, 5-iodo-6-nitrocoumarin, 3,4-dihydro-5-methyl-isoquinolinone, 4-amino-1,8-naphthalimide, 3-methoxybenzamide, 8-hydroxy-2-methyl-3-hydro-quinazolin-4-one, 2-{3-[4-(4-fluorophenyl)-3,6-dihydro-1(2h)-pyridinyl]propyl}-8-methyl-4(3h)-quinazolinone, 5- These include, but are not limited to, fluoro-1-[4-(4-phenyl-3,6-dihydropyridine-1(butyl]quinazoline-2,4(1h,3h)-dione, 3-(4-chlorophenyl)quinazoline-5-carboxamide, 2-(3′-methoxyphenyl)benzimidazole-4-carboxam, benzamide, 3-aminobenzamide, 3-aminophthalhydrazide, and 1,5-dihydroxyisoquinoline.

[0365] The above compounds that may be used in combination with compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof can be prepared and administered as described in the art, such as in the documents cited above.

[0366] The above compounds are ACMSD inhibitors, antidiabetic agents, antiobesity agents, cholesterol-lowering agents, NAD inhibitors, and the like that may be used in the compositions of the present disclosure. + Compounds that increase levels of NAD + These compounds are merely illustrative of compounds that inhibit consumption, and as this list of compounds is not intended to be comprehensive, the methods of the present disclosure may be used with any anti-obesity agent and any anti-diabetic agent and are not limited to any particular structural class of compounds.

[0367] As used herein, "combination therapy" includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, with at least a second agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, a synergistic effect, e.g., a synergistic effect, and / or pharmacokinetic or pharmacodynamic co-action, or any combination thereof, resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination typically occurs over a defined period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" may, but generally is not intended to, encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combination of the present disclosure.

[0368] "Combination therapy" is intended to encompass both sequential administration of these therapeutic agents (where the therapeutic agents are administered at different times in any order, or alternating in any order) and substantially simultaneous administration of these therapeutic agents or at least two of these therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent, or by administering multiple separate capsules, one for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent of a selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The order in which the therapeutic agents are administered is largely immaterial.

[0369] Biological assays and animal studies Methods for screening ACMSD1 inhibition The activity of compounds as inhibitors of ACMSD1 is determined in an in vitro spectrophotometric assay. A pre-assay mixture is incubated, followed by the addition of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and an ACMSD1 solution. The effect of ACMS concentration on enzyme activity is investigated by varying the concentration of 3-hydroxyanthranilic acid (3OH-HA) in the pre-assay mixture. Kinetic parameters are calculated from the initial rate data using a Lineweaver-Burk plot.

[0370] Cellular Assays Mouse hepatocyte cell line is grown and plated.Cells are maintained in culture at 37 ℃, and when cells adhere, different concentrations of the compound of formula (I) or (II) or its pharmaceutically acceptable salt, or DMSO are added.Primary hepatocytes are harvested after about 24 hours. Determination of ACMSD-1 regulation in HEK293T cells.

[0371] HEK293T cells were seeded and transfected to transiently express ACMSD. The cells were then stimulated with different concentrations of compounds of formula (I) or (II), lysed, and ACMSD activity was measured in an in vitro spectrophotometric assay. The total protein content in the cell lysates was detected by Bradford analysis, which was used to obtain the normalized specific activity of the enzyme across all samples.

[0372] NAD in human primary hepatocytes + Determination of content After seeding, primary hepatocytes are treated with different concentrations of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or MEHP (control). The compound is replaced every 24 hours, after which the cells are directly harvested, lysed, and analyzed for NAD by LC-MS / MS (liquid chromatography mass spectrometry / mass spectrometry). + The content is detected.

[0373] Regulation of SOD2 activity in AML12 cells and mouse primary hepatocytes Primary hepatocytes or AML-12 cells are lysed, and total protein concentration is measured using a Bradford assay. SOD2 activity is measured at the indicated time points after treatment with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof using an SOD assay kit. Absorbance is determined, and the results are expressed as U / mL / mg of protein according to a standard curve and the measured protein concentration.

[0374] NAD in mouse primary hepatocytes + Determination of content NAD +The protein is extracted using an acid extraction method, and the sample is collected and homogenized. After the insoluble protein portion is pelleted, the sample is separated by high-performance liquid chromatography (HPLC) and analyzed by mass spectrometry. Protein in the pellet is quantified by Bradford assay and used for normalization.

[0375] RNA preparation and RT-qPCR analysis of ACMSD- and SIRT1-regulated genes in cells Cells (AML-12, Hepa-1.6, HEK-293, primary human and mouse hepatocytes) are treated with different concentrations of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and gene expression of ACMSD, Pgc1a, Sod1, and Sod2 (MnSOD) is determined using RT-qPCR. Total RNA is extracted from the cells, treated with DNase, and used for reverse transcription (RT).

[0376] Regulation of caspase 3 / 7 activity in MDCK cells MDCK cells are cultured in basal medium to a final concentration of 10%. The cells are plated in 96-well plates, and 24 hours after plating, the medium is replaced with fresh medium supplemented with 1% FBS. Cytotoxicity is then induced using cisplatin. Different concentrations of Formula (I) or (II) or a pharmaceutically acceptable salt thereof (in DMSO) are added in combination with or before cisplatin. Caspase 3 / 7 activity (Promega) is determined according to standard procedures using a luminescent signal readout on a plate reader. Each experiment / condition is performed in triplicate. Caspase activity is analyzed as a percentage effect normalized to cells treated with cisplatin alone and vehicle.

[0377] Cytotoxicity and hERG screening HePG2 and AML-12 cells were seeded and dose-response tests were performed on various concentrations of compounds. Cells were stimulated and supernatants were used to measure LDH release as a measure of necrosis, while cells were lysed to detect ATP levels and determine cell viability.

[0378] The Predictor hERG assay kit is stably transfected with the hERG potassium channel and a high-affinity red fluorescent hERG channel ligand and is used to measure the hERG channel affinity binding of compounds of Formula (I) or (II) or pharmaceutically acceptable salts. Compounds that bind to the hERG channel protein (competitors) are identified by their ability to displace the tracer, resulting in lower fluorescence polarization.

[0379] C. elegans experiments—ACMSD1 silencing, lifespan assay, mobility assessment, and GFP quantification ACMSD1 silencing: Bacterial-feeding RNAi experiments to determine the effects of acmsd-1 downregulation or silencing on gene expression and survival are performed in the nematode Caenorhabditis elegans (C. elegans). The clones used for cell-feeding experiments are acmsd-1, SIR-2.1, and DAF-16. Total RNA is extracted from cells, and the extracted RNA is treated with DNase and used for reverse transcription (RT).

[0380] Earthworms were grown on NGM agar plates containing carbenicillin and IPTG and seeded with bacterial cultures. After RNAi treatment, the worms were transferred to plates containing paraquat and seeded with RNAi bacteria. Control animals were grown on RNAi bacteria containing an empty vector (control) and then transferred to plates containing paraquat and seeded with RNAi bacteria. Quantification of gene expression of sod-3 at the mRNA and protein levels was performed using RT-qPCR and survival analysis. Earthworm movements were recorded on days 1, 3, and 5 of adulthood.

[0381] Antidiabetic effects in C57BL / 6J and KK-Ay mice Mice are fed a normal chow diet or a high-fat diet (HFD). A compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily, and blood and tissue samples are collected for RNA isolation, lipid analysis, and histology. Oxygen consumption is measured, and histological analysis and transmission electron microscopy are performed. Oral glucose tolerance tests and intraperitoneal insulin tolerance tests are also performed to quantify glucose and measure plasma insulin concentrations.

[0382] Anti-diabetic and anti-obesity studies in db / db mice carrying the LepR mutation The animals are fed a high-fat diet (HFD). In the case of subchronic intervention, the animals are treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof once a day for 14 days. Blood samples are collected, and the glucose concentration of each blood sample is determined. In the case of acute intervention, an initial blood sample is collected, and then a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered. Thereafter, access to food is restricted, and a second blood sample is collected. The mice undergo an oral glucose tolerance test, and blood glucose concentration is determined.

[0383] For the euglycemic-hyperinsulinemic clamp assay, animals were primed with continuous [3- 3 H]glucose infusion, after which blood samples were collected to assess plasma insulin, glucose, and [3- 3 [H] glucose concentrations are determined and the basal endogenous glucose appearance rate is calculated. Mice are then gavaged with vehicle or a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The animals are then administered insulin-containing [3- 3 The patient receives a 2-deoxyD-[1-H] glucose infusion. Blood glucose levels are measured, and a target blood glucose level is established by adjusting the glucose infusion rate. 14[C] glucose is administered intravenously and blood samples are collected. Mice are then sacrificed. Gastrocnemius and epididymal adipose tissue are collected and analyzed for plasma [C] glucose in deprotonated plasma. 3 H]- and [ 14 C]-radioactivity is determined.

[0384] Body weight is assessed, and brown adipose tissue (BAT) and gonadal white adipose tissue (WAT) are dissected and weighed. Oxygen production (VO2) and carbon dioxide production (VCO2) are measured and reported as mean hourly VO2 (mL / h / kg) normalized to body weight. Activity counts by infrared beam interruption and food intake are measured simultaneously.

[0385] Study of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in male C57BL / 6J mice Mice were fed a "Western" HF-HSD (high-fat-high-sucrose diet) or a normal chow diet (NCD) as a control. The animals were then treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for 4, 12, or 20 weeks and then sacrificed. Body weight and food intake were monitored weekly, and total fat mass was analyzed. An intraperitoneal glucose tolerance test (IPGTT) was also performed to measure tail vein glucose levels after glucose administration. Insulin resistance was calculated using a homeostatic model of insulin resistance. The mice were then sacrificed by cardiac puncture blood sampling. Plasma was obtained, and tissues were collected along with the plasma for further biochemical and molecular or histological analysis.

[0386] Study of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in methionine- and choline-deficient mice Mice weighing 25 g are fed either a methionine- and choline-deficient diet (MCD to induce NASH) or a chow diet (as a control). Animal experiments and assessment of NAFLD and NASH are performed as described above for C57BL / 6J mice fed a high-fat, high-sucrose diet.

[0387] Atherosclerosis in LDL-R knockout mice fed a high-cholesterol diet LDL-R knockout (KO) mice are sacrificed approximately 12 weeks after the initiation of the atherogenic diet, and then the hearts and aortas are perfused with PBS and then fixed. Atherosclerosis and biochemical parameters are measured using appropriate commercially available kits. For in vivo lipopolysaccharide (LPS) studies, mice are injected intraperitoneally with LPS, and blood is collected from the tail vein. TNFα levels are quantified using a mouse TNFα ELISA assay. Blood counts are determined.

[0388] Sco2 KO / KI Study of inherited mitochondrial diseases in mice A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is dissolved in water and added to a standard powder diet at the appropriate concentration. Diet is changed every 3 days and administered ad libitum for one month. Tissues are collected for histological analysis. In quadriceps muscle samples, spectrophotometric activity of cI, cII, cIII, and cIV, as well as CS, is measured. NAD + are extracted from tissue using acidic and alkaline extraction methods, respectively, and analyzed using mass spectrometry.

[0389] Study of inherited mitochondrial disease in Deletor mice Deletor and WT male mice are administered a chow diet (CD) or either a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof mixed with CD. Mice are regularly monitored for body weight, food consumption, and physical endurance, and their exercise capacity is measured. Oxygen consumption and carbon dioxide production, as well as spontaneous movement and feeding activity, are recorded. Tissue sections are collected and prepared from the quadriceps, liver, and BAT. Frozen sections of the quadriceps are analyzed for in situ histochemical COX and succinate dehydrogenase (SDH) activity, cristae content of both BAT and muscle is determined from electron micrographs, and skeletal muscle samples are analyzed for citrate synthase activity.

[0390] Kidney Disease Research C57BL / 6J WT mice are fed a standard commercial diet and divided into four groups: control, cisplatin, and the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The mice are sacrificed, and tissue samples and serum are collected. Serum creatinine and BUN levels are measured, and the proinflammatory cytokines TNF-α, IL-1b, and IL-6 from serum or homogenates from kidney tissue are quantified. Mouse kidneys are collected and stained for analysis. Tubular damage is examined and scored based on the percentage of cortical tubular necrosis. Neutrophil infiltration is quantitatively assessed in the stained tissue by counting the number of neutrophils per high-power field.

[0391] Alternatively, C57BL / 6J WT mice are numbered, acclimatized for a period of time, and then randomized into different treatment groups based on their body weight. The different groups are maintained on the designated diet for a period of time. Body weight measurements are taken, and food consumption is assessed. Blood is collected by retro-orbital puncture under light anesthesia and used to analyze basal blood urea nitrogen levels (BUN).

[0392] Mice are anesthetized and placed on the operating table. Both kidneys are exposed through an incision, and the renal pedicles are occluded using vascular clamps. The clamps are then removed, and the surgical site is sutured. A sham-operated group undergoes a similar surgical procedure, except that no occlusion clamps are applied. Animals are monitored until they recover from anesthesia and are returned to their home cages. Animals are observed daily for general clinical signs and symptoms, as well as death.

[0393] One day before termination, animals are individually housed in metabolic cages, and urine is collected to estimate urea, creatinine, sodium, and potassium. Blood is also collected by retroorbital puncture under light anesthesia, and plasma is used for analysis of blood urea nitrogen levels (BUN) and serum creatinine. Animals are then euthanized, and organs are collected. One kidney is fixed, and the other is snap-frozen and used to estimate lipid peroxidation, GSH, MPO, and SOD levels.

[0394] Study of ischemia / reperfusion-induced acute kidney injury CD-1 (ICR) mice are treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof by oral gavage once daily. The CD-1 mice are divided into four groups: (1) young mice with sham injury, (2) young mice with ischemia / reperfusion (I / R) injury, (3) adult mice with sham injury, and (4) adult mice with I / R injury. An additional 27 adult mice are randomized into two groups: mice administered with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and mice administered with a vehicle as a control. Serum creatinine levels are measured, and BUN measurements are recorded. Renal tissue is then evaluated, and tubular damage is recorded.

[0395] Study of cisplatin-induced acute kidney injury C57BL6 mice are treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof by oral gavage once daily. The animals are allowed to recover and are sacrificed 48, 72, and 96 hours after cisplatin injection.

[0396] Serum creatinine levels are measured as the primary endpoint. Tubular damage is scored on a scale of 0 to 4 (0 = <5%, 1 = 5-25%, 2 = 25-50%, 3 = 50-75%, and 4 = >75%) based on the percentage of tubules with necrosis, dilation, or cellular swelling. All high-power fields (400x) in the cortex and outer medulla are evaluated by a pathologist in a blinded manner.

[0397] Impact on sepsis-induced acute kidney injury C57BL6 mice (12-15 weeks old) are treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof by intraperitoneal injection after cecal ligation and puncture-induced sepsis.

[0398] Blood and kidney tissues were collected at sacrifice and primary and secondary endpoints were measured. Primary endpoint (48 h): serum creatinine. Secondary endpoints (48 h): macrophage phenotype markers (IF staining), plasma NGAL, plasma and kidney inflammatory markers (IL-6, IL-18, TNF), and kidney injury markers (KIM-1, NGAL, TIMP2, and IGFBP7). Additional endpoints included cell death (IF: annexin V and propidium iodide; caspase 3 / 7), autophagy, biosynthesis (PGC-1α, mitochondrial DNA), OXPHOS (complex I, III, IV activity), Sirt1 and Sirt3 expression, AMPK (total, p-AMPK, p-ACC, and HIF-1α).

[0399] Histological analysis was performed using H&E and PAS staining using standard protocols. Images were collected and analyzed using a light microscope (IX71, Olympus, Tokyo, Japan) and DP analyzer software (DP70-BSW, Tokyo, Japan). Tubular damage in PAS-stained kidney sections was scored based on the percentage of cortical tubular necrosis: 0 = normal, 1 = 1-10, 2 = 11-25, 3 = 26-45, 4 = 46-75, and 5 = 76-100%. Protection against kidney injury was assessed using the tubular damage score.

[0400] Determination of effects on FoxO1 phosphorylation levels AML-12 cells are treated with different concentrations of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.Then, the cells are lysed and analyzed by SDS-PAGE / Western blot.Then, blocking and antibody incubation are performed, and each protein present is detected with its specific antibody.

[0401] Inhibitory effect The present disclosure also relates to a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, in a method for inhibiting the activity of ACMSD. The method comprises contacting a cell with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In a related embodiment, the method further provides that the compound is present in an amount effective to provide a concentration sufficient to selectively inhibit ACMSD in the cell.

[0402] Thus, preferably, in an assay for ACMSD inhibition (i.e., an ACMSD assay described herein, e.g., Biological Example 1, or an ACMSD assay known in the literature), preferred compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof reduce, or preferably inhibit, ACMSD and NAD +The compounds are capable of increasing the levels and / or activating SIRT and downstream targets of SIRT, such as PGC-1α, FoxO1, and / or SOD. Preferably, the inhibition is achieved by measuring the IC50 of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the ACMSD inhibition assay. 50 Preferred compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof have an IC50 of less than 1 μM, more preferably less than 300 nM, for example less than 100 nM, such as less than 50 nM, for ACMSD inhibition. 50 It has.

[0403] Illustrative Embodiments Some embodiments of the present disclosure are the following embodiment I.

[0404] Embodiment I-1. A compound of formula (I),

[0405] [ka]

[0406] During the ceremony, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl; W is N or C; (i) If W is N, then: L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0407] [ka]

[0408] , -(C(R 5 )2) m Y1 (C(R 5 )2) p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and (ii) If W is C, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0409] [ka]

[0410] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and Y 1 But, O, NR 4 , or S(O) q and Y 2 are each independently O, NH, or S; R 1 But absent or C6-C 10 arylene or heteroarylene, wherein the heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S; 10 The arylene or the heteroarylene is selected from the group consisting of 1 to 2 R e optionally replaced by R 2 is H or C1-C4 alkyl; R 2’ is H, C1-C4 alkyl, or C3-C7 cycloalkyl, or R 2 and R 2’together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S; R 3 is H or C1-C4 alkyl; R 4 is H or C1-C4 alkyl; R 5 is each independently at each occurrence H or C1-C4 alkyl; R 6 is each independently at each occurrence H or C1-C4 alkyl; R 7 is H, A, B, or C, A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r Isoxazol-3-ol, -(CH2) r P(O)(OH)OR x , -(CH2) r S(O)2OH, -(CH2) r C(O)NHCN, or -(CH2) r C(O)NHS(O)2 alkyl, -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r isoxazol-3-ol optionally substituted with C1-C6 alkyl; B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) rS(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(CH2) r C(O)NR g R g’ , -(CH2) r S(O)NR g R g’ , -(CH2) r C(O)NHS(O)NR g R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x and C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R 6 )2) r Heteroaryl, -O(C(R6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R 6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2) r C(O)NHS(O)2C1-C4 alkyl, wherein the aryl and the heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S; R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x and R d But methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH, or -CN; R f is absent, H, or methyl; R gis H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2; R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10 aryl, or a 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and —OH, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and —OH; R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and said heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl, R i However, (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl is substituted with one or more NH2; (ii) (CH2CH2O) n or (iii) a C1-C6 alkyl substituted with one or more substituents independently selected from OH, and a 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms each selected from O, N, or S; R j is absent, H, C1-C6 alkyl, or -CN; R x each independently at each occurrence is H, C-C alkyl, or C-C 10 is aryl, R y and R zare each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; m, p, q, r, and t are each independently 0, 1, or 2; n is 0, 1, 2, or 3; s is 1 or 2, o is 0, 1, 2, 3, or 4;

[0411] [ka]

[0412] represents a single or double bond, however, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, R 7 is not -COOH, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, and R 7 is tetrazole, R c But not H, X is O and R f is H, W is C, and R j is -CN and L is -SC(R 5 )2 or -SCH2CH2-, and R 1 If absent, R 7 is not COOH or tetrazole, X is O and R f is H, W is N, and R j is absent, and R d is methyl, an optionally substituted 5- to 10-membered aryl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered cycloalkyl, L is -SCH2- or -OCH2-, and R 1is phenylene, R 7 -COOH, -CH2COOH,

[0413] [ka]

[0414] Instead, X is O and R f is H, W is N, and R j is absent, L is -NHCH2-, -CH2NH-, or -NH-C(O)-, and R 1 is phenylene, R d is not phenyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0415] Embodiment I-2. X is O, OH, OR h , F, Br, or Cl.

[0416] Embodiment I-3.X is H, S, SR 2 , N.R. 2 , or NR 2 R 2’ The compound according to embodiment I-1, wherein

[0417] Embodiment I-4.R f The compound according to any one of embodiments I-1 to I-3, wherein is absent.

[0418] Embodiment I-5.R f The compound according to any one of embodiments I-1 to I-3, wherein is H or methyl.

[0419] Embodiment I-6. A compound according to any one of embodiments I-1 to I-5, wherein W is N.

[0420] Embodiment I-7.R j The compound according to embodiment I-6, wherein is absent.

[0421] Embodiment I-8. The compound of any one of Embodiments I-1 to I-5, wherein W is C.

[0422] Embodiment I-9.R j The compound according to embodiment I-8, wherein is H, C1-C6 alkyl, or -CN.

[0423] Embodiment I-10.R j The compound according to embodiment I-8 or I-9, wherein is —CN.

[0424] Embodiment I-11.R c The compound according to any one of embodiments I-1 to I-10, wherein is C1-C6 alkyl, -CN, or halogen.

[0425] Embodiment I-12.R c The compound according to any one of embodiments I-1 to I-11, wherein is —CN or halogen.

[0426] Embodiment I-13.R c The compound according to any one of embodiments I-1 to I-12, wherein is —CN.

[0427] Embodiment I-14.R d The compound according to any one of embodiments I-1 to I-13, wherein is methyl.

[0428] Embodiment I-15.R d The compound according to any one of embodiments I-1 to I-13, wherein is optionally substituted 5-10 membered aryl.

[0429] Embodiment I-16.R d The compound according to any one of embodiments I-1 to I-13, wherein is an optionally substituted 5- or 6-membered heteroaryl.

[0430] Embodiment I-17.R d The compound according to any one of embodiments I-1 to I-13, wherein is an optionally substituted 5- or 6-membered cycloalkyl.

[0431] Embodiment I-18.R d The compound according to any one of embodiments I-1 to I-13, wherein is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.

[0432] 19.R d The compound according to any one of embodiments I-1 to I-13, wherein is methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl, or optionally substituted phenyl.

[0433] Embodiment I-20.R d The compound according to any one of embodiments I-1 to I-13, wherein is methyl.

[0434] Embodiment I-21.R d The compound according to any one of embodiments I-1 to I-13, wherein is —CF 3 .

[0435] Embodiment I-22.R d is CR f The compound according to any one of embodiments I-1 to I-13, wherein F2.

[0436] Embodiment I-23.R d But -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r -5- or 6-membered heteroaryl, -(C(R 6 )2) r The compound according to any one of embodiments I-1 to I-13, which is a 5- or 6-membered cycloalkyl.

[0437] Embodiment I-24.R d -(C(R 6 )2) r C6-C 10 The compound according to any one of embodiments I-1 to I-13, which is aryl.

[0438] Embodiment I-25. L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p The compound according to any one of embodiments I-1 to I-24, wherein

[0439] Embodiment I-26.Y 1 The compound according to embodiment I-25, wherein is S.

[0440] Embodiment I-27.L is -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -or-(C(R 5 )2) m Y 1 (C(R 5 )2) p The compound according to any one of embodiments I-1 to I-24, wherein -cyclopropyl-.

[0441] Embodiment I-28.R 1 C6-C 10 The compound according to any one of embodiments I-1 to I-27, which is an arylene.

[0442] Embodiment I-29.R 1 The compound according to any one of embodiments I-1 to I-27, wherein is heteroarylene.

[0443] Embodiment I-30.R 1 The compound according to any one of embodiments I-1 to I-27, wherein is absent.

[0444] Embodiment I-31.R 7 The compound according to any one of embodiments I-1 to I-30, wherein is A.

[0445] Embodiment I-32.A is -(C(R 6 )2) r CO2R x or -(CH2)r tetrazole, and the -(CH) r Compounds according to embodiment I-31, wherein the tetrazole is optionally substituted with C1-C6 alkyl.

[0446] Embodiment I-33.R 7 The compound according to any one of embodiments I-1 to I-30, wherein is B.

[0447] Embodiment I-34.B is -(CH2) r C(O)NR g R g’ or -(CH2) r S(O)NR g R g’ The compound of embodiment I-31, wherein

[0448] Embodiment I-35.R 7 The compound according to any one of embodiments I-1 to I-30, wherein is C.

[0449] Embodiment I-36.C is -(CH2) r CN, -(CH2) s OH, or -(C(R 6 )2) r C6-C 10 Compounds according to embodiment I-31, wherein R is aryl, said aryl being substituted with 1 to 3 substituents each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH.

[0450] Embodiment I-37. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or tautomer thereof:

[0451] [Table 5-1]

[0452] [Table 5-2]

[0453] [Table 5-3]

[0454] [Table 5-4]

[0455] [Table 5-5]

[0456] Embodiment I-38. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or tautomer thereof:

[0457] [Table 6-1]

[0458] [Table 6-2]

[0459] [Table 6-3]

[0460] [Table 6-4]

[0461] [Table 6-5]

[0462] [Table 6-6]

[0463] [Table 6-7]

[0464] [Table 6-8]

[0465] [Table 6-9]

[0466] [Table 6-10]

[0467] Embodiment I-39. A pharmaceutical composition comprising a compound according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0468] Embodiment I-40. The pharmaceutical composition of embodiment I-39, comprising one or more additional therapeutic agents.

[0469] Embodiment I-41. A method for treating, preventing, or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing said disease or disorder a therapeutically effective amount of one or more compounds according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof.

[0470] Embodiment I-42. Nicotinamide adenine dinucleotide (NAD + 1. A method for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of NAD, comprising: +A method comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of one or more compounds according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof.

[0471] Embodiment I-43. The method of any one of embodiments I-41 to I-42, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

[0472] Embodiment I-44. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder intracellular nicotinamide adenine dinucleotide (NAD + 1-38。

[0023] The method of claim 1-38, comprising administering a therapeutically effective amount of one or more compounds of any one of embodiments I-1 to I-38 or pharmaceutically acceptable salts thereof to increase the

[0473] Embodiment I-45 The method of embodiment I-44, wherein the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease.

[0474] Embodiment I-46 The method of embodiment I-45, wherein the common metabolic disorder is obesity or type 2 diabetes.

[0475] Embodiment I-47. A method of promoting oxidative metabolism, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder intracellular nicotinamide adenine dinucleotide (NAD + ) comprising administering a therapeutically effective amount of one or more compounds according to any one of embodiments I-1 to I-38 or pharmaceutically acceptable salts thereof to increase the vasopressin-releasing hormone (vasopressin) levels in the blood.

[0476] Embodiment I-48. A compound according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0477] Embodiment I-49. Nicotinamide adenine dinucleotide (NAD + A compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (IL-1), erythropoietin (IL-2), or erythropoietin (IL-3).

[0478] Embodiment I-50. A compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0479] Embodiment I-51. A compound according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for use in promoting oxidative metabolism.

[0480] Embodiment I-52. Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0481] Embodiment I-53. Nicotinamide adenine dinucleotide (NAD +Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of ATP.

[0482] Embodiment I-54. Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0483] Embodiment I-55. Use of a compound according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for promoting oxidative metabolism.

[0484] Embodiment I-56. Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0485] Embodiment I-57. Nicotinamide adenine dinucleotide (NAD + Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (erythropoietin).

[0486] Embodiment I-58. Use of a compound according to any of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0487] Embodiment I-59. Use of a compound according to any one of embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting oxidative metabolism.

[0488] Embodiment I-60. A method for treating, preventing, or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing said disease or disorder a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[0489] Embodiment I-61. Nicotinamide adenine dinucleotide (NAD + 1. A method for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of NAD, comprising: + A method comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of a pharmaceutical composition of embodiment I-39.

[0490] Embodiment I-62. The method of any one of embodiments I-60 to I-61, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

[0491] Embodiment I-63. A method for treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[0492] Embodiment I-64 The method of embodiment I-63, wherein the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease.

[0493] Embodiment I-65. The method of claim 64, wherein the common metabolic disorder is obesity or type 2 diabetes.

[0494] Embodiment I-66. A method for promoting oxidative metabolism, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[0495] Embodiment I-67. A pharmaceutical composition according to embodiment I-39 for use as a medicament.

[0496] Embodiment I-68. Nicotinamide adenine dinucleotide (NAD + The pharmaceutical composition of embodiment I-39 for use in treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (erythropoietin).

[0497] Embodiment I-69. The pharmaceutical composition of embodiment I-39 for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0498] Embodiment I-70. The pharmaceutical composition of embodiment I-39 for use in promoting oxidative metabolism.

[0499] Embodiment I-71. Use of the pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0500] Embodiment I-72. Nicotinamide adenine dinucleotide (NAD +Use of the pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of ATP.

[0501] Embodiment I-73. Use of the pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0502] Embodiment I-74. Use of the pharmaceutical composition of embodiment I-39 for promoting oxidative metabolism.

[0503] Embodiment I-75. Use of the pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0504] Embodiment I-76. Nicotinamide adenine dinucleotide (NAD + Use of the pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin.

[0505] Embodiment I-77. Use of the pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0506] Embodiment I-78. Use of the pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for promoting oxidative metabolism.

[0507] Embodiment II-1. A compound of formula (II):

[0508] [ka]

[0509] During the ceremony, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl; W is N or C; (i) When W is N, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0510] [ka]

[0511] , -(C(R 5 )2) m Y 1 (C(R 5 )2) p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and (ii) When W is C, L is -(C(R 5 )2) mCH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0512] [ka]

[0513] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R 5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and Y 1 But, O, NR 4 , or S(O) q and Y 2are each independently O, NH, or S; R 1 But absent, C6-C 10 arylene, heteroarylene, or C3-C8 cycloalkylene, wherein the heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S; 10 The arylene, the heteroarylene, and the C3-C8 cycloalkylene each independently represent one to two R e optionally replaced by R 2 is H or C1-C4 alkyl; R 2’ is H, C1-C4 alkyl, or C3-C7 cycloalkyl, or R 2 and R 2’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S; R 3 is H or C1-C4 alkyl; R 4 is H or C1-C4 alkyl; R 5 is each independently at each occurrence H or C1-C4 alkyl; R 6 is each independently at each occurrence H or C1-C4 alkyl; R 7 is H, A, B, or C, A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazolone, -(C(R 6)2) r Thiadiazolol, -(C(R 6 )2) r Isoxazol-3-ol, -(C(R 6 )2) r P(O)(OH)OR x , -(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r C(O)NHCN, or -(C(R 6 )2) r C(O)NHS(O)2 alkyl, -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazolone, -(C(R 6 )2) r Thiadiazolol, -(C(R 6 )2) r isoxazol-3-ol optionally substituted with C1-C6 alkyl; B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) r S(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NR g R g’ , -(C(R 6 )2) r S(O)NR g R g’ , -(C(R 6 )2) r C(O)NHS(O)NR g R g’, -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x and C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R 6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2) rC(O)NHS(O)2C1-C4 alkyl, wherein the aryl and the heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S; R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x and R d But methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH, or -CN; R f is absent, H, or methyl; R g is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2; R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10aryl, or a 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and —OH, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and —OH; R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and said heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl, R i However, (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl is substituted with one or more NH2; (ii) (CH2CH2O) n or (iii) a C1-C6 alkyl substituted with one or more substituents independently selected from OH, and a 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms each selected from O, N, or S; R j is absent, H, C1-C6 alkyl, or -CN; R x each independently at each occurrence is H, C-C alkyl, or C-C 10 is aryl, R y and R z are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; m, p, q, r, and t are each independently 0, 1, or 2; n is 0, 1, 2, or 3; s is 1 or 2, o is 0, 1, 2, 3, or 4;

[0514] [ka]

[0515] represents a single or double bond, however, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, R 7 is not -COOH, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, and R 7 is tetrazole, R c But not H, X is O and R f is H, W is C, and R j is -CN and L is -SC(R 5 )2 or -SCH2CH2-, and R 1 If absent, R 7 is not COOH or tetrazole, X is O and R f is H, W is N, and R j is absent, and R d is methyl, an optionally substituted 5- to 10-membered aryl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered cycloalkyl, L is -SCH2- or -OCH2-, and R 1 is phenylene, R 7 -COOH, -CH2COOH,

[0516] [ka]

[0517] Instead, X is O and R f is H, W is N, and R j is absent, L is -NHCH2-, -CH2NH-, or -NH-C(O)-, and R 1 is phenylene, R d is not phenyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0518] Embodiment II-2. A compound of formula (I),

[0519] [ka]

[0520] During the ceremony, X is H, S, SR 2 , N.R. 2 , N.R. 2 R 2’ , O, OH, OR h , F, Br, or Cl; W is N or C; (i) If W is N, then: L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -,

[0521] [ka]

[0522] , -(C(R 5 )2) m Y 1 (C(R 5 )2) p -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-, -(C(R 5 )2) m Y1 CH=CH-, -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and (ii) If W is C, L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -, -(C(R 5 )2) o -, -(C(R 5 )2) m Y 1 (C(R 5 )2) p -,

[0523] [ka]

[0524] , -(C(R 5 )2) m Y 1 CH=CH-, -(C(R 5 )2) m C=(O)(CH2) p -, -(C(R 5 )2) m C=(O)O(C(R 5 )2) p -, -(C(R 5 )2) m C=(O)NR 3 (C(R 5 )2) p -, -(C(R 5)2) m NR 3 C=(O)(C(R 5 )2) p -, -(C(R 5 )2) m Phenyl (C(R 5 )2) p -, -(C(R 5 )2) m Pyridinyl (C(R 5 )2) p - or -(C(R 5 )2) m Thiophenyl (C(R 5 )2) p - and Y 1 But, O, NR 4 , or S(O) q and Y 2 are each independently O, NH, or S; R 1 But absent or C6-C 10 arylene or heteroarylene, wherein the heteroarylene contains one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S; 10 The arylene or the heteroarylene is selected from the group consisting of 1 to 2 R e optionally replaced by R 2 is H or C1-C4 alkyl; R 2’ is H, C1-C4 alkyl, or C3-C7 cycloalkyl, or R 2 and R 2’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S; R 3 is H or C1-C4 alkyl; R 4 is H or C1-C4 alkyl; R 5 is each independently at each occurrence H or C1-C4 alkyl; R 6 is each independently at each occurrence H or C1-C4 alkyl; R 7 is H, A, B, or C, A is -(C(R 6 )2) r CO2R x , -Y 2 (C(R 6 )2) r CO2R x , -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r Isoxazol-3-ol, -(CH2) r P(O)(OH)OR x , -(CH2) r S(O)2OH, -(CH2) r C(O)NHCN, or -(CH2) r C(O)NHS(O)2 alkyl, -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazolone, -(CH2) r Thiadiazolol, -(CH2) r isoxazol-3-ol optionally substituted with C1-C6 alkyl; B is -(C(R 6 )2) r S(O)2OC1-C4 alkyl, -O(C(R 6 )2) r S(O)2OC1-C4 alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g’ , -Y 2 (C(R 6 )2) r S(O)NR g R g’ , -(CH2) r C(O)NR g R g’, -(CH2) r S(O)NR g R g’ , -(CH2) r C(O)NHS(O)NR g R g’ , -(C(R 6 )2) r CO2R i , -(C(R 6 )2) r NH2CO2R x , -(C(R 6 )2) r P(O)(OR x )2, -O(C(R 6 )2) r P(O)(OR x )2, -(C(R 6 )2) r S(O)2OH, -O(C(R 6 )2) r S(O)2OH, -(C(R 6 )2) r P(O)2OR x , or -O(C(R 6 )2) r P(O)2OR x and C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r S-C6-C 10 Aryl, -(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heteroaryl, -O(C(R 6 )2) r Heterocycloalkyl, -O(C(R 6 )2) r OH, -OR y , -(C(R 6 )2) r C(O)NHCN, -CH=CHCO2R x , or -(C(R 6 )2)r C(O)NHS(O)2C1-C4 alkyl, wherein the aryl and the heteroaryl are each substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH, and the heterocycloalkyl is substituted with 1 to 2 =O or =S; R c is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x , or -CO2R x and R d But methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5- or 6-membered heteroaryl, -(C(R 6 )2) t - 5- or 6-membered cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; R e each independently at each occurrence is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH, or -CN; R f is absent, H, or methyl; R g is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2; R g’ is a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, N, O, and S; 10aryl, or a 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and —OH, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, and —OH; R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2, and said heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl, R i However, (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl is substituted with one or more NH2; (ii) (CH2CH2O) n or (iii) a C1-C6 alkyl substituted with one or more substituents independently selected from OH, and a 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms each selected from O, N, or S; R j is absent, H, C1-C6 alkyl, or -CN; R x each independently at each occurrence is H, C-C alkyl, or C-C 10 is aryl, R y and R z are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl; m, p, q, r, and t are each independently 0, 1, or 2; n is 0, 1, 2, or 3; s is 1 or 2, o is 0, 1, 2, 3, or 4;

[0525] [ka]

[0526] represents a single or double bond, however, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, R 7 is not -COOH, X is O and R f is H, W is C, and R j is -CN, L is -SCH2-, and R 1 is phenylene or pyridine, and R 7 is tetrazole, R c But not H, X is O and R f is H, W is C, and R j is -CN and L is -SC(R 5 )2 or -SCH2CH2-, and R 1 If absent, R 7 is not COOH or tetrazole, X is O and R f is H, W is N, and R j is absent, and R d is methyl, an optionally substituted 5- to 10-membered aryl, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered cycloalkyl, L is -SCH2- or -OCH2-, and R 1 is phenylene, R 7 -COOH, -CH2COOH,

[0527] [ka]

[0528] Instead, X is O and R f is H, W is N, and R j is absent, L is -NHCH2-, -CH2NH-, or -NH-C(O)-, and R 1 is phenylene, R d is not phenyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0529] Embodiment II-3. X is O, OH, OR h , F, Br, or Cl.

[0530] Embodiment II-4.X is H, S, SR 2 , N.R. 2 , or NR 2 R 2’ The compound according to embodiment II-1 or II-2, wherein

[0531] Embodiment II-5.R f The compound according to any one of embodiments II-1 to II-4, wherein is absent.

[0532] Embodiment II-6.R f The compound according to any one of embodiments II-1 to II-4, wherein is H or methyl.

[0533] Embodiment II-7. A compound according to any one of embodiments II-1 to II-6, wherein W is N.

[0534] Embodiment II-8.R j The compound according to embodiment II-7, wherein is absent.

[0535] Embodiment II-9. The compound according to any one of Embodiments II-1 to II-6, wherein W is C.

[0536] Embodiment II-10.R jThe compound of embodiment II-9, wherein is H, C1-C6 alkyl, or -CN.

[0537] Embodiment II-11.R j The compound according to embodiment II-9 or II-10, wherein is —CN.

[0538] Embodiment II-12.R c The compound according to any one of embodiments II-1 to II-11, wherein is C1-C6 alkyl, -CN, or halogen.

[0539] Embodiment II-13.R c The compound according to any one of embodiments II-1 to II-12, wherein is —CN or halogen.

[0540] Embodiment II-14.R c The compound according to any one of embodiments II-1 to II-12, wherein is —CN.

[0541] Embodiment II-15.R d The compound according to any one of embodiments II-1 to II-14, wherein is methyl.

[0542] Embodiment II-16.R d The compound according to any one of embodiments II-1 to II-14, wherein is optionally substituted 5-10 membered aryl.

[0543] Embodiment II-17.R d The compound according to any one of embodiments II-1 to II-14, wherein is an optionally substituted 5- or 6-membered heteroaryl.

[0544] Embodiment II-18.R d The compound according to any one of embodiments II-1 to II-14, wherein is an optionally substituted 5- or 6-membered cycloalkyl.

[0545] Embodiment II-19.R dThe compound according to any one of embodiments II-1 to II-14, wherein is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.

[0546] Embodiment II-20.R d The compound according to any one of embodiments II-1 to II-14, wherein is methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl, or optionally substituted phenyl.

[0547] Embodiment II-21.R d The compound according to any one of embodiments II-1 to II-14, wherein is methyl.

[0548] Embodiment II-22.R d The compound according to any one of embodiments II-1 to II-14, wherein is —CF 3 .

[0549] Embodiment II-23.R d is CR f The compound according to any one of embodiments II-1 to II-14, wherein F2.

[0550] Embodiment II-24.R d But -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r -5- or 6-membered heteroaryl, -(C(R 6 )2) r The compound according to any one of embodiments II-1 to II-14, which is a 5- or 6-membered cycloalkyl.

[0551] Embodiment II-25.R d -(C(R 6 )2) r C6-C 10 The compound according to any one of embodiments II-1 to II-14, which is aryl.

[0552] Embodiment II-26. L is -(C(R5 )2) m Y 1 (C(R 5 )2) p The compound according to any one of embodiments II-1 to II-25, wherein

[0553] Embodiment II-27.Y 1 The compound according to embodiment II-26, wherein is S.

[0554] Embodiment II-28.L is -(C(R 5 )2) m NR 3 C=(O)(C(R 5 )2) p -or-(C(R 5 )2) m Y 1 (C(R 5 )2) p The compound according to any one of embodiments II-1 to II-25, wherein -cyclopropyl-.

[0555] Embodiment II-29.R 1 C6-C 10 The compound according to any one of embodiments II-1 to II-28, which is an arylene.

[0556] Embodiment II-30.R 1 The compound according to any one of embodiments II-1 to II-28, wherein is heteroarylene.

[0557] Embodiment II-31.R 1 The compound according to any one of embodiments II-1 to II-28, wherein is absent.

[0558] Embodiment II-32.R 7 The compound according to any one of embodiments II-1 to II-31, wherein is A.

[0559] Embodiment II-33.A is -(C(R 6 )2) r CO2R x or -(CH2)r tetrazole, and the -(CH) r The compound according to embodiment II-32, wherein the tetrazole is optionally substituted with C1-C6 alkyl.

[0560] Embodiment II-34.R 7 The compound according to any one of embodiments II-1 to II-31, wherein is B.

[0561] Embodiment II-35.B is -(CH) r C(O)NR g R g’ or -(CH2) r S(O)NR g R g’ The compound of embodiment II-32, wherein

[0562] Embodiment II-36.R 7 The compound according to any one of embodiments II-1 to II-31, wherein is C.

[0563] Embodiment II-37.C is -(CH2) r CN, -(CH2) s OH, or -(C(R 6 )2) r C6-C 10 The compound of embodiment II-32, wherein said aryl is substituted with 1 to 3 substituents each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH.

[0564] Embodiment II-38. A compound selected from the group consisting of: or a pharmaceutically acceptable salt or tautomer thereof:

[0565] [Table 7-1]

[0566] [Table 7-2]

[0567] [Table 7-3]

[0568] [Table 7-4]

[0569] [Table 7-5]

[0570] Embodiment II-39. A compound selected from the group consisting of:

[0571] [Table 8-1]

[0572] [Table 8-2]

[0573] Embodiment II-40. A compound selected from the group consisting of:

[0574] [Table 9-1]

[0575] [Table 9-2]

[0576] [Table 9-3]

[0577] [Table 9-4]

[0578] [Table 9-5]

[0579] [Table 9-6]

[0580] [Table 9-7]

[0581] [Table 9-8]

[0582] [Table 9-9]

[0583] [Table 9-10]

[0584] Embodiment II-41. A pharmaceutical composition comprising a compound according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0585] Embodiment II-42. The pharmaceutical composition of embodiment II-41, comprising one or more additional therapeutic agents.

[0586] Embodiment II-43. A method for treating, preventing, or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing said disease or disorder a therapeutically effective amount of one or more compounds according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof.

[0587] Embodiment II-44. Nicotinamide adenine dinucleotide (NAD + 1. A method for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of NAD, comprising: + A method comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of one or more compounds according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof.

[0588] Embodiment II-45. The method of any one of embodiments II-43 to II-44, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

[0589] Embodiment II-46. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder intracellular nicotinamide adenine dinucleotide (NAD+ ) comprising administering a therapeutically effective amount of one or more compounds according to any one of embodiments II-1 to II-40 or pharmaceutically acceptable salts thereof to increase the vasopressin-releasing hormone (vasopressin) levels in the blood.

[0590] Embodiment II-47. The method of embodiment II-46, wherein the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease.

[0591] Embodiment II-48. The method of embodiment II-47, wherein the common metabolic disorder is obesity or type 2 diabetes.

[0592] Embodiment II-49. A method of promoting oxidative metabolism, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder intracellular nicotinamide adenine dinucleotide (NAD + ) comprising administering a therapeutically effective amount of one or more compounds according to any one of embodiments II-1 to II-40 or pharmaceutically acceptable salts thereof to increase the vasopressin-releasing hormone (vasopressin) levels in the blood.

[0593] Embodiment II-50. A compound according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0594] Embodiment II-51. Nicotinamide adenine dinucleotide (NAD + A compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (erythropoietin).

[0595] Embodiment II-52. A compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0596] Embodiment II-53. A compound according to any one of Embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use in promoting oxidative metabolism.

[0597] Embodiment II-54. Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0598] Embodiment II-55. Nicotinamide adenine dinucleotide (NAD + Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of ATP.

[0599] Embodiment II-56. Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0600] Embodiment II-57. Use of a compound according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for promoting oxidative metabolism.

[0601] Embodiment II-58. Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0602] Embodiment II-59. Nicotinamide adenine dinucleotide (NAD +Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (erythropoietin).

[0603] Embodiment II-60. Use of a compound according to any of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0604] Embodiment II-61. Use of a compound according to any one of embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting oxidative metabolism.

[0605] Embodiment II-62. A method for treating, preventing, or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to developing said disease or disorder a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[0606] Embodiment II-63. Nicotinamide adenine dinucleotide (NAD + 1. A method for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of NAD, comprising: + A method comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of a pharmaceutical composition of embodiment II-41.

[0607] Embodiment II-64. The method of any one of embodiments II-62 to II-63, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

[0608] Embodiment II-65. A method for treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[0609] Embodiment II-66. The method of embodiment II-65, wherein the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease.

[0610] Embodiment II-67. The method of embodiment II-66, wherein the common metabolic disorder is obesity or type 2 diabetes.

[0611] Embodiment II-68. A method for promoting oxidative metabolism, comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[0612] Embodiment II-69. A pharmaceutical composition according to embodiment II-41 for use as a medicament.

[0613] Embodiment II-70. Nicotinamide adenine dinucleotide (NAD + The pharmaceutical composition of embodiment II-41 for use in treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin (IL-1).

[0614] Embodiment II-71. The pharmaceutical composition of embodiment II-41 for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0615] Embodiment II-72. The pharmaceutical composition according to embodiment II-41 for use in promoting oxidative metabolism.

[0616] Embodiment II-73. Use of the pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0617] Embodiment II-74. Nicotinamide adenine dinucleotide (NAD + Use of the pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of ATP.

[0618] Embodiment II-75. Use of the pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0619] Embodiment II-76. Use of the pharmaceutical composition according to embodiment II-41 for promoting oxidative metabolism.

[0620] Embodiment II-77. Use of the pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0621] Embodiment II-78. Nicotinamide adenine dinucleotide (NAD + Use of the pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of erythropoietin.

[0622] Embodiment II-79. Use of the pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0623] Embodiment II-80. Use of the pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for promoting oxidative metabolism. [Example]

[0624] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will become apparent from the different examples. The provided examples illustrate different components and methodologies useful in practicing the present disclosure. Generally speaking, the present disclosure extends to any novel feature or any novel combination thereof disclosed herein (including the accompanying claims and drawings). These examples do not limit the claimed disclosure. Thus, any feature, integer, property, compound, or chemical moiety described in connection with a particular aspect, embodiment, or example of the present disclosure should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. Based on the present disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure. Furthermore, unless otherwise specified, any feature disclosed herein may be replaced with an alternative feature serving the same or similar purpose.

[0625] The present disclosure will now be described, by way of example only, with reference to the following examples.

[0626] Example Preparation of compounds General Methods and Materials All chemicals were purchased from Sigma-Aldrich, Alfa Aesar. Deuterated solvents were used as follows: 1 H NMR spectra were recorded at 200 MHz and 400 MHz. 13 C NMR spectra were recorded at 100.6 MHz and 50.3 MHz. TLC was performed on aluminum-backed silica plates (silica gel 60 F254). All reactions were performed under a nitrogen atmosphere using distilled solvents. All tested compounds were found to have a purity greater than 95% as determined by HPLC analysis. HPLC-grade water was obtained from a tandem Milli-Ro / Milli-Q instrument. Analytical HPLC measurements were performed on a Shimadzu LC-20A Prominence equipped with a CBM-20A communication bus module, two LC-20AD dual piston pumps, an SPD-M20A photodiode array detector, and a Rheodyne 7725i injector with a 20 μL stainless steel loop.

[0627] Abbreviations used in the examples below and elsewhere are as follows:

[0628] [Table 10]

[0629] Example 1: Intermediate 1.4. 4-Oxo-6-thiophen-2-yl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile

[0630] [ka]

[0631] To a stirred solution of compounds 1.1 (0.96 g, 8.8 mmol), 1.2 (672 mg, 8.8 mmol), and 1.3 (1 g, 0.83 mL) in ethanol (55 mL) was added K2CO3 (1.57 g, 11.44 mmol). Stirring was continued under reflux overnight. The resulting yellowish solid was collected after cooling, taken up in warm water, and filtered again. The aqueous phase was acidified to pH 1, and the precipitate was filtered and dried under reduced pressure. The title compound 1.4 was obtained as a yellowish solid (1 g, 4.25 mmol). Yield: 49%. 1 H NMR (200MHz, DMSO-d6) δ 7.22 (m, 1H), 7.68 (m, 1H), 7.85 (d, J = 4.8Hz, 1H), 8.05 (s, 1H).

[0632] Example 2: Intermediate 2.2. Sodium 6-oxo-4-trifluoromethyl-1,6-dihydro-pyrimidine-2-thiolate

[0633] [ka]

[0634] Sodium (0.35 g, 16.29 mmol) was dissolved in absolute EtOH (25 mL) under a nitrogen atmosphere. To the resulting solution, ethyl trifluoroacetoacetate 2.1 (1.59 mL, 10.86 mmol) and thiourea 1.2 (0.91 g, 11.94 g) were added. The mixture was stirred at reflux for 4 h. After cooling to room temperature, the resulting precipitate was collected by filtration under vacuum and washed with cold EtOH (2 × 5 mL) to give intermediate 2.2 (1.34 g, 6.14 mmol). Yield: 38%. MS-ESI (-) m / z: 194.8 [M−H].

[0635] Example 3: Intermediate 3.3. 2-Mercapto-6-oxo-4-phenyl-1,6-dihydro-pyridine-3-carbonitrile

[0636] [ka]

[0637] To a stirred solution of KOH (0.58 g, 10.41 mmol) in anhydrous EtOH (20 mL) were added ethyl 3-oxo-3-phenyl-propionate 3.1 (1.80 mL, 10.41 mmol) and 2-cyanothioacetamide 3.2 (1.04 g, 10.41 mmol), and the resulting mixture was stirred at reflux for 3 h. It was then cooled to room temperature and concentrated under reduced pressure. The crude was poured into HO (20 mL) and washed with AcOEt (2 × 15 mL). The organic phase was acidified to pH 2 by adding 37% aqueous HCl, and the resulting precipitate was collected by filtration under vacuum and washed with HO (2 × 5 mL). The solid was then triturated with AcMe to give intermediate 3.3 (0.49 g, 2.14 mmol) as a yellowish solid. Yield: 21%. MS-ESI(-)m / z:227.3[MH] -

[0638] Example 4: Intermediate 4.2. 4-Benzyl-2-mercapto-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile

[0639] [ka]

[0640] To a solution of phenylacetaldehyde 4.1 (1.5 g, 16.65 mmol), ethyl cyanoacetate 1.1 (1.41 g, 16.65 mmol), and thiourea 1.2 (950 mg, 16.65 mmol) in EtOH (35 mL) was added K2CO3 (2.2 g, 21.6 mmol). Stirring was continued under reflux for 16 h. The mixture was cooled to room temperature. The white solid was collected and dissolved in water. The pH was adjusted to 3 by adding 3 N HCl. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. The title intermediate 4.2 (800 mg, 3.28 mmol) was obtained as a pale yellow solid. Yield: 20%. 1 H NMR (200MHz, DMSO-d6) δ 3.93 (s, 2H), 7.26-7.41 (m, 5H), 13.15 (brs, 1H).

[0641] Example 5: Intermediate 5.2. 2-Mercapto-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridine-3-carbonitrile

[0642] [ka]

[0643] To a stirred solution of KOH (0.28 g, 5.04 mmol) in anhydrous EtOH (10 mL) was added ethyl 3-oxo-3-thiophen-2-yl-propionate 5.1 (0.77 mL, 5.04 mmol) and 2-cyanothioacetamide 3.2 (0.50 g, 5.04 mmol), and the resulting mixture was stirred under reflux for 8 h. After cooling to room temperature, the resulting precipitate was collected by filtration under vacuum and washed with EtOH (2 × 5 mL) to give intermediate 5.2 (0.17 g, 0.72) as a yellowish solid. Yield: 12%. MS-ESI (-) m / z: 233.3 [M−H] - .

[0644] Example 6: Intermediate 6.4. 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydro-pyridine-3,5-dicarbonitrile

[0645] [ka]

[0646] Step 1: 2-Cyano-3-thiophen-2-yl-acrylic acid ethyl ester (6.1) To a solution of thiophene-2-carboxaldehyde 1.3 (1 g, 8.9 mmol), ethyl cyanoacetate 1.1 (0.94 mL, 8.9 mmol) in EtOH (20 mL) was added piperidine (3 drops). Stirring was continued at room temperature for 16 h. The solvent was removed in vacuo. The crude was taken up in water and extracted with EtOAc (3 × 50 mL). The organic phase was collected, washed with brine, and dried over anhydrous NaSO. The title intermediate 6.1 (1.3 g, 6.27 mmol) was obtained as a white solid. Yield: 70%.

[0647] Step 2: 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydro-pyridine-3,5-dicarbonitrile (6.2) To a solution of intermediate 6.1 (1.2 g, 5.79 mmol) in EtOH (15 mL) was added piperidine (4 drops). Stirring was continued under reflux for 16 h. Upon cooling, a red precipitate formed. The precipitate was collected, washed with cold EtOH, and dried under vacuum. The title intermediate 6.2 (640 mg, 2.46 mmol) was obtained as a red powder. Yield: 42%. 1 H NMR (200MHz, DMSO-d6) δ 7.24-7.27 (m, 1H), 7.53-7.55 (m, 1H), 7.94-7.95 (m, 1H), 13.0 (brs, 1H).

[0648] Example 7: Intermediate 7.1. Potassium 3-cyano-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridine-2-thiolate

[0649] [ka]

[0650] To a stirred solution of KOH (0.91 g, 16.29 mmol) in anhydrous EtOH (32 mL) was added ethyl trifluoroacetoacetate 2.1 (2.38 mL, 16.29 mmol) and 2-cyanothioacetamide 3.2 (1.63 g, 16.29 mmol), and the resulting mixture was stirred at reflux for 7 h. It was then cooled to room temperature and allowed to stand overnight. The resulting copious precipitate was collected by filtration under vacuum and washed with EtOH (2 × 5 mL) to give intermediate 7.1 (2.01 g, 7.78 mmol) as a white solid. Yield: 48%. MS-ESI (-) m / z: 218.9 [M−H] -

[0651] Example 8: Intermediate 8.3. (3-Bromomethyl-phenyl)-acetic acid ethyl ester

[0652] [ka]

[0653] Step 1: m-Tolyl-acetic acid ethyl ester (8.2) To a solution of 8.1 (15 g, 99.88 mmol) in EtOH (anhydrous) (400 mL) was added HCl (concentrated) (0.3 mL, 9.9 mmol) and stirring was continued under reflux for 4 h. The volatiles were removed under reduced pressure. The crude was taken up in DCM (200 mL), dried over Na2SO4, and evaporated under reduced pressure. The title compound 8.2 was obtained as a colorless oil (17 g, 95.39 mmol). Yield 96%. 1 H NMR (200MHz, CDCl3) δ 1.28(t,J=7.1Hz,3H),2.37(s,2H),3.6(s,2H),4.18(q,J=7.11Hz,2H),7.20-7.35(m,4H). GC / MS m / z 178.1(M+).

[0654] Step 2: (3-Bromomethyl-phenyl)-acetic acid ethyl ester (8.3) NBS (10.1 g, 58.9 mmol) and BPO (70%) (68 mg, 0.28 mmol) were added to a solution of intermediate 8.2 (10 g, 56.11 mmol) in CHCN (300 mL). Stirring was continued under reflux for 4 h. The volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO (300 mL). The organic phase was collected and dried over NaSO. The crude product was purified by flash chromatography (dry load) eluting with PET / EtO (2% to 4% based on the product). The title compound 8.3 (10 g, 38.89 mmol) was obtained as a yellowish oil. Yield: 66%. 1 H NMR (200MHz, CDCl3) δ 1.27(t,J=7.1Hz,3H),3.62(s,2H),4.17(q,J=7.13Hz,2H),4.50(s,2H),7.09-7.13(m,3H),7.21-7.28(m,1H).

[0655] Example 9: Intermediate 9.3. 3-Bromomethyl-benzamide

[0656] [ka]

[0657] Step 1: 3-Methyl-benzamide (9.2) A solution of compound 9.1 (1.54 mL, 12.8 mmol) and KCO (707 mg, 5.12 mmol) in HO (5 mL) was heated under microwave irradiation at 130 °C, 200 psi, and 200 W for 20 min. Upon cooling, the resulting white precipitate was collected and dried under reduced pressure to give the title compound 9.2 (870 mg, 6.4 mmol) as white crystals. Yield 50%. GC-MS (m / z) 135.1 (M+).

[0658] Step 2: 3-Bromomethyl-benzamide (9.3) NBS (434.6 mg, 2.4 mmol) and BPO (70%) (8 mg, 0.022 mmol) were added to a solution of intermediate 9.2 (300 mg, 2.22 mmol) in CHCN (20 mL). Stirring was continued under reflux for 4 h. The volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO (300 mL). The organic phase was collected and dried over NaSO. The title compound 9.3 (250 mg, 1.16 mmol) was obtained as a yellowish solid. Yield 53%.

[0659] Example 10: Intermediate 10.4. 3'-Bromomethyl-3,5-difluoro-4-methoxy-biphenyl

[0660] [ka]

[0661] Step 1: 3,5-Difluoro-4-methoxy-3'-methyl-biphenyl (10.3) To a solution of compound 10.1 (0.18 mL, 1.33 mmol) in DME (15 mL) was added palladium tetrakis (50 mg, 0.039 mmol). Stirring was continued at room temperature for 5 min. m-Tolylboronic acid 10.2 (202 mg, 1.35 mmol) and K2CO3 (745 mg, 3.56 mmol) were added sequentially. Stirring was continued under reflux for 4 h. The solvent was removed under reduced pressure. The crude residue was taken up in water and extracted with DCM (3 × 20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Pure title compound 10.3 (282 mg, 1.22 mmol) was obtained as a colorless oil, which was used in the next step without further purification. Yield 91%. 1 H NMR (400MHz, CDCl3) δ 2.43(s,3H),4.04(s,3H),7.14(d,J=9.3,2H),7.32-7.33(m,4H).

[0662] Step 2: 3'-Bromomethyl-3,5-difluoro-4-methoxy-biphenyl (10.4) To a solution of intermediate 10.3 (260 mg, 1.1 mmol) in CHCN (15 mL) was added BPO (4 mg, 0.0055 mmol) and NBS (210 mg, 1.22 mmol). Stirring was continued under reflux overnight. The solvent was removed under reduced pressure. The reaction was partitioned between saturated NaHCO solution and DCM. The organic phase was washed with brine and dried over NaSO. The crude was purified by flash chromatography eluting with PET / EtO to give the title compound 10.4 (250 mg, 0.77 mmol) as a yellow oil. Yield 72%. 1 H NMR (400MHz, CDCl3) δ 4.06(d,J=3.7Hz,3H),4.55(s,2H),7.14(d,J=6.2Hz,1H),7.16(d,J=6.1Hz,1H),7.41-7.47(m,3H),7.54(s,1H).

[0663] Example 11: Intermediate 11.2. (3-Bromomethyl-phenyl)-acetic acid

[0664] [ka]

[0665] To a suspension of compound 11.1 (750 mg, 5 mmol) in CCl4 (15 mL) was added AIBN (41 mg, 0.25 mmol) and NBS (933.7 mg, 5.24 mmol). Stirring was continued under reflux overnight. The solvent was removed under reduced pressure. The reaction was taken up in water, extracted with EtOAc (3 x 20 mL), washed with brine, and dried over Na2SO4. The crude was purified by flash chromatography eluting with CHCl2 / MeOH (3% relative to the product) to give the title intermediate 11.2 (800 mg, 3.49 mmol) as a white solid. Yield 70%. GC / MS (m / z) 227.9 (M+).

[0666] Example 12: Intermediate 12.2. [3-(4-chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid

[0667] [ka]

[0668] Step 1: [3-(5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (12.1) To a stirred suspension of intermediate 1.4 (500 mg, 2.12 mmol) and DIPEA (0.4 mL, 2.12 mmol) in DMSO (5 mL) was added intermediate 11.2 (487 mg, 2.12 mmol). Stirring was continued at room temperature overnight. The crude reaction mixture was poured into water, and the resulting aqueous mixture was washed with EtOAc, acidified to pH 3, and extracted with EtOAc (3 × 50 mL). After flash chromatography purification eluting with CHCl / MeOH (10% relative to the product) and trituration with EtO / acetone mixture, the title intermediate 12.1 (200 mg, 0.52 mmol) was obtained as a pure yellowish solid. Yield 25%. 1 H NMR(400MHz,DMSO-d6) δ 3.49(s,2H),4.53(s,2H),7.16(d,J=6.8Hz,1H),7.26(t,J=7.2Hz,1H),7.36(m,3H),8.05(d,J=4.4Hz,1H),8.27(s,1H),12.13(s,1H); 13 C NMR(100MHz,DMSO-d6) δ 34.3,40.9,88.5,116.8,127.6,128.9,129.1,129.8,130.4,131.9,135.2,135.8,137.0,139.9,159.1,161.6,165.7,172.9. HPLC 95.8%.

[0669] Step 2: [3-(4-chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (12.2) A mixture of intermediate 12.1 (300 mg, 0.78 mmol) and POCl (6 mL) was heated at 80 °C for 4 h. The crude reaction mixture was then poured into ice. The resulting yellow precipitate was collected and dried under reduced pressure to give the title intermediate 12.2 (250 mg, 0.62 mmol) as a yellowish solid. Yield 79%. 1 H NMR(400MHz,DMSO-d6) δ 3.53(s,2H),4.50(s,2H),7.16(d,J=7.5Hz,1H),7.27(t,J=7.4Hz,1H),7.3 6-7.39(m,3H),8.13(d,J=4.9Hz,1H),8.3(d,J=3.9Hz,1H),12.25(brs,1H). 13 C NMR (100MHz, DMSO-d6) δ 35.1,40.9,97.7,115.5,127.6,128.8,129,130.2,130.4,133.3,135.7,136,137,138.6,160.3,163.2,172.9,174.

[0670] Example 13: Intermediate 13.3. [3-(4-chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid

[0671] [ka]

[0672] Step 1: 3-(5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (13.2) To a stirred suspension of intermediate 1.4 (250 mg, 1.06 mmol) and KCO (440 mg, 3.18 mmol) in CHCN (15 mL) was added 3-(chloromethyl)benzoic acid 13.1 (180 mg, 1.06 mmol). Stirring was continued under reflux overnight. Then, the volatiles were removed under reduced pressure. The crude product was taken up in water, washed with EtOAc, acidified to pH 1, and extracted with EtOAc (3 × 50 mL). Trituration with hot acetone afforded the title intermediate 13.2 (45 mg, 0.12 mmol) as a yellowish solid. Yield: 12%. 1 H NMR(400MHz,DMSO-d6) δ 4.62(s,2H),7.33(t,J=4.3Hz,1H),7.44(t,J=7.6Hz,1H),7.72(d,J=7.5Hz, 1H),7.82(d,J=7.5Hz,1H),8.05(m,2H),8.26(d,J=3.8Hz,1H),12.99(s,1H); 13 C NMR(100MHz,DMSO) δ 33.9,88.7,116.5,128.8,129.3,129.9,130.2,131.5,132.1,133.7,135.4,137.9,139.7,159.0,161.2,165.3,167.4. HPLC:97.2%

[0673] Step 2: 3-(4-chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (13.3) A mixture of Intermediate 13.2 (300 mg, 0.81 mmol) and POCl (6 mL) was heated at 80 °C for 4 h. The reaction mixture was then poured into ice. The resulting yellow precipitate was collected and purified by flash chromatography eluting with DCM / MeOH (3% relative to the product) to give Intermediate 13.3 (120 mg, 0.3 mmol) as a yellowish solid. Yield: 79%. 13 C NMR(100MHz,DMSO-d6) δ 33.8,88.7,116.5,128.8,129.3,129.9,130.2,131.4,132.1,133.7,135.5,137.9,139.6,159,161.1,165.2,167.3;

[0674] Example 14: Intermediate 14.2. 3-Bromomethyl-benzonitrile

[0675] [ka]

[0676] To a solution of compound 14.1 (2 mL, 17.07 mmol) in CCl4 was added a mixture of NBS (2.9 g, 17.1 mmol) and BPO (16 mg, 0.06 mmol). Stirring was continued at reflux for 16 h, after which the reaction was allowed to warm to room temperature. The resulting solid was collected, washed with CCl4, and dried under reduced pressure. Title compound 14.2 (2.84 g, 14.5 mmol) was obtained as a white solid. Yield 85%. GC-) 196.9 (M+).

[0677] Example 15: Intermediate 15.1. 2-(3-Bromomethyl-phenyl)-ethanol

[0678] [ka]

[0679] To a solution of intermediate 11.2 (500 mg, 2.17 mmol) in THF (10 mL) was added BH3-THF (1 M in THF, 2.8 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h and then at room temperature for 12 h. The mixture was diluted with THF / HO (1:1 v:v, 15 mL) and washed with saturated aqueous K2CO3. The phases were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4. Flash chromatography purification of the crude product (eluted with DCM / MeOH) afforded the title intermediate 15.1 (400 mg, 1.85 mmol) as a white solid. Yield 85%. GC / MS (m / z) 214 (M+).

[0680] Example 16: Intermediate 16.2. 2(3-Bromomethyl-phenyl)-acetonitrile

[0681] [ka]

[0682] NBS (338 mg, 1.9 mmol) and BPO (70%) (28.7 mg, 0.11 mmol) were added to a solution of intermediate 16.1 (0.5 mL, 2.37 mmol) in CHCN (15 mL). Stirring was continued under reflux for 4 h. The volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO (100 mL). The organic phase was collected and dried over NaSO. After flash chromatography purification (eluted with PET / EtOAc), the title compound 16.2 (250 mg, 1.18 mmol) was obtained as a yellowish solid. Yield: 50%.

[0683] Example 17: Intermediate 17.3. 5-(3-Bromomethyl-phenyl)-2-methyl-2H-tetrazole

[0684] [ka]

[0685] Step 1: 5-m-Tolyl-2H-tetrazole (17.1) A mixture of compound 14.1 (1.02 mL, 8.54 mmol), NaN (832 mg, 12.8 mmol), and EtN HCl (1.76 g, 12.8 mmol) in toluene (20 mL) was heated under reflux for 4 h. The solvent was then removed under reduced pressure. The crude product was poured into water, and the resulting aqueous solution was acidified to pH 1 with 3 N HCl and extracted with EtOAc (3 × 20 mL). The organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. Title compound 17.1 (1.22 g, 7.6 mmol) was obtained as a white solid. Yield: 89%. 1 H NMR (200MHz, DMSO-d6) δ 2.39(s,3H),7.39(m,1H),7.48(t,J=7.58Hz,1H),7.80(s,1H),7.85(m,1H);GC / MS(m / z)160.1(M+).

[0686] Step 2: 2-Methyl-5-m-tolyl-2H-tetrazole (17.2) To a solution of intermediate 17.1 (1 g, 6.2 mmol) in water (5 mL) and NaOH (500 mg, 12.5 mmol) was added a solution of MeI (0.38 mL, 6.1 mmol) in acetone (10 mL). Stirring was continued under reflux for 6 h. Then the solvent was removed under reduced pressure and the resulting residue was taken up in EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated to dryness in vacuo. Purification of the crude product afforded the title intermediate 17.2 (500 mg, 2.87 mmol) as a white solid. Yield: 46%. 1 H NMR (400MHz, CDCl3) δ 4.37(s,3H),7.26-7.39(m,1H),7.35-7.39(m,1H),7.91-7.96(m,2H).

[0687] Step 3: 5-(3-Bromomethyl-phenyl)-2-methyl-2H-tetrazole (17.3) To a suspension of compound 17.2 (200 mg, 1.15 mmol) in CHCN (15 mL) was added BPO (21 mg, 0.057 mmol) and NBS (163.5 mg, 0.92 mmol). Stirring was continued at 92 °C overnight. The solvent was removed under reduced pressure. The reaction mixture was taken up in water, extracted with EtOAc (3 × 20 mL), washed with brine, and dried over NaSO. The crude product was purified by flash chromatography eluting with CHCl / MeOH (7% relative to the product) to give the title compound 17.3 (261 mg, 1.03 mmol) as a white solid. Yield 90%. 1 H NMR (400MHz, CDCl3) δ 4.41(s,3H),4.56(s,2H),7.46-7.52(m,1H),8.07-8.09(m,1H),8.19(s,1H).

[0688] Example 18: Intermediate 18.1. 5-(3-Bromomethyl-phenyl)-1H-tetrazole

[0689] [ka]

[0690] To a suspension of compound 17.1 (300 mg, 1.87 mmol) in CHCN (15 mL) was added AIBN (31 mg, 0.18 mmol) and NBS (333 mg, 1.87 mmol). Stirring was continued under reflux overnight. The solvent was removed under reduced pressure. The reaction was taken up in water, extracted with EtOAc (3 × 20 mL), washed with brine, and dried over NaSO. The crude was purified by flash chromatography eluting with CHCl / MeOH (7% relative to the product) to give the title compound 18.1 (150 mg, 0.62 mmol) as a pale yellow solid. Yield: 34%.

[0691] Example 19: Intermediate 19. 5.3-Bromomethyl-benzenesulfonamide

[0692] [ka]

[0693] Step 1: 3-Chlorosulfonyl-benzoic acid (19.2) A mixture of compound 19.1 (1 g, 8.13 mmol) and chlorosulfonic acid (4 mL) was stirred at 125 °C for 2 h. The mixture was poured dropwise into ice water. The resulting solid was collected, solubilized in EtOAc, and washed with water (3 × 20 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. Title intermediate 19.2 (1.19 g, 5.39 mmol) was obtained as a white solid. Yield 65%. 1 H NMR (400MHz, DMSO-d6) δ 7.45(t,J=7.69Hz,1H),7.65(d,J=7.8Hz,1H),7.86(d,J=7.6Hz,1H),8.1(s,1H),13.9(brs,1H).

[0694] Step 2: 3-Sulfamoyl-benzoic acid (19.3) To a cold solution of 25% NHOH (10 mL) was added intermediate 19.2 (1.10 g, 5.39 mmol) in small portions. Stirring was continued at room temperature for 2 h, and the resulting mixture was concentrated. The crude product was suspended in water (4 mL), and then 37% HCl solution was added dropwise to the mixture. The resulting precipitate was collected and dried under reduced pressure to give the title intermediate 19.3 (943 mg, 4.6 mmol) as a white solid. Yield 87%. 1 H NMR (400MHz, DMSO-d6) δ 7.50(brs,2H),7.71(t,J=7.78Hz,1H),8.04(d,J=7.8Hz,1H),8.13(d,J=7.7Hz,1H),8.38(s,1H),13.4(brs,1H).

[0695] Step 3: 3-Hydroxymethyl-benzenesulfonamide (19.4) To a stirred solution of intermediate 19.3 (940 mg, 4.67 mmol) was added BH3-THF complex (14 mL, 14.01 mmol) dropwise at 0 °C, and stirring was continued for 4 h at room temperature. The reaction mixture was then cooled to 0 °C and quenched by the dropwise addition of MeOH. After 15 min, a 3N HCl (37 mL) solution was added to the mixture, and the volatiles were removed under reduced pressure. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4 to give the title intermediate 19.4 (785 mg, 4.2 mmol) as a colorless oil. Yield: 89%. 1 H NMR (400MHz, DMSO-d6) δ 4.51(s,2H),7.34(s,2H),7.5(d,J=5Hz,2H),7.68(t,J=5.2Hz,1H),7.8(s,1H).

[0696] Step 4: 3-Bromomethyl-benzenesulfonamide (19.5) To a stirred suspension of intermediate 19.4 (200 mg, 1.07 mmol) in DCM (3.5 mL) was added PBr3, and stirring was continued at 20 °C for 16 h. Then, water was carefully added to the mixture, and the phases were separated. The aqueous phase was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine and dried over Na2SO4 to give the title intermediate 19.5 (120 mg, 0.47 mmol) as a colorless oil. Yield: 45%. 1 H NMR (400MHz, CDCl3) δ 4.53(s,2H),7.54(t,J=10.7Hz,1H),7.69(d,J=7.6Hz,1H),7.88(d,J=7.8Hz,1H),7.97(s,1H).

[0697] Example 20: Intermediate 20.2. 4-Benzyl-2-mercapto-6-oxo-1,6-dihydro-pyridine-3-carbonitrile

[0698] [ka]

[0699] To a solution of intermediate 20.1 (1.2 g, 6.24 mmol) and potassium tert-butoxide (764 mg, 6.24 mmol) in DMF (15 mL) was added compound 3.2 (31 mg, 0.18 mmol). Stirring was continued at 85 °C overnight. The reaction was poured into water, and the pH was acidified to 5 by adding AcOH, followed by washing with EtOAc (3 × 20 mL). The pH was then brought to 3 by adding 3N HCl solution. The aqueous phase was extracted with EtOAc (3 × 30 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The title compound (600 mg, 2.47 mmol) was obtained as a pale yellow solid. Yield: 40%. 1 H NMR (400MHz, DMSO-d6) δ 3.63 (s, 2H), 5.81 (s, 1H), 7.17-7.36 (m, 5H), 13.1 (brs, 1H).

[0700] Example 21: [3-(5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid ethyl ester (compound I-1)

[0701] [ka]

[0702] To a stirred suspension of intermediate 1.4 (2.13 g, 9.1 mmol) and K2CO3 (1.88 g, 13.6 mmol) in CH3CN (80 mL) was added intermediate 8.3 (2.45 g, 9.52 mmol), and stirring was continued under gentle reflux for 16 h. The solvent was then removed under reduced pressure. The crude product was taken up in water, and the resulting aqueous solution was neutralized with 3 N HCl solution. The resulting pale yellow solid was collected, washed with ice-cold water, and dried under reduced pressure. After trituration with Et2O, the title compound I-1 (3.1 g, 7.46 mmol) was obtained as a gray solid. Yield: 82%. 1 H NMR(400MHz,DMSO-d6) δ 1.15(d,J=7.03Hz,3H),3.62(s,2H),4.03(q,J=7.16Hz,2H),4.55(s,2H),7.17(d,J=7.1 Hz,1H),7.28(t,J=7.7Hz,1H),7.38(m,3H),8.1(d,J=4.7Hz,1H),8.29(d,J=3.35Hz,1H). 13 C NMR(100MHz,DMSO-d6) δ 14.4,34.2,60.7,88.6,116.6,127.8,129.1,129.1,129.9,130.3,132.1,135.2,135.5,137.1,139.7,159.1,161.1,165.3,171.4. HPLC>97.9%.

[0703] Example 22: 3-(5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzamide (Compound I-2)

[0704] [ka]

[0705] To a stirred suspension of intermediate 1.4 (182 mg, 0.78 mmol) and intermediate 9.3 (200 mg, 0.65 mmol) in CHCN (20 mL) was added KCO (119 mg, 0.86 mmol), and stirring was continued under gentle reflux for 16 h. Volatiles were removed under reduced pressure. The crude product was taken up in water, and the resulting aqueous mixture was acidified to pH 3 with 3 N HCl solution and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine, dried over NaSO, and triturated with hot EtO to give the title compound I-2 (120 mg, 0.24 mmol) as a yellowish solid. Yield: 42%. 1 H NMR(400MHz,DMSO-d6) δ 4.61(s,2H),7.3(m,1H),7.41(m,2H),7.63(d,J=7.12Hz,1H),7.76(d,J=7.3Hz,1H),7.97(s,2H),8.01(d,J=4.47Hz,1H),8.3(d,J=2.8Hz,1H). 13 C NMR(100MHz,DMSO-d6) δ 34.5,88.1,117.1,127.3,129.1,129.3,130.4,132.5,132.5,135.5,135.9,137.7,140.2,159.4,161.6,165.7,168.4. HPLC>94.2%.

[0706] Example 23: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}sulfanyl)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (Compound I-3)

[0707] [ka]

[0708] Step 1: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}sulfanyl)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (22.1) To a stirred solution of Intermediate 1.4 (152 mg, 0.65 mmol) and Intermediate 10.4 (250 mg, 0.77 mmol) in DMSO (6 mL) was added DIPEA (0.13 mL, 0.72 mmol), and stirring was continued at room temperature for 4 h. The crude mixture was poured into water, and the resulting aqueous mixture was washed with EtOAc, acidified to pH 3, and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine, dried over NaSO, and purified by flash chromatography eluting with CHCl / MeOH (4% relative to the product) to give Intermediate 22.1 (180 mg, 0.038 mmol) as a pale yellow powder. Yield: 55%. 1 H NMR(400MHz,DMSO-d6) δ 3.93(s,3H),4.60(s,2H),7.34-7.43(m,4H),7.5(d,J=4.3Hz,1H),7.60(d,J=7.5 Hz,1H),7.84(s,1H),8.0(d,J=4.9Hz,1H),8.29(d,J=4.9Hz,1H),13.9(brs,1H).

[0709] Step 2: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}sulfanyl)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (compound I-3) To a stirred suspension of intermediate 22.1 (170 mg, 0.36 mmol) in DCM (25 mL) was added a 1 M solution of BBr in DCM (0.72 mL, 0.72 mmol), and stirring was continued under reflux for 16 h. The reaction mixture was quenched by the addition of MeOH, and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography eluting with DCM / MeOH (5% relative to the product). After trituration with hot EtO, the title compound I-3 (90 mg, 0.2 mmol) was obtained as a white solid. Yield: 42%. 1H NMR(400MHz,DMSO) δ 4.59(s,3H),7.31(d,J=9.1Hz,2H),7.36(m,1H),7.39(d,J=7.6Hz,1H),7.45(d,J=7.7Hz,1H) ,7.56(d,J=7.5Hz,1H),7.81(s,1H),8.07(d,J=5Hz,1H),8.3(d,J=3.8Hz,1H),10.34(s,1H). 13 C NMR(100MHz,DMSO-d6) δ 88.7,110.3( 2 J CF =15.1Hz), 110.3( 2 J CF =15.5Hz),125.8,127.4,128.5,129.7.130,130.5,132.1,133.5( 3 J CF =16Hz), 133.7( 3 J CF =16Hz),135.3,138.1,138.4,139.7,152.9( 1 J CF =239.9Hz), 153.01( 1 J CF =240.1MHz),159.0,161.3,165.5. HPLC:98.4%.

[0710] Example 24: [3-(5-cyano-4-methoxy-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-4)

[0711] [ka]

[0712] To a stirred solution of intermediate 12.2 (80 mg, 0.19 mmol) and MeOH (0.04 mL, 0.95 mmol) in DMF (3 mL) was added K2CO3 (60 mg, 0.43 mmol), and stirring was continued at room temperature for 16 hours. The reaction mixture was poured into water, and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and dried over Na2SO4. Flash chromatography purification of the crude product (eluted with DCM / MeOH, 1.5% based on the product) afforded the title compound I-4 (45 mg, 0.11 mmol) as a white solid. Yield: 58%; 1 H NMR(400MHz,DMSO-d6) δ 3.56(s,3H),3.66(s,2H),4.54(s,2H),7.17(d,J=7.2Hz,1H),7.27(t,J=7 .6Hz,1H),7.33-7.38(m,3H),8.07(d,J=4.8Hz,1H),8.28(d,J=3.6Hz,1H). 13 C NMR(100MHz,DMSO-d6) δ 34.2,40.3,52.1,88.5,116.6,127.8,129,129.1,129.8,130.3,132,135.1,135.3,137.1,139.8,159.1,161.4,165.5,171.8. HPLC>97.1%.

[0713] Example 25: [3-(4-Bromo-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-5)

[0714] [ka]

[0715] To a stirred solution of intermediate 12.2 (30 mg, 0.051 mmol) in AcOH (3.0 mL) was added HBr (36% AcOH solution, 0.17 mL, 1.029 mmol), and the resulting mixture was stirred at 60 °C for 72 h. The reaction mixture was then diluted with DCM (10 mL), washed with HO (3 × 10 mL), brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH / AcOH, 99:1:0.1 to 92:8:0.1) to afford the title compound I-5 (17 mg, 0.038 mmol) as a yellow solid. Yield 75%. MS / MS ESI(+): 447.8, 401.9, 338.3. 1 H-NMR (CDCl3,400MHz) δ:3.63(s,2H),4.45(s,2H),7.21(m,1H),7.31(m,2H),7.39(m,2H),7.70(brs,1H),8.45(brs,1H). 13 C-NMR(CDCl3,100MHz) δ:29.3,40.7,100.1,116.0,127.9,128.7,128.9,129.4,130.1,133.1,133.6,134.6,136.6,138.7,155.8,159.7,174.3,177.1. HPLC>95%.

[0716] Example 26: [3-(5-cyano-4-cyclopropylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-6)

[0717] [ka]

[0718] To a stirred solution of intermediate 12.2 (200 mg, 0.49 mmol) in DMF (3 mL) was added cyclopropylamine (0.037 mL, 0.55 mmol), and stirring was continued at room temperature for 16 h. The reaction mixture was quenched with brine and poured into water, and the resulting aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. After trituration with EtO, the title compound I-6 (80 mg, 0.2 mmol) was obtained as a white solid. Yield: 39%. 1 H NMR(400MHz,DMSO-d6) δ 0.73(m,4H),2.95(m,1H),3.53(s,2H),4.45(s,2H),7.13(d,J=7.4Hz,1H),7.23-7.29(m,2H ),7.33-7.35(m,2H),7.93(d,J=4.9Hz,1H),8.18(d,J=3.2Hz,1H),8.21(s,1H),12.3(s,1H). 13 C NMR(100MHz,DMSO-d6) δ 6.6,6.6,25,34.3,40.8,79.7,116.7,127.3,128.5,128.6,129.2,130.1,130.7,133.2,135.4,138.3,140.1,158.7,162.8,172.8,172.8. HPLC>99.3%.

[0719] Example 27: [3-(4-amino-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-7)

[0720] [ka]

[0721] [3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (12.2) (100 mg, 0.248 mmol) was dissolved in 0.4 M NH in THF (18 mL, 7.466 mmol), and the resulting milky solution was stirred at room temperature for 72 h. The mixture was then poured into AcOEt (15 mL), washed with 3 M HCl (5 mL), saturated aqueous NaHCO (10 mL), brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The crude material was purified by flash chromatography (CHCl / MeOH / AcOH, 99:1:0.1 to 90:10:0.1) to afford the title compound I-7 (86 mg, 0.22 mmol) as a white solid. Yield 94%; MS / MS ESI(+): 382.9. 1 H NMR(400MHz,DMSO-d6) δ 3.53(s,2H),4.39(s,2H),7.13(d,J=7.3Hz,1H),7.24(t,J=7.1Hz,1H),7.29(m,1H) ),7.35(m,2H),7.8(brs,1H),7.94(d,J=4.3Hz,1H),8.20(m,1H),12.32(brs,1H). 13 C NMR (100MHz, DMSO-d6) δ 34.3,40.9,78.9,116.9,127.6,128.6,128.7,129.3,130.4,130.8,133.4,135.5,138.3,140.4,159.1,163.7,173. HPLC>97.9%.

[0722] Example 28: [3-(5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-8)

[0723] [ka]

[0724] EtN (0.15 mL, 1.119 mmol) was added to a stirred solution of intermediate 12.2 (150 mg, 0.373 mmol) in THF (3.7 mL). The resulting solution was continuously hydrogenated for 12 h using a Thales Nano H-Cub Hydrogenator (cartridge: Pd / C 10%, H pressure: 8 bar, temperature: 40 °C, transport solvent: THF, flow rate: 1.0 mL / min). The resulting reaction mixture (about 5 mL) was diluted with EtOAc (15 mL), washed with 3 M HCl (5 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (column: RP-18, eluted with HO / MeOH 80 / 20 to 10 / 90) to give the title compound I-8 as a white powder. Yield: 34%. MS / MSESI(+):368.1. 1 H-NMR (DMSO-d6,400MHz) δ:3.60(s,2H),4.45(s,2H),7.15(m,1H),7.25(m,1H),7.36(m,4H),8.06(br-s,1H),8.30(ps-s,1H),9.03(s,1H).

[0725] Example 29: [3-(5-cyano-4-methylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-9)

[0726] [ka]

[0727] To a stirred solution of intermediate 12.2 (100 mg, 0.25 mmol) in DMF (3 mL) was added a solution of 33% MeNH (0.03 mL, 0.27 mmol) in ethanol, and stirring was continued at room temperature for 16 hours. The reaction mixture was quenched with brine, poured into water, and acidified to pH 6 by the addition of 3 M HCl solution, followed by extraction with EtOAc (3 × 20 mL). The combined organic phase was washed with brine and dried over Na SO to give the title compound I-9 (80 mg, 0.2 mmol) as a white solid. Yield: 80%.1 H NMR(400MHz,DMSO-d6) δ 2.93(d,J=4.5Hz,3H),3.53(s,2H),2.92(s,2H),7.13(d,J=7.6Hz,1H),7.24(d,J=7.5Hz,1H),7.27-7.2 9(m,1H),7.33(m,2H),7.94(d,J=5.1Hz,1H),8.1(q,J=4.5Hz,1H),8.18(d,J=3.8Hz,1H),12.33(s,1H). 13 C NMR(100MHz,DMSO-d6) δ 28.6,34.5,40.9,79.6,116.9,127.4,128.6,128.7,129.3,130.2,130.7,133.3,135.5,138.3,140.3,158.5,161.9,172.9,173.1. HPLC>98.1%.

[0728] Example 30: 3-(5-cyano-4-methylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (compound I-10)

[0729] [ka]

[0730] To a stirred solution of intermediate 13.3 (90 mg, 0.23 mmol) in DMF (3 mL) was added a solution of 33% MeNH (0.03 mL, 0.25 mmol) in ethanol, and stirring was continued at room temperature for 16 h. The reaction mixture was quenched with brine, poured into water, and acidified to pH 6 by the addition of 3 M HCl solution, followed by extraction with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na SO . The crude product was purified by flash chromatography eluting with DCM / MeOH (4% relative to the product) to give the title compound I-10 (45 mg, 0.12 mmol) as a white solid. Yield: 51%. 1H NMR(400MHz,DMSO-d6) δ 2.94(d,J=4.4Hz,3H),4.49(s,2H),7.28(t,J=4.4Hz,1H),7.44(t,J=7.7Hz,1H),7.70(d,J=7.5Hz,1H),7.81(d ,J=7.7Hz,1H),7.92(d,J=5.Hz,1H),8.04(q,J=4.5Hz,1H),8.06(s,1H)),8.18(d,J=3.8Hz,1H),12.92(s,1H). 13 C NMR(100MHz,DMSO-d6) δ 28.6,34.2,79.8,116.8,128.3,129.1,129.2,130,130.7,131.3,133.3,133.5,139.3,140.2,158.5,161.9,167.4,172.9. HPLC>95.1%.

[0731] Example 31: 2-(3-cyano-benzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-11)

[0732] [ka]

[0733] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and K2CO3 (133 mg, 0.93 mmol) in acetone (20 mL) was added intermediate 14.2 (133 mg, 0.93 mmol), and stirring was continued at room temperature for 16 h. The solvent was then removed under reduced pressure. The resulting mixture was poured into water and acidified to pH 6 by the addition of 3 M HCl solution, followed by extraction with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by flash chromatography eluting with DCM / MeOH to give the title compound I-11 (50 mg, 0.17 mmol) as a white solid. Yield 17%. 1H NMR(400MHz,DMSO-d6) δ 4.60(s,2H),7.35(d,J=4.8Hz,1H),7.54(t,J=7.8Hz,1H),7.74(d,J=7.7Hz,1H),7.83(d, J=7.9Hz,1H),7.96(s,1H),8.1(d,J=5.02Hz,1H),8.27(d,J=3.9Hz,1H),13.80(brs,1H). 13 C NMR (100MHz, DMSO-d6) δ 33.2,88.8,111.8,116.5,118.9,130,130.2,131.6,132.1,132.8,134.1,135.4,139.3,139.6,159,161.2,165.1. HPLC>99.1%.

[0734] Example 32: 2-[3-(2-hydroxy-ethyl)-benzylsulfanyl]-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (Compound I-12)

[0735] [ka]

[0736] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and DIPEA (0.16 mL, 0.93 mmol) in acetone (15 mL) was added intermediate 15.1 (201 mg, 0.93 mmol), and stirring was continued at room temperature for 16 hours. The solvent was then removed under reduced pressure. The resulting mixture was poured into water and acidified to pH 6 by the addition of 3 M HCl solution, followed by extraction with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na SO . The crude product was purified by flash chromatography eluting with DCM / MeOH to give the title compound I-12 (120 mg, 0.32 mmol) as a white solid. Yield: 38%. 1H NMR(400MHz,DMSO-d6) δ 2.47,(t,J=8.35Hz,2H),2.67(t,J=7.01Hz,2H),4.48(s,2H),4.51(brs,1H),7.11(d,J=7.5Hz,1H),7.22(t,J=7. 5Hz,1H), 7.29(d,J=7.7Hz,1H),7.32-7.36(m,2H),8.06(d,J=4.9Hz,1H),8.27(d,J=3.9Hz,1H),13.80(brs,1H). 13 C NMR(100MHz,DMSO-d6) δ 34.3,62.3,62.3,88.3,116.9,126.8,128.5,128.8,129.8,129.9,131.8,135.1,136.9,139.9,140.3,159,162,165.9. HPLC>96.1%.

[0737] Example 33: 2-(3-cyanomethyl-benzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-13)

[0738] [ka]

[0739] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and DIPEA (0.2 mL, 0.94 mmol) in acetone (20 mL) was added intermediate 16.2 (196 mg, 0.94 mmol), and stirring was continued at room temperature for 16 hours. The solvent was then removed under reduced pressure. The resulting mixture was poured into water and acidified to pH 6 by the addition of 3 M HCl solution, followed by extraction with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na SO . The crude product was purified by flash chromatography eluting with DCM / MeOH (2.5% relative to the product) to give the title compound I-13 (300 mg, 0.82 mmol) as a yellow solid. Yield: 96%. 1H NMR(400MHz,DMSO-d6) δ 4.01(s,2H),4.52(s,2H),7.24(d,J=7.49Hz,1H),7.31-7.36(m,2H),7.4 3-7.45(m,2H),8.0(d,J=5Hz,1H),8.23(d,J=3.8Hz,1H),13.80(brs,1H). 13 C NMR(100MHz,DMSO-d6) δ 22.6,33.9,87.9,117.5,119.5,127.5,128.5,128.9,129.6,129.6,131.3,131.9,134.5,138.6,140.3,159.1,164.1,166.7. HPLC>97.7%.

[0740] Example 34: 2-[3-(2-methyl-2H-tetrazol-5-yl)-benzylsulfanyl]-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-14)

[0741] [ka]

[0742] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and DIPEA (0.17 mL, 0.93 mmol) in acetone (15 mL) was added intermediate 17.3 (236 mg, 0.93 mmol), and stirring was continued at room temperature for 16 hours. The solvent was then removed under reduced pressure. The resulting solid was collected and dried under reduced pressure to give the title compound I-14 (200 mg, 0.49 mmol) as a yellowish solid. Yield: 58%. 1 H NMR(400MHz,DMSO-d6) δ 4.40(s,3H),4.66(s,2H),7.35(m,1H),7.51(t,J=7.5Hz,1H),7.66(d,J=6.9Hz,1H), 7.94(d,J=7.2Hz,1H),8.08(d,J=4.1Hz,1H),8.21(s,1H),8.28(s,1H),13.80(s,1H). 13C NMR(100MHz,DMSO-d6) δ 33.9,40.5,88.7,116.5,125.7,127.2,127.5,129.9,130,131.3,132.1,135.4,138.6,139.7,159.1,161.1,164.2,165.2. HPLC>99.3%.

[0743] Example 35: [3-(5-cyano-4-morpholin-4-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-15)

[0744] [ka]

[0745] To a stirred suspension of intermediate 12.2 (100 mg, 0.25 mmol) in CHCN (10 mL) was added morpholine (0.023 mL, 0.27 mmol), and stirring was continued at room temperature for 16 h. The solvent was then removed under reduced pressure. The crude product was taken up in water, and the resulting aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO to give the title compound I-15 (80 mg, 0.18 mmol) as a white solid. Yield: 71%. 1 H NMR(400MHz,CDCl3) δ 3.60(s,2H),3.79(m,4H),3.93(m,4H),4.41(s,2H),7.17-7.20(m,2H),7.27-7. 36(m,2H),7.37(d,J=8.23Hz,2H),7.61(d,J=5.1Hz,1H),8.32(d,J=3.5Hz,1H). 13 C NMR(100MHz,CDCl3) δ 35.1,40.6,47.7,47.7,66.5,66.5,80.6,118.4,127.7,128.3,128.6,128 .8,129.7,131.7,132.4,133.5,137.6,139.9,161.6,162.9,172.6,176.3. HPLC>98.1%.

[0746] Example 36: [3-(5-cyano-4-piperazin-1-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-16)

[0747] [ka]

[0748] Step 1. 4-[2-(3-Carboxymethyl-benzylsulfanyl)-5-cyano-6-thiophen-2-yl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (36.1). To a stirred suspension of intermediate 12.2 (250 mg, 0.62 mmol) and K2CO3 (128 mg, 0.93 mmol) in DMF (4 mL) was added 1-boc-piperazine (127 mg, 0.68 mmol), and stirring was continued at room temperature for 16 h. The solvent was then removed under reduced pressure. The resulting mixture was taken up in water, and the aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by flash chromatography eluting with DCM / MeOH (4% relative to the product) to afford the title intermediate 35.1 (60 mg, 0.11 mmol) as a yellowish solid. Yield: 18%.

[0749] Step 2. [3-(5-Cyano-4-piperazin-1-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (I-16). To a stirred solution of intermediate 35.1 (65 mg, 0.12 mmol) in DCM (15 mL) was added TFA (0.28 mL, 3.6 mmol), and stirring was continued at room temperature for 16 h. The solvent was then removed under reduced pressure. The crude mixture was taken up in water, and the resulting aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. After trituration with hot EtO, the title compound I-16 (20 mg, 0.044 mmol) was obtained as a white solid. Yield 37%. 1H NMR(400MHz,DMSO-d6) δ 2.83(m,4H),3.51(s,2H),3.81(m,4H),4.39(s,3H),7.13(d,J=7.03Hz,1H),7.24-7.33(m,4H),7.95(d,J=4.4Hz,1H),8.20(d,J=2.8Hz,1H). 13 C NMR(100MHz,DMSO-d6) δ 34.6,41.2,45.5,45.5,48.4,48.4,118.7,127.2,128.6,128.7,129.2 ,130.1,131.8,133.7,135.8,138.1,140.1,161.5,162.4,172,173.1. HPLC>90.9%.

[0750] Example 37. [3-(5-Cyano-1-methyl-4-oxo-6-thiophen-2-yl-1,4-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid ethyl ester (compound I-17).

[0751] [ka]

[0752] To a stirred suspension of compound I-1 (300 mg, 0.73 mmol) and K2CO3 (151 mg, 1.09 mmol) in DMF (15 mL) was added MeI (0.047 mL, 0.77 mmol) dropwise, and stirring was continued at room temperature for 16 hours. The resulting mixture was poured into water and then extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine and dried over Na2SO4 to give the title compound I-17 (298 mg, 0.7 mmol) as a yellowish solid. Yield: 96%. 1H NMR(400MHz,DMSO-d6) δ 0.14(t,J=7.12Hz,3H),3.41(s,3H),3.62(s,2H),4.03(q,J=7.1Hz,2H),4.64(s,2H),7.19(d,J=7.6Hz, 1H),7.27-7.31(m,1H),7.35(t,J=4.1Hz,1H),7.40(m,2H),8.08(d,J=4.9Hz,1H),8.28(d,J=3.8Hz,1H). 13 C NMR(100MHz,DMSO-d6) δ 14.4,31.1,36.1,40.5,60.6,87.5,116.5,127.9,129.1,129.2,130,1 30.4,132.1,135.3,135.4,136.2,139.5,157.1,160.1,166.4,171.3. HPLC>95.1%.

[0753] Example 38. 3-(5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzenesulfonamide (Compound I-18)

[0754] [ka]

[0755] To a stirred solution of intermediate 1.4 (107 mg, 0.45 mmol) and DIPEA (0.08 mL, 0.49 mmol) in acetone (15 mL) was added intermediate 19.5 (125 mg, 0.49 mmol), and stirring was continued at room temperature for 16 h. The solvent was then removed under reduced pressure. The crude mixture was taken up in water and then extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. After trituration with hot EtO, the title compound I-18 (50 mg, 0.12 mmol) was obtained as a yellowish solid. Yield 28%. 1H NMR(400MHz,DMSO-d6) δ 4.65(s,2H),7.34(t,J=4.6Hz,1H),7.40(s,2H),7.52(t,J=7.6Hz,1H),7.72(t,J= 6.1Hz,2H),7.94(s,1H),8.06(d,J=4.8Hz,1H),8.27(d,J=3.6Hz,1H),13.8(s,1H). 13 C NMR (100MHz, DMSO-d6) δ 33.7,88.6,116.6,125.2,126.1,129.7,129.9,132,132.5,135.4,138.4,139.7,144.8,159.1,161.4,165.3. HPLC>95.1%.

[0756] Example 39: [3-(3-cyano-6-oxo-4-phenyl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-19)

[0757] [ka]

[0758] To a stirred suspension of intermediate 3.3 (100 mg, 0.44 mmol) and DIPEA (0.09 mL, 0.53 mmol) in acetone (15 mL) was added intermediate 11.2 (94 mg, 0.44 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected, washed with cold water, and dried under vacuum. Compound I-19 (60 mg, 0.16 mmol) was obtained as a brownish powder. Yield: 37%. 1 H NMR(400MHz,DMSO-d6) δ 3.55(s,2H),4.5(s,2H),6.51(s,1H),7.16(d,J=7.4Hz,1H),7.27(t,J=7.7 Hz,1H),7.37(m,2H),7.51-7.53(m,3H),7.55-7.56(m,2H),12.17(brs,2H); 13C NMR(100MHz,DMSO-d6) δ 33.5,40.6,95.9,108,116.2,127.6,128.3,128.3,128.5,128.5,128.9,128. 9,130,130.3,135.4,135.9,137.5,155.9,162.1,164.9,172.7;HPLC:96.88%.

[0759] Example 40: [3-(3-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-20)

[0760] [ka]

[0761] To a stirred suspension of intermediate 5.2 (153 mg, 0.56 mmol) and DIPEA (0.12 mL, 0.67 mmol) in DMSO / acetone (15 / 4 mL) was added intermediate 11.2 (121 mg, 0.56 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected, washed with cold water, and dried under vacuum. Compound I-20 (90 mg, 0.22 mmol) was obtained as a brownish powder. Yield: 42%. 1 H NMR(400MHz,DMSO-d6) δ 3.55(s,2H),4.51(s,2H),6.62(s,1H),7.15(d,J=7.4Hz,1H),7.24-7.28(m,2H),7 .35(d,J=6.4Hz,2H),7.75(d,J=3.5Hz,1H),7.85(d,J=4.9Hz,1H),12.1(brs,1H); 13 C NMR(100MHz,DMSO-d6) δ 33.6,40.6,93.8,104.5,116.5,127.6,128.6,128.6,128.7,128.7,129. 5,130.3,130.3,135.4,136.6,137.4,147.4,165.1,172.7;HPLC:96.5%.

[0762] Example 41: [3-(3,5-dicyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-21)

[0763] [ka]

[0764] To a stirred solution of intermediate 6.2 (200 mg, 0.77 mmol) and DIPEA (0.16 mL, 0.92 mmol) in acetone (15 mL) was added intermediate 11.2 (165 mg, 0.77 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected, washed with cold water, and dried under vacuum. Compound I-21 (110 mg, 0.27 mmol) was obtained as a brownish powder. Yield: 35%. 1 H NMR(400MHz,DMSO-d6) δ 3.56(s,2H),4.48(s,2H),7.63(d,J=7.6Hz,1H),7.24-7.28(m,2H),7.38-7.40(m,2H),7.54 (dd,J=1.1Hz,J=3.6Hz,1H),7.93(dd,J=1.1Hz,J=5Hz,1H),8.12(brs,1H),12.29(brs,1H); 13 C NMR(100MHz,DMSO-d6) δ 33.3,40.6,85.8,93.1,115.5,127.8,128,128,128.6,130.5,130.9,131. 4,131.4,132.9,135.3,137.4,,150.8,159.8,166.9,172.8,;HPLC:97.5%.

[0765] Example 42: 2-Oxo-6-[3-(1H-tetrazol-5-yl)-benzylsulfanyl]-4-thiophen-2-yl-1,2-dihydro-pyridine-3,5-dicarbonitrile (Compound I-22)

[0766] [ka]

[0767] To a stirred solution of intermediate 6.2 (150 mg, 0.57 mmol) and DIPEA (0.18 mL, 0.68 mmol) in acetone (15 mL) was added intermediate 18.1 (138 mg, 0.57 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected, washed with cold water, and dried under vacuum. Compound I-22 (90 mg, 0.27 mmol) was obtained as a yellowish powder. Yield: 38%. 1 H NMR(400MHz,DMSO-d6) δ 4.6(s,2H),7.26(dd,J=5.0Hz,J=3.6Hz,1H),7.54-7.56(m,2H),7.76(d,J=7.7Hz,1H),7.90-7.94(m,2H),8.1(s,1H); 13 C NMR(100MHz,DMSO-d6) δ HPLC: 96.7%

[0768] Example 43: [3-(4-benzyl-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (compound I-23)

[0769] [ka]

[0770] To a stirred solution of intermediate 20.2 (154 mg, 0.63 mmol) and DIPEA (0.12 mL, 0.7 mmol) in acetone (15 mL) was added intermediate 11.2 (150 mg, 0.7 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected, washed with cold water, and dried under vacuum. Compound I-23 (100 mg, 0.25 mmol) was obtained as a yellowish powder. Yield: 40%. 1 H NMR (400MHz, DMSO-d6) δ 3.37 (s, 2H), 3.98 (s, 2H), 4.48 (s, 2H), 6.34 (s, 1H), 7.13-7.32 (m, 9H), 12.1 (brs, 1H); HPLC: 98.5%.

[0771] Example 44: (5-cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanyl)-acetic acid (Compound I-24)

[0772] [ka]

[0773] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and DIPEA (0.18 mL, 1.02 mmol) in acetone / DMSO (20:2 mL) was added chloroacetic acid (80 mg, 0.85 mmol). Stirring was continued overnight at room temperature. An additional 0.3 equivalents of DIPEA and chloroacetic acid were then added to drive the reaction to completion. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3 N HCl. The precipitate was collected and purified by reverse flash chromatography eluting with HO / MeOH (10 to 80%). Compound I-24 (210 mg, 0.71 mmol) was obtained as a yellowish powder. Yield: 83%. 1 H NMR(400MHz,DMSO-d6) δ 4.0(s,2H),7.33(t,J=4.7Hz,1H),8.1(d,J=4.9Hz,1H),8.25(d,J=3.8Hz,1H),12.8(brs,1H); 13C NMR (100MHz, DMSO-d6) δ 33.4,88.5,116.5,129.8,132.3,135.6,139.5,159,161.1,165.2,169.3;HPLC:99.6%.

[0774] Example 45: 6-Oxo-2-(1H-tetrazol-5-ylmethylsulfanyl)-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-25)

[0775] [ka]

[0776] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and DIPEA (0.18 mL, 1.02 mmol) in acetone / DMSO (20:2 mL) was added intermediate 5-chloromethyl-1H-tetrazole (101 mg, 0.85 mmol). Stirring was continued overnight at room temperature. An additional 0.3 equivalents of DIPEA and 5-chloromethyl-1H-tetrazole were then added to drive the reaction to completion. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3N HCl. The precipitate was collected and purified by reverse flash chromatography eluting with HO / MeOH (10 to 80%). Compound I-25 (120 mg, 0.37 mmol) was obtained as a yellowish powder. Yield: 44%. 1 H NMR(400MHz,DMSO-d6) δ 4.82(s,2H),7.31(t,J=4.2Hz,1H),8.0(d,J=4.9Hz,1H),8.22(d,J=3.8Hz,1H); 13 C NMR (100MHz, DMSO-d6) δ 23.6,88.7,116.4,129.9,132.2,135.6,139.4,157.1,159.0,161.4,164.4;HPLC:94.6%.

[0777] Example 46: 2-(1H-tetrazol-5-ylmethylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (Compound I-26)

[0778] [ka]

[0779] To a stirred solution of intermediate 2.1 (100 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.73 mmol) in acetone (5 mL) was added 5-chloromethyl-1H-tetrazole (87 mg, 0.73 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3N HCl. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. Compound I-26 (60 mg, 0.19 mmol) was obtained as a white powder. Yield: 35%. 1 H NMR(400MHz,DMSO-d6) δ 4.69(s,2H),6.67(s,1H),15.1(brs,1H); 13 C NMR(100MHz,DMSO-d6) δ 23.1,107.7,120.6(q,J CF =2.7Hz),152,154.3,163.9,164.8;HPLC:97.9%

[0780] Example 47: (6-Oxo-4-trifluoromethyl-1,6-dihydro-pyrimidin-2-ylsulfanyl)-acetic acid (Compound I-27)

[0781] [ka]

[0782] To a stirred solution of intermediate 2.1 (200 mg, 0.85 mmol) and DIPEA (0.16 mL, 0.94 mmol) in DMSO (5 mL) was added chloroacetic acid (89 mg, 0.94 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3 N HCl. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. The crude reaction was purified by reverse flash chromatography eluting with HO / MeOH (5 to 65% based on product). Compound I-27 (125 mg, 0.49 mmol) was obtained as a white powder. Yield: 58%. 1 H NMR(400MHz,DMSO-d6) δ 3.96(s,2H),6.63(s,1H); 13 C NMR (100MHz, DMSO-d6) δ 33.1,108,120.6(q,JCF=2.7Hz),163.1,165.4,169.5;HPLC:95.9%.

[0783] Example 48: [3-(6-oxo-4-trifluoromethyl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-28)

[0784] [ka]

[0785] To a stirred solution of intermediate 2.1 (150 mg, 0.64 mmol) and DIPEA (0.12 mL, 0.71 mmol) in DMSO (5 mL) was added intermediate 11.2 (152 mg, 0.71 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3 N HCl. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over NaSO. The crude reaction was purified by reverse flash chromatography eluting with HO / MeOH (5 to 80% based on product). Compound I-28 (100 mg, 0.29 mmol) was obtained as a white powder. Yield: 45%. 1H NMR(400MHz,DMSO-d6) δ 3.54(s,2H),4.52(s,2H),6.87(s,1H),7.16(d,J=7.3Hz,1H),7.26(t,J=7.4Hz,1H),7.33-7.35(m,2H),12.18(brs,1H);HPLC:98.1%.

[0786] Example 49: 2-[3-(1H-tetrazol-5-yl)-benzylsulfanyl]-6-trifluoromethyl-3H-pyrimidin-4-one (Compound I-29)

[0787] [ka]

[0788] To a stirred solution of intermediate 2.1 (150 mg, 0.64 mmol) and DIPEA (0.12 mL, 0.71 mmol) in DMSO (5 mL) was added intermediate 18.1 (152 mg, 0.64 mmol). Stirring was continued at room temperature overnight. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3N HCl. The white solid was collected and assumed to be the title compound. Compound I-29 (160 mg, 0.45 mmol) was obtained as a white powder. Yield 70%. 1 H NMR(400MHz,DMSO-d6) δ 4.50(s,2H),6.63(s,1H),7.54(t,J=7.7Hz,1H),7.64(d,J=7.5Hz,1H),7.9(d,J=7.6Hz,1H),8.13(s,1H),13.3(brs,1H);HPLC:95.2%.

[0789] Example 50: (4-Benzyl-5-cyano-6-oxo-1,6-dihydro-pyrimidin-2-ylsulfanyl)-acetic acid (Compound I-30)

[0790] [ka]

[0791] To a stirred solution of intermediate 4.2 (110 mg, 0.45 mmol) and DIPEA (0.086 mL, 0.5 mmol) in ...

Claims

1. A compound represented by formula (II): 【Chemistry 1】 (In the formula, X is O or OR ｈ and W is N; L is -SCH ２ - and R １ But, absent, C ６ -C １０ arylene or heteroarylene, the heteroarylene containing one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, ６ -C １０ arylene, the heteroarylene is one to two R ｅ optionally replaced by R ６ each independently at each occurrence is H or C １ -C ４ is alkyl, R ７ is A, A is -(C(R ６ ) ２ ) ｒ Tetrazole, -(C(R ６ ) ２ ) ｒ Tetrazolone, -(C(R ６ ) ２ ) ｒ Thiadiazolol, or -(C(R ６ ) ２ ) ｒ isoxazol-3-ol, R ｃ is H, a halogen, or -CN; R ｄ But, CF ３ , C.R. ｆ F ２ , -(C(R ６ ) ２ ) ｔ C ６ -C １０ Aryl, or -(C(R ６ ) ２ ) ｔ - 5- or 6-membered heteroaryl; R ｅ each independently, at each occurrence, １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, -NHR ｚ , —OH, or —CN; R ｆ is H, R ｈ is H, R ｊ is absent, R ｚ But, H, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, r is 0, 1, or 2; t is 1 or 2; 【Chemistry 2】 represents a single bond or a double bond) The compound, or a pharma- ceutically acceptable salt or tautomer thereof.

2. R ｃ The compound of claim 1 , wherein

3. R ｃ The compound of claim 1, wherein is -CN.

4. R ｄ Ga-CF ３ 2. The compound of claim 1 ,

5. R ｄ -CR ｆ F ２ 2. The compound of claim 1,

6. R ｄ But -(C(R ６ ) ２ ) ｔ C ６ -C １０ Aryl, or -(C(R ６ ) ２ 2. The compound of claim 1, wherein: t -is a 5- or 6-membered heteroaryl.

7. R ｄ Ga-CH ２ -C ６ -C １０ The compound of claim 1 which is aryl.

8. R １ C ６ -C １０ The compound of claim 1 which is an arylene.

9. R １ The compound of claim 1 , wherein is heteroarylene.

10. R １ C ６ -C １０ arylene, R ７ is A, and A is -(CH ２ ) ｒ The compound of claim 1 which is a tetrazole.

11. R １ is heteroarylene, R ７ is A, and A is -(CH ２ ) ｒ The compound of claim 1 which is a tetrazole.

12. R １ is absent, and R ７ is A, and A is -(CH ２ ) ｒ The compound of claim 1 which is a tetrazole.

13. A compound selected from the group consisting of: 【Table 1】

14. A compound selected from the group consisting of: 【Table 2】

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and at least one of a pharma- ceutically acceptable carrier, diluent, or excipient, and optionally one or more further therapeutic agents.

16. 16. The pharmaceutical composition of claim 15 for treating, preventing, or reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD), wherein the pharmaceutical composition is administered to a subject suffering from or susceptible to developing said disease or disorder.

17. 17. The pharmaceutical composition of claim 16, wherein the disease or disorder is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a renal disorder, or a chronic inflammatory disease.

18. 17. The pharmaceutical composition of claim 16, wherein the disease or disorder is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, pregnancy-related intrahepatic cholestasis, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

19. Nicotinamide adenine dinucleotide (NAD ＋ 15. A pharmaceutical composition for treating, preventing, or reducing the risk of a disease or disorder associated with decreased levels of NAD, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharma- ceutical acceptable salt thereof. ＋ The pharmaceutical composition is administered to a subject suffering from or susceptible to developing a disease or disorder associated with decreased levels of the compound.

20. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a renal disorder, or a chronic inflammatory disease.

21. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, pregnancy-related intrahepatic cholestasis, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

22. 16. The pharmaceutical composition according to claim 15 for treating a disorder associated with mitochondrial dysfunction, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof is administered to a subject suffering from or susceptible to developing a metabolic disorder.

23. 23. The pharmaceutical composition of claim 22, wherein the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an age-related disorder, a kidney disorder, or a chronic inflammatory disease, and optionally the common metabolic disorder is obesity or type 2 diabetes.

24. The metabolic disorder is type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hypercholesterolemia, hypertension, hyperlipoproteinemia, dyslipidemia, hypertriglyceridemia, cardiovascular disease, atherosclerosis, peripheral vascular disease, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatosis, dyspepsia, hypoglycemia, cancer, or edema; the neurodegenerative disorder is photoreceptor degeneration, dementia, Alzheimer's disease, Parkinson's disease, or edema.

24. The pharmaceutical composition of claim 23, wherein the chronic inflammatory disease is celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), irritable bowel disease, atherosclerosis, arthritis, or psoriasis; the renal disorder is acute kidney injury (AKI) or chronic kidney disease (CKD); and the age-related disorder is cancer, dementia, cardiovascular disease, hypertension, diabetes mellitus (type 1 or type 2), arthritis, cataracts, Alzheimer's disease, macular degeneration, and osteoporosis.

25. 24. The pharmaceutical composition of claim 23, wherein the chronic inflammatory disease is associated with the liver and / or kidney.

26. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD).

27. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD+) levels.

28. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder associated with mitochondrial dysfunction.

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