Inhibitors of α-amino-β-carboxyhexanedioate semialdehyde decarboxylase

Abstract

The present invention discloses a compound capable of regulating the activity of α-amino-β-carboxyhexanedioate semialdehyde decarboxylase (ACMSD), which is suitable for preventing and / or treating diseases related to NAD + Diseases and conditions associated with defects in biosynthesis, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with aging. The present application also discloses pharmaceutical compositions comprising the compounds and uses of the compounds as medicaments.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Technical Field

[0003] The present invention relates to compounds that can modulate the activity of α-amino-β-carboxyhexanedioate semialdehyde decarboxylase (ACMSD). The compounds of the present invention can be used to prevent and / or treat diseases related to NAD + The invention is used in methods for treating diseases and disorders associated with defects in biosynthesis, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, renal diseases, and diseases associated with aging. Background Art

[0004] ACMSD is a key enzyme for tryptophan metabolism and regulates NAD from tryptophan + Biosynthesis. ACMSD is involved in the synthesis of picolinic acid (PA), quinolinic acid (QA) and NAD + ACMSD is a zinc-dependent amidohydrolase that is stable in the presence of tryptophan NAD. + The final fate of the amino acid is determined at the branch point of the biosynthetic pathway, i.e., conversion to PA, complete oxidation via the citric acid cycle, or conversion to NAD via QA synthesis. + .

[0005] ACMSD has been purified from human tissues including liver, kidney, and brain. Two isoforms, ACMSD1 and ACMSD2, exist, derived from differential splicing of ACMSD gene transcripts, but only ACMSD1 possesses enzymatic activity. ACMSD1 directs ACMS (α-amino-ω-carboxyhexanedioic acid semialdehyde) to the acetyl-CoA pathway, and when ACMSD1 is inhibited, ACMS is non-enzymatically converted to quinolinic acid (QA), resulting in NAD + The formation and NAD + increase in intracellular content.

[0006] It has been shown that NAD + Increased levels of NAD prevented neurodegeneration, improved muscle function and oxidative metabolism in mice, and increased lifespan in worms. + Reduced levels of α-glucose have been associated with a range of pathophysiological conditions including type 2 diabetes (T2D), hyperlipidemia (elevated cholesterol and TAG), mitochondrial disease, neutropenia, cancer and renal disorders.

[0007] Inhibition of ACMSD thus indicates that increasing NAD +Content and modification of NAD + Novel approaches to the pathophysiology of diseases associated with defects in biosynthesis. Summary of the Invention

[0008] The object of the present invention is to provide a series of novel compounds capable of modulating the activity of α-amino-β-carboxyhexanedioate semialdehyde decarboxylase (ACMSD), which are suitable for preventing and / or treating diseases related to NAD. + Diseases and disorders associated with defects in biosynthesis, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, renal diseases, and diseases associated with aging.

[0009] The compounds of formula (I) or (II) as defined herein are useful in the treatment of diseases or conditions in which ACMSD plays a role. + A method for treating a disease or condition associated with abnormal biosynthesis, comprising administering to an individual suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more agents that increase intracellular NAD by inhibiting ACMSD1. + The amount of one or more compounds is sufficient to activate sirtuins (SIRT) and downstream targets of SIRT, such as PGC-1α, FoxO1 and / or superoxide dismutase (SOD). The method of the present invention can be used to treat NAD by inhibiting ACMSD. + Inhibition of ACMSD may provide prevention and treatment of metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, renal diseases, diseases associated with aging, and other ACMSD-dependent diseases or diseases characterized by defective NAD + A novel approach to synthetic disease.

[0010] The present invention provides a compound represented by formula (I):

[0011]

[0012] and pharmaceutically acceptable salts and tautomers thereof, wherein:

[0013] X is H, S, SR 2 NR 2 NR 2 R 2' 、O、OH、OR h , F, Br or Cl;

[0014] W is N or C;

[0015] (i) When W is N, then: L is -(C(R 5 )2) m CH=CH(C(R 5 )2)p -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0016] (ii) When W is C, then: 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 -、 -(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(R5 )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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0017] Y 1 O, NR 4 or S(O) q ;

[0018] Each Y 2 are independently O, NH or S;

[0019] R 1 Not present or C6-C 10 Arylene or heteroarylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, and wherein the C6-C 10 Arylene or heteroarylene optionally substituted with one to two R e replace;

[0020] R 2 is H or C1-C4 alkyl;

[0021] R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl; or

[0022] R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O and S;

[0023] R 3 is H or C1-C4 alkyl;

[0024] R 4 is H or C1-C4 alkyl;

[0025] Each R 5 is independently H or C1-C4 alkyl at each occurrence;

[0026] Each R 6 is independently H or C1-C4 alkyl at each occurrence;

[0027] R 7 is H, A, B or C;

[0028] 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 Tetrazodone, -(CH2) r Thiadiazole, -(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)2alkyl, where -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r Isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group,

[0029] B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g '、-(CH2)r C(O)NR g R g '、-(CH2) r S(O)2NR g R g '、-(CH2) r C(O)NHS(O)2NR 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 ,

[0030] 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 xor -(C(R 6 )2) r C(O)NHS(O)2C1-C4alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents each independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;

[0031] R c H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x or -CO2R x ;

[0032] R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl;

[0033] Each R e is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN;

[0034] R f is absent, H or methyl;

[0035] R g is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or S(O)2N(C1-C6 alkyl)2;

[0036] R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10 aryl or a 5- to 7-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents independently selected from C1-C6 alkyl group, halogen, and -OH;

[0037] Rh is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0038] R i (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl group is substituted with one or more NH2; (ii) (CH2CH2O) n CH2CH2OH; or (iii) C1-C6 alkyl, substituted by one or more substituents each independently selected from the group consisting of OH and a 4- to 7-membered heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, N or S;

[0039] R j is absent, H, C1-C6 alkyl or -CN;

[0040] Each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 aryl;

[0041] Each R y and R z are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0042] Each of m, p, q, r and t is independently 0, 1 or 2;

[0043] n is 0, 1, 2, or 3;

[0044] s is 1 or 2;

[0045] o is 0, 1, 2, 3 or 4; and

[0046] represents a single bond or a double bond; and

[0047] The restrictions are

[0048] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 When it is phenylene or pyridine, then R 7 Not -COOH;

[0049] When X is O; R f is H; W is C; R jis -CN; L is -SCH2-; R 1 is phenylene or pyridine; and R 7 When it is tetrazole, R c Not for H;

[0050] When X is O; R f is H; W is C; R j is -CN; L is -SC(R 5 )2 or -SCH2CH2-; R 1 If it does not exist, then R 7 Not COOH or tetrazole;

[0051] When X is O; R f is H; W is N; R j Does not exist; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH2- or -OCH2-; and R 1 When it is phenylene, then R 7 Not -COOH, -CH2COOH, and

[0052] When X is O; R f is H; W is N; R j Not present; L is -NHCH2-, -CH2NH- or -NH-C(O)-; and R 1 When it is phenylene, then R d Not a phenyl group.

[0053] The present invention provides a compound represented by formula (II):

[0054]

[0055] and pharmaceutically acceptable salts and tautomers thereof, wherein:

[0056] X is H, S, SR 2 NR 2 NR 2 R 2' 、O、OH、OR h , F, Br or Cl;

[0057] W is N or C;

[0058] (I) When W is N, then: L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -、 -(C(R5 )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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0059] (ii) When W is C, then: 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 -、 -(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)NR3 (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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0060] Y 1 O, NR 4 or S(O) q ;

[0061] Each Y 2 are independently O, NH or S;

[0062] R 1 Does not exist, C6-C 10 Arylene, heteroarylene or C3-C8 cycloalkylene, wherein the heteroarylene includes one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O and S, and wherein the C6-C 10 Arylene, heteroarylene and C3-C8 cycloalkylene are optionally substituted by one or two R e replace;

[0063] R 2 is H or C1-C4 alkyl;

[0064] R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl; or

[0065] R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O and S;

[0066] R 3 is H or C1-C4 alkyl;

[0067] R 4 is H or C1-C4 alkyl;

[0068] Each R 5 is independently H or C1-C4 alkyl at each occurrence;

[0069] Each R 6 is independently H or C1-C4 alkyl at each occurrence;

[0070] R 7 is H, A, B or C;

[0071] 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 Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(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)2alkyl, wherein -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(C(R 6 )2) r Isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group,

[0072] B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) rS(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g '、-(C(R 6 )2) r C(O)NR g R g '、-(C(R 6 )2) r S(O)2NR g R g '、-(C(R 6 )2) r C(O)NHS(O)2NR 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 ,

[0073] 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 10Aryl, -(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-C4alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents each independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;

[0074] R c H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x or -CO2R x ;

[0075] R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl;

[0076] Each R e is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN;

[0077] R f is absent, H or methyl;

[0078] R g is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or S(O)2N(C1-C6 alkyl)2;

[0079] R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10 aryl or a 5- to 7-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents independently selected from C1-C6 alkyl group, halogen, and -OH;

[0080] R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0081] R i (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl group is substituted with one or more NH2; (ii) (CH2CH2O) n CH2CH2OH; or (iii) C1-C6 alkyl, substituted by one or more substituents each independently selected from the group consisting of OH and a 4- to 7-membered heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, N or S;

[0082] R j is absent, H, C1-C6 alkyl or -CN;

[0083] Each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 aryl;

[0084] Each R y and R z are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0085] Each of m, p, q, r and t is independently 0, 1 or 2;

[0086] n is 0, 1, 2, or 3;

[0087] s is 1 or 2;

[0088] o is 0, 1, 2, 3 or 4; and

[0089] represents a single bond or a double bond; and

[0090] The restrictions are

[0091] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 When it is phenylene or pyridine, then R 7 Not -COOH;

[0092] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 is phenylene or pyridine; and R 7 When it is tetrazole, R c Not for H;

[0093] When X is O; R f is H; W is C; R j is -CN; L is -SC(R 5 )2 or -SCH2CH2-; R 1 If it does not exist, then R 7 Not COOH or tetrazole;

[0094] When X is O; R f is H; W is N; R j Does not exist; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH2- or -OCH2-; and R 1 When it is phenylene, then R 7 Not -COOH, -CH2COOH, and

[0095] When X is O; R f is H; W is N; R j Not present; L is -NHCH2-, -CH2NH- or -NH-C(O)-; and R 1 When it is phenylene, then R d Not a phenyl group.

[0096] Another aspect of the present invention 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.

[0097] Another aspect of the present invention provides a compound of formula (I) or (II) for use as a medicament. Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) for use as a medicament.

[0098] Another aspect of the invention provides a method for treating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to an individual suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more compounds of formula (I) or (II). Another aspect of the invention provides a method for preventing a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to an individual suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more compounds of formula (I) or (II). Another aspect of the invention provides a method for reducing the risk of a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to an individual suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more compounds of formula (I) or (II).

[0099] Another aspect of the present invention provides a method for treating nicotinamide adenine dinucleotide (NAD + ) level is decreased, comprising administering to a patient suffering from or susceptible to a disease or condition associated with NAD + Another aspect of the present invention provides a method for preventing nicotinamide adenine dinucleotide (NAD + ) level is decreased, comprising administering to a patient suffering from or susceptible to a disease or condition associated with NAD + Another aspect of the present invention provides a method for reducing the level of nicotinamide adenine dinucleotide (NAD + ) levels, comprising administering to a patient suffering from or susceptible to a disease or condition associated with NAD + A therapeutically effective amount of one or more compounds of Formula (I) or (II) is administered to an individual suffering from a disease or condition associated with a decrease in the level of IL-12.

[0100] Another aspect of the present invention provides a method for treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II) that increase intracellular nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides a method for preventing a condition associated with mitochondrial dysfunction, comprising administering to an individual suffering from or susceptible to a metabolic condition a therapeutically effective amount of one or more compounds of formula (I) or (II) that increase intracellular nicotinamide adenine dinucleotide (NAD +Another aspect of the present invention provides a method for reducing the risk of a condition associated with mitochondrial dysfunction, comprising administering to an individual suffering from or susceptible to a metabolic condition a therapeutically effective amount of one or more compounds of formula (I) or (II) that increase intracellular nicotinamide adenine dinucleotide (NAD + ).

[0101] Another aspect of the present invention provides a method for promoting oxidative metabolism, comprising administering to an individual suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II), said one or more compounds increasing intracellular nicotinamide adenine dinucleotide (NAD + ).

[0102] Another aspect of the invention provides a compound of formula (I) or (II) for use in treating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the invention provides a compound of formula (I) or (II) for use in preventing a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the invention provides a compound of formula (I) or (II) for use in reducing the risk of a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0103] Another aspect of the present invention provides a compound of formula (I) or (II) for use in treating diseases related to nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides a compound of formula (I) or (II) for use in preventing diseases or conditions associated with decreased nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides a compound of formula (I) or (II) for reducing the level of nicotinamide adenine dinucleotide (NAD + ) content reduces the risk of diseases or conditions associated with it.

[0104] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) of formula (I) or (II) for use in treating conditions associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) of formula (I) or (II) for preventing conditions associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for reducing the risk of a disorder associated with mitochondrial dysfunction.

[0105] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) of formula (I) or (II), which is used to promote oxidative metabolism.

[0106] Another aspect of the invention provides the use of a compound of formula (I) or (II) for treating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the invention provides the use of a compound of formula (I) or (II) for preventing a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the invention provides the use of a compound of formula (I) or (II) for reducing the risk of a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0107] Another aspect of the present invention provides the use of a compound of formula (I) or (II) for treating a disease associated with nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides the use of a compound of formula (I) or (II) for preventing diseases or conditions associated with decreased nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides the use of a compound of formula (I) or (II) for reducing the level of nicotinamide adenine dinucleotide (NAD + ) content reduces the risk of diseases or conditions associated with it.

[0108] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for treating a condition associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for preventing conditions associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for reducing the risk of a disorder associated with mitochondrial dysfunction.

[0109] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for promoting oxidative metabolism.

[0110] Another aspect of the present invention provides the use of a compound of formula (I) or (II) for the manufacture of a medicament for treating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the present invention provides the use of a compound of formula (I) or (II) for the manufacture of a medicament for preventing a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). Another aspect of the present invention provides the use of a compound of formula (I) or (II) for the manufacture of a medicament for reducing the risk of a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0111] Another aspect of the present invention provides the use of a compound of formula (I) or (II) for the manufacture of a drug for treating nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides a method for the manufacture of a pharmaceutical composition for preventing a disease or condition associated with a decrease in nicotinamide adenine dinucleotide (NAD + Another aspect of the present invention provides a method for treating a disease or condition associated with a decrease in nicotinamide adenine dinucleotide (NAD) content. + ) content to reduce the risk of a disease or condition associated with the drug.

[0112] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for the manufacture of a medicament for treating a disorder associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for the manufacture of a medicament for preventing a disorder associated with mitochondrial dysfunction. Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for the manufacture of a medicament for reducing the risk of a disorder associated with mitochondrial dysfunction.

[0113] Another aspect of the present invention provides a method for increasing intracellular nicotinamide adenine dinucleotide (NAD + ) for the manufacture of a medicament for promoting oxidative metabolism.

[0114] In certain aspects, compounds of the invention may be administered alone or in combination with other compounds (including other ACMSD modulating compounds) or other therapeutic agents.

[0115] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs. In this specification, unless the context clearly stipulates otherwise, the singular also includes the plural. Although methods and materials similar to or equivalent to the methods and materials described herein can be used for practicing or testing the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. It is not recognized that the references cited herein are the prior art of the present invention as required. If there is a conflict, this specification (including definitions) will prevail. In addition, materials, methods and examples are only illustrative and are not intended to be limiting.

[0116] Other features and advantages of the invention will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0117] All references cited in this specification, including any patents or patent applications, are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Furthermore, no admission is made that any of the prior art constitutes part of the common general knowledge in the art.

[0118] As used throughout the present invention, unless otherwise indicated, the following terms should be understood to have the following meanings. If a term is omitted, the conventional term known to those skilled in the art will prevail.

[0119] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense. Throughout the description and claims of this specification, the words "comprise" and "contain," and variations of the words such as "comprising / comprises," mean "including but not limited to," and do not exclude other parts, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. Specifically, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0120] As used herein, the articles "a" and "an" may refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0121] Unless otherwise indicated, the term "and / or" used in the present invention may mean either "and" or "or".

[0122] To provide a more concise description, some of the quantitative expressions given herein are not limited by the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each amount given herein is intended to refer to the actual given value, and it is also intended to refer to the approximate value of the given value reasonably inferred based on the given value by one of ordinary skill in the art, including equivalent values ​​and approximate values ​​obtained due to the experimental and / or measurement conditions of the given value. Whenever the yield is given as a percentage, such yield refers to the mass of the same entity relative to the maximum amount of the entity that can be obtained under specific stoichiometric conditions, wherein the yield is given for the entity. Unless otherwise indicated, the concentration given as a percentage refers to the mass ratio.

[0123] As used herein, the term "alkyl" refers to a saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains one to eight carbon atoms (C 1-8 Alkyl), more preferably one to six carbon atoms (C 1-6 Alkyl), especially one to four carbon atoms (C 1-4 In a preferred embodiment, "alkyl" includes C 1-4 Alkyl, which may include, inter alia, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Correspondingly, the term "alkylene" refers to the corresponding diradical (-alkyl-).

[0124] As used herein, the term "cycloalkyl" or "carbocycle" refers to a cyclic alkyl group, preferably containing three to ten carbon atoms (C 3-10 Cycloalkyl or C 3-10 carbon ring), such as three to eight carbon atoms (C 3-8 Cycloalkyl or C 3-10 carbon ring), preferably three to six carbon atoms (C 3-6 Cycloalkyl or C 3-10 The term "cycloalkyl" as used herein may also include polycyclic groups such as bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl. Correspondingly, the term "cycloalkylene" refers to the corresponding diradical (-cycloalkyl-). Alkyl and cycloalkyl groups may be optionally substituted with 1 to 4 substituents. Examples of substituents on alkyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo, and -CN.

[0125] As used herein, the term "alkenyl" 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 comprises two to eight carbon atoms (C 2-8 alkenyl), such as two to six carbon atoms (C 2-6 alkenyl), especially two to four carbon atoms (C 2-4 alkylene) containing at least one double bond. Examples of alkenyl groups include ethenyl; 1- or 2-propenyl; 1-, 2-, or 3-butenyl, or 1,3-butadienyl; 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 cyclohexenyl. Correspondingly, the term "alkenylene" refers to the corresponding diradical (-alkenyl-). Alkenyl groups may be optionally substituted with 1 to 4 substituents. Examples of substituents on alkenyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxy, carbamoyl, oxo, and -CN.

[0126] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including diynes, triynes, and polyynes. Typically, an alkynyl group comprises two to eight carbon atoms (C 2-8 Alkynyl), such as two to six carbon atoms (C 2-6 Alkynyl), especially two to four carbon atoms (C 2-4 alkynyl), containing at least one triple bond. Examples of preferred alkynyl groups include ethynyl; 1-propynyl or 2-propynyl; 1-butynyl, 2-butynyl or 3-butynyl, or 1,3-butadiynyl; 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, or 1,3-hexadiynyl, or 1,3,5-hexadiynyl; 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl or 7-octynyl, or 1,3-octa-diynyl or 1,3,5-octa-triynyl, or 1,3,5,7-octa-tetraynyl. Correspondingly, the term "alkynylene" refers to the corresponding diradical (-alkynyl-). Alkynyl groups may be optionally substituted with 1 to 4 substituents. Examples of substituents on alkynyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxy, carbamoyl, oxo, and -CN.

[0127] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine or iodine. Thus, trihalomethyl represents, for example, trifluoromethyl or trichloromethyl. Preferably, the terms "halo" and "halogen" refer to fluorine or chlorine.

[0128] As used herein, the term "haloalkyl" 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.

[0129] The term "alkoxy" as used herein refers to "alkyl-O-" wherein alkyl is as defined above.

[0130] As used herein, "hydroxyalkyl" refers to an alkyl group (as defined above) substituted one or more times with a hydroxy group. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0131] As used herein, "oxy" refers to a "-O-" group.

[0132] The term "oxo," as used herein, refers to a "=0" group.

[0133] As used herein, the term "amine" refers to primary (R-NH2, (R)≠H) amines, secondary ((R)2-NH, (R)2≠H) amines, and tertiary ((R)3-N, R≠H) amines. Substituted amines are intended to mean amines in which at least one of the hydrogen atoms has been replaced by a substituent.

[0134] As used herein, the term "carbamyl" refers to an "H2N(C=O)-" group.

[0135] Unless otherwise specified, the term "aryl" as used herein includes carbocyclic aromatic ring systems derived from aromatic hydrocarbons by removing hydrogen atoms. Aryl groups also include 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. Unless otherwise specified, "aryl" is preferably phenyl, naphthyl, or indanyl, especially phenyl. Any aryl group used may be optionally substituted. Correspondingly, the term "arylene" refers to the corresponding diradical (-aryl-). An aryl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on an aryl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0136] As used herein, the term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from O, S and N, preferably one to four heteroatoms and more preferably one to three heteroatoms. Heteroaryl groups further include bicyclic, tricyclic and polycyclic groups in which at least one ring of the group is aromatic and at least one of the rings contains a heteroatom selected from O, S and N. Heteroaryl groups also include 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, isoindanyl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, In some embodiments, the present invention includes oxadiazolyl, indole, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, 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 diradical (-heteroaryl-). The heteroaryl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the heteroaryl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxy, and -CN.

[0137] 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 one to four heteroatoms, and more preferably one to three heteroatoms. Heterocyclyl further includes bicyclic, tricyclic, and polycyclic non-aromatic groups, and 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, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridyl, oxanyl, 2-H-pyranyl, 4-H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazacyclo hexyl, pyrimidinyl, 1,3-diazacyclohexanyl, pyrazinyl, piperazinyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-diazacyclohexanyl, 1,4-oxazinyl, morpholinyl, thiomorpholinyl, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromayl, isochromayl, 4H-chromenyl, 1H-isochromenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, In some embodiments, the term "heterocyclylene" refers to a 1H-pyrrolidino, 1H-pyrrolidino, 1H-quinolizinyl, 1H-pyrrolidino, 1H-quinolizinyl, and 1H-8-bicyclo[3.2.1]octane. Correspondingly, the term "heterocyclylene" refers to the corresponding diradical (-heterocyclyl-). A heterocyclyl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on a heterocyclyl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0138] As used herein, the term "N-heterocycle" refers to a heterocyclic or heteroaryl group as defined above, which has at least one nitrogen atom and is bonded through a nitrogen atom. Examples of such N-heterocycles are pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, piperidinyl, pyridinyl, pyridazinyl, pyrazinyl, piperazinyl, morpholinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, and the like.

[0139] In this specification, for convenience, in some cases, the structural formula of the compound represents a certain isomer, but the present invention includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers and the like. Therefore, it should be understood that the definition of the compound of formula (I) or (II) includes each individual isomer corresponding to the following formula: formula (I) or (II), including cis-trans isomers, stereoisomers and tautomers and racemic mixtures of these and pharmaceutically acceptable salts thereof. Therefore, the definition of the compound of formula (I) or (II) is also intended to cover all R-isomers and S-isomers in any ratio of the chemical structure, such as one of the possible isomers (i.e., enantiomeric excess or diastereomeric excess) and other isomers of corresponding smaller ratios. In addition, for the compound represented by formula (I) or (II), there may be crystal polymorphism. It should be noted that any crystalline form, crystalline form mixture or its anhydride or hydrate is included in the scope of the present invention. Furthermore, so-called metabolites produced by degradation of the compounds of the present invention in vivo are encompassed within the scope of the present invention.

[0140] "Isomeric" refers to compounds that have the same molecular formula 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 termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0141] A carbon atom bonded to four different substituents is called a "chiral center."

[0142] "Chiral isomer" refers to a compound with at least one chiral center. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, stereoisomers can be characterized by the absolute configuration (R or S) of the 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 "Sequence Rule" 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).

[0143] Diastereomers (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 the racemic mixture according to conventional methods, for example, by treating with an optically active acid or base to form diastereomeric salts. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated by crystallization, followed by release of the optically active base from these salts. An alternative method for separating optical isomers includes the use of a chiral chromatography column optimally selected to maximize the separation of enantiomers. Another useful method involves synthesizing covalent diastereomeric molecules by reacting a compound of formula (I) or (II) with an optically pure acid or optically pure isocyanate in an activated form. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds. The optically active compounds of formula (I) can also be obtained by utilizing optically active starting materials and / or by utilizing chiral catalysts. These isomers can be in the form of free acids, free bases, esters or salts. Examples of chiral separation techniques are given in Chiral Separation Techniques, A Practical Approach, 2nd edition, G. Subramanian, Wiley-VCH, 2001.

[0144] "Geometric isomers" refers to diastereomers that owe their existence to hindered rotation about a double bond. These configurations are designated by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0145] Furthermore, the structures and other compounds discussed herein encompass all atropisomers thereof. "Atropisomers" are a type of stereoisomer in which the atoms of the two isomers are arranged in space differently. Atropisomers exist due to restricted rotation caused by hindered rotation of large groups around a central bond. Such atropisomers typically exist as mixtures; however, recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers under selected circumstances.

[0146] "Tautomers" are one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another isomeric form. This conversion results in the formal migration of hydrogen atoms, accompanied by the exchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In solid form, one tautomer is usually dominant. In solutions where tautomerization may occur, chemical equilibrium of the tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be converted into each other by tautomerization is called tautomerism.

[0147] Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism, as exhibited by glucose, occurs when an aldehyde group (-CHO) in a sugar chain molecule reacts with a hydroxyl group (-OH) in the same molecule to provide it with a cyclic (ring-shaped) form.

[0148] Common tautomeric pairs are: keto-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. It is understood that the compounds of the present invention may be depicted as different tautomers. It is also understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any tautomeric form.

[0149] The terms "crystal polymorph," "polymorph," or "crystal form" refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to dominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0150] In addition, the compounds of the present invention (e.g., salts of the compounds) can exist in hydrated or unhydrated (anhydrous) form or in the form of 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.

[0151] "Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance in which the water retains its molecular state as HO.

[0152] As used herein, a "subject" or "subject in need thereof" is a subject having a disease or condition associated with α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) dysfunction or inhibition by α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD). "Subject" includes mammals. The mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, a poultry, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. The mammal is preferably a human.

[0153] The present invention contemplates all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include C-13 and C-14.

[0154] Compound

[0155] The present invention relates to compounds of formula (I):

[0156]

[0157] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein.

[0158] The present invention relates to compounds of formula (II):

[0159]

[0160] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein.

[0161] In certain embodiments of formula (I) or (II), wherein W is N, the present invention relates to compounds of formula (II):

[0162]

[0163] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for formula (I) and (II). In certain embodiments of formula (I) or (II), wherein W is C, the present invention relates to compounds of formula (I-2):

[0164]

[0165] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for Formula (I) and (II). In certain embodiments of Formula (I) or (II), wherein R 1 is phenyl, the present invention relates to a compound of formula (I-3):

[0166]

[0167] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for formula (I) and (II).

[0168] In certain embodiments of Formula (I) or (II), wherein R 1 does not exist, the present invention relates to a compound of formula (I-4):

[0169]

[0170] and pharmaceutically acceptable salts and tautomers thereof, wherein the substituents are as described herein for formula (I) and (II).

[0171] As described above, X is H, S, SR 2 NR 2 NR 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 NR 2 or NR 2 R2' 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.

[0172] As described above, R 2 is H or C1-C4 alkyl. In certain embodiments, R 2 is H. In certain embodiments, R 2 is a C1-C4 alkyl group. 2 is -CH3.

[0173] As described above, R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl. 2' is H. In certain embodiments, R 2' is a C1-C4 alkyl group. 2' It is a C3-C7 cycloalkyl group.

[0174] As described above, R 2 and R 2' Together with the nitrogen atom to which it is attached, they form a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O, and S. In certain embodiments, R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 6-membered heterocycloalkyl ring.

[0175] As described above, R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl is optionally substituted with one or more substituents each 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, wherein the alkyl group is optionally substituted with one or more substituents each independently selected from the group consisting of NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2.h is a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0176] As described above, R f is absent, H or methyl. In certain embodiments, R f In certain embodiments, R f is H. In certain embodiments, R f It is a methyl group.

[0177] As described above, W is N or C. In certain embodiments, W is N. In certain embodiments, W is C.

[0178] As described above, R j is absent, H, C1-C6 alkyl or -CN. In certain embodiments, R j In certain embodiments, R j is H. In certain embodiments, R j is a C1-C6 alkyl group. j It is -CN.

[0179] In some embodiments, W is N and R j In certain embodiments, W is C and R j In certain embodiments, W is C and R j It is -CN.

[0180] As described above, R c 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 a C1-C6 alkyl group. c is a C1-C6 haloalkyl group. c In certain embodiments, R c In certain embodiments, R c For-OR x In certain embodiments, R c -CO2R x .

[0181] As described above, R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10In certain embodiments, R x is H. In certain embodiments, R x is a C1-C6 alkyl group. x C6-C 10 Aryl.

[0182] As described above, R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl.

[0183] In certain embodiments, R d In certain embodiments, R d is CF3. In certain embodiments, R d CR f F2. In certain embodiments, R d -(C(R 6 )2) t C6-C 10 In certain embodiments, R d -CH2C6-C 10 In certain embodiments, R d In certain embodiments, R d -(C(R 6 )2) t -5-membered or 6-membered heteroaryl. In certain embodiments, R d -(C(R 6 )2) t -5-membered 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-membered or 6-membered heteroaryl. d is an optionally substituted 5-membered or 6-membered cycloalkyl group.

[0184] As described above, R f is absent, H or methyl. In certain embodiments, R f In certain embodiments, Rf is H. In certain embodiments, R f It is a methyl group.

[0185] 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.

[0186] As described above, when W is N, then L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -.

[0187] 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 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 CH=CH-. 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 Pyridyl (C (R 5 )2) p -. In certain embodiments, W is N and L is -(C(R 5 )2) m Thienyl (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 , such as -SCH2- or -NHCH2-. In certain embodiments, W is N and L is -SCH2-. In certain embodiments, W is N and L is -NHCH2-.

[0188] 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 -、 -(C(R 5 )2) m Y 1CH=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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -.

[0189] 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 In certain embodiments, W is C and L is -(C(R 5 )2) m Y 1 CH=CH-. 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 Pyridyl (C (R 5 )2) p -. In certain embodiments, W is C and L is -(C(R 5 )2) m Thienyl (C (R 5 )2) p -.

[0190] As described above, Y 1 O, NR 4 or S(O) q In certain embodiments, Y 1 is 0. In certain embodiments, Y 1 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 It is a C1-C4 alkyl group.

[0191] In certain embodiments, Y 1 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.

[0192] As described above, each R 5 is independently H or C1-C4 alkyl at each occurrence. In certain embodiments, R 5 is H. In certain embodiments, R5 It is a C1-C4 alkyl group.

[0193] As described above, R 3 is H or C1-C4 alkyl. In certain embodiments, R 3 is H. In certain embodiments, R 3 It is a C1-C4 alkyl group.

[0194] As described above, each m and p is 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.

[0195] As described above, 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.

[0196] As described above, R 1 Not present or C6-C 10 Arylene or heteroarylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, and wherein the C6-C 10 Arylene or heteroarylene is optionally substituted with one to two R e In certain embodiments, R 1 In certain embodiments, R 1 C6-C 10 Arylene, which is optionally substituted by one to two R e In certain embodiments, R 1 is a heteroarylene group, wherein the heteroarylene group includes one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O and S and is optionally substituted by one to two R e In certain embodiments of formula (II), R 1 It is a C3-C8 cycloalkylene group, such as a C3 cycloalkylene group, a C4 cycloalkylene group, a C5 cycloalkylene group, a C6 cycloalkylene group, a C7 cycloalkylene group or a C8 cycloalkylene group.

[0197] As described above, each R e is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN.

[0198] 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 For C.

[0199] 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 Tetrazodone, -(CH2) r Thiadiazole, -(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)2alkyl, where -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r The isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group.

[0200] 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(R 6 )2) r Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(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)2alkyl, wherein -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(C(R 6 )2) r Isoxazol-3-ol is optionally substituted with C1-C6 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) r S(O)2OH. 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)2alkyl.

[0201] In certain embodiments, A is -(C(R 6 )2) r CO2R x In certain embodiments, A is -Y 2 (C(R 6 )2) rCO2R x In certain embodiments, A is -(CH2) r In certain embodiments, A is -(CH2) r In certain embodiments, A is -(CH2) r In certain embodiments, A is -(CH2) r In certain embodiments, A is -(CH2) r In certain embodiments, A is -(CH2) r P(O)(OH)OR x In certain embodiments, A is -(CH2) r S(O)2OH. In certain embodiments, A is -(CH2) r C(O)NHCN. In certain embodiments, A is -(CH2) r C(O)NHS(O)2alkyl. In certain embodiments, -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r Isoxazol-3-ol is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r The tetrazole is optionally substituted with a C1-C6 alkyl group.

[0202] As described above for formula (I), B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NRg R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g '、-(CH2) r C(O)NR g R g '、-(CH2) r S(O)2NR g R g '、-(CH2) r C(O)NHS(O)2NR 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 .

[0203] As described above for formula (II), -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g'、-(C(R 6 )2) r C(O)NR g R g '、-(C(R 6 )2) r S(O)2NR g R g '、-(C(R 6 )2) r C(O)NHS(O)2NR 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)2NR g R g In certain embodiments, B is -(C(R 6 )2) r C(O)NHS(O)2NR g R g '.

[0204] In certain embodiments, B is -(C(R 6 )2) r S(O)2OC1-C4alkyl. In certain embodiments, B is -O(C(R 6 )2)r S(O)2OC1-C4alkyl. 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)2NR g R g In certain embodiments, B is -(CH2) r C(O)NR g R g In certain embodiments, B is -(CH2) r S(O)2NR g R g In certain embodiments, B is -(CH2) r C(O)NHS(O)2NR 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 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 .

[0205] As described above, C is -(CH2) r CN, -(CH2) s OH, halogen, -(C(R6 )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-C4alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents each independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S.

[0206] In certain embodiments, C is -(CH2) r In certain embodiments, C is -(CH2) s 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 OH. 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=CHCO2Rx In certain embodiments, C is -(C(R 6 )2) r C(O)NHS(O)2C1-C4alkyl. In the above, aryl and heteroaryl are substituted with one to three substituents each independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, halogen and OH, and wherein the heterocycloalkyl is substituted with one to two =O or =S.

[0207] As described above, each R 6 is independently H or C1-C4 alkyl at each occurrence. In certain embodiments, R 6 is H. In certain embodiments, R 6 It is a C1-C4 alkyl group.

[0208] As described above, each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 In certain embodiments, R x is H. In certain embodiments, R x is a C1-C6 alkyl group. x C6-C 10 Aryl.

[0209] As described above, each Y 2 is independently O, NH or S. In certain embodiments, Y 2 is 0. In certain embodiments, Y 2 In certain embodiments, Y 2 For S.

[0210] 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.

[0211] As described above, s is 1 or 2. In certain embodiments, s is 1. In certain embodiments, s is 2.

[0212] As described above, R g It is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or -S(O)2N(C1-C6 alkyl)2.

[0213] As described above, R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10aryl or 5- to 7-membered heteroaryl including 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 wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, halogen and -OH.

[0214] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0215] a)W is N;

[0216] b)R c For CN;

[0217] c)R d is a 5-membered or 6-membered heteroaryl group, such as a thienyl group;

[0218] d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0219] e)R 1 is phenylene;

[0220] f)R 7 is A, such as COOH or tetrazole.

[0221] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0222] a)W is N;

[0223] b)R d is CF3;

[0224] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0225] d)R 1 is phenylene;

[0226] e)R 7 is A, such as COOH or tetrazole.

[0227] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0228] a)W is N;

[0229] b)R c For CN;

[0230] c)R d is a 5-membered or 6-membered heteroaryl group, such as a thienyl group;

[0231] d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0232] e)R 1 does not exist;

[0233] f)R 7 is A, such as COOH or tetrazole.

[0234] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0235] a)W is N;

[0236] b)R d is CF3;

[0237] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0238] d)R 1 does not exist;

[0239] e)R 7 is A, such as COOH or tetrazole.

[0240] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0241] a)W is C;

[0242] b)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5-membered or 6-membered heteroaryl);

[0243] c)L is -(C(R 5 )2) m Y1 (C(R 5 )2) p , such as -SCH2-;

[0244] d)R 1 is phenylene;

[0245] e)R 7 is A, such as COOH or tetrazole.

[0246] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0247] a)W is C;

[0248] b)R d is -CF3;

[0249] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0250] d)R 1 is phenylene;

[0251] e)R 7 is A, such as COOH or tetrazole.

[0252] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0253] a)W is N;

[0254] b)R c For CN;

[0255] c)R d is a 5-membered or 6-membered heteroaryl group, such as a thienyl group;

[0256] d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0257] e)R 1 is phenylene;

[0258] f)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2)r Tetrazole.

[0259] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0260] a)W is N;

[0261] b)R d is CF3;

[0262] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0263] d)R 1 is phenylene;

[0264] e)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole.

[0265] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0266] a)W is N;

[0267] b)R c For CN;

[0268] c)R d is a 5-membered or 6-membered heteroaryl group, such as a thienyl group;

[0269] d) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0270] e)R 1 does not exist;

[0271] f)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole.

[0272] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0273] a)W is N;

[0274] b)R d is CF3;

[0275] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0276] d)R 1 does not exist;

[0277] e)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole.

[0278] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0279] a)W is C;

[0280] b)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5-membered or 6-membered heteroaryl);

[0281] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0282] d)R 1 is phenylene;

[0283] e)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole.

[0284] In some embodiments, the present invention provides compounds of formula (I) having one, two, or three of the following characteristics:

[0285] a)W is C;

[0286] b)R d is -CF3;

[0287] c)L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p , such as -SCH2-;

[0288] d)R 1 is phenylene;

[0289] e)R 7 A, such as -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazole.

[0290] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Ia) having at least one of the following features:

[0291]

[0292] and its pharmaceutical salts and tautomers, wherein

[0293] a)R d is a 5-membered or 6-membered heteroaryl group;

[0294] b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0295] c)R 7 A or C;

[0296] d) X, R d 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0297] In certain embodiments, R d In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, R 7 is C. In certain embodiments, C is -(C(R 6 )2) r C6-C 10Aryl, substituted with one to three substituents each independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH. 7 is A. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl.In certain embodiments, Formula (Ia) has one, two, three, or four of features (a) to (d).

[0298] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Ib) having at least one of the following features:

[0299]

[0300] and its pharmaceutical salts and tautomers, wherein

[0301] a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0302] b)R 7 is A;

[0303] c)X, R c 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0304] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2)r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r The tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, Formula (Ib) has one, two, or three of features (a) to (c).

[0305] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Ic) having at least one of the following features:

[0306]

[0307] and its pharmaceutical salts and tautomers, wherein

[0308] a)R d is a 5-membered or 6-membered heteroaryl group;

[0309] b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0310] c)R 7 is A;

[0311] d) X, R d 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0312] In certain embodiments, R d In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) rTetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group.In certain embodiments, Formula (Ic) has one, two, three, or four of features (a) to (d).

[0313] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Id) having at least one of the following features:

[0314]

[0315] and its pharmaceutical salts and tautomers, wherein

[0316] a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0317] b)R 7 is A;

[0318] c)X, R d 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0319] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl.In certain embodiments, Formula (Id) has one, two, or three of features (a) to (c).

[0320] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Ie) having at least one of the following features:

[0321]

[0322] and its pharmaceutical salts and tautomers, wherein

[0323] a)R d -(C(R 6 )2) t C6-C 10 Aryl or -(C(R 6 )2) t -5-membered or 6-membered heteroaryl);

[0324] b) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0325] c)R 7 It is A.

[0326] d) X, R d 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0327] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl.In certain embodiments, Formula (Ie) has one, two, three, or four of features (a) to (d).

[0328] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (If) having at least one of the following features:

[0329]

[0330] and its pharmaceutical salts and tautomers, wherein

[0331] a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0332] b)R 7 is A;

[0333] c)X, R c 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0334] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. c In certain embodiments, Formula (If) has one, two, or three of features (a) to (c).

[0335] In certain embodiments, subject to certain of the above features of Formula (I), the present invention provides compounds of Formula (Ig) having at least one of the following features:

[0336]

[0337] and its pharmaceutical salts and tautomers, wherein

[0338] a) L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p ;

[0339] b)R 7 is A;

[0340] c)X, R d 、R f 、R j ,A,R 5 、Y 1 , m and p are defined with respect to formula (I).

[0341] In certain embodiments, L is -SCH2- or -NHCH2-. In certain embodiments, A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl. In certain embodiments, A is -(C(R 6 )2) r COOH or -(CH2) r Tetrazolyl, where -(CH2) r Tetrazole is optionally substituted with a C1-C6 alkyl group. In certain embodiments, A is -COOH, -CH2COOH, -tetrazole, or -(CH2)tetrazole, wherein tetrazole and -(CH2) r Tetrazole is optionally substituted with C1-C6 alkyl.In certain embodiments, Formula (Ig) has one, two, or three of features (a) to (c).

[0342] In some embodiments, the compound of formula (I) is a compound selected from the group consisting of:

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound of formula (I) or (II) is a compound selected from the following:

[0349]

[0350]

[0351]

[0352] In some embodiments, the compound of formula (I) is selected from the following compounds or pharmaceutically acceptable salts or tautomers thereof:

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362] or a pharmaceutically acceptable salt or tautomer thereof.

[0363] In some embodiments, the compound of formula (I) or (II) is a compound selected from the following compounds or pharmaceutically acceptable salts or tautomers thereof:

[0364]

[0365] It should be understood that these references are intended to encompass not only the above formula, but also each of the Examples discussed below, etc. It should also be understood that, unless stated to the contrary, such references also encompass isomers, isomer mixtures, pharmaceutically acceptable salts, solvates, and prodrugs of compounds of Formula (I) or (II).

[0366] Methods for preparing compounds

[0367] The compounds of the present invention (e.g., compounds of formula (I)) can be prepared in a variety of ways familiar to those skilled in the art of organic synthesis. As an example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include (but are not limited to) the methods described below. The final products of the reactions described herein can be isolated by conventional techniques, such as extraction, crystallization, distillation, chromatography, and the like.

[0368] The compounds of the present invention can be synthesized by following the steps outlined in the following general schemes A to F, which include assembling different sequences of intermediates Ia-Ih and Ij-Io. Starting materials are commercially available or prepared by known procedures reported in the literature or as described. Applicable steps that can be used in the preparation of the compounds will be known to the skilled artisan. The following methods are given as non-limiting examples of how the compounds can be prepared.

[0369] General Process A

[0370]

[0371] where R 1 、R c 、R d and L is as defined in formula (I).

[0372] A general approach for preparing compounds of formula (I) using intermediates Ia and Ib is outlined in General Scheme A. Ia and Ib are coupled using a base, i.e., potassium carbonate (KCO), in a solvent, i.e., acetonitrile (CHCN), optionally at elevated temperature, to afford the desired product of formula (I). Bases that can be used include, but are not limited to, sodium carbonate (NaCO), potassium carbonate (KCO), N,N-diisopropylethylamine (DIPEA), and triethylamine. The solvent used in the coupling reaction can be polar or non-polar. For example, the solvent can be acetonitrile (CHCN), acetone, or dimethyl sulfoxide (DMSO).

[0373] General Process B

[0374]

[0375] Wherein X is a good leaving group, i.e. Cl, Br, -SCH3 or S(O)2CH3, and R 1 、R 2 、R c 、R d and p is as defined in formula (I).

[0376] Alternatively, compounds of formula (I) can be prepared using intermediates Ic and Id as outlined in General Scheme B. Intermediates Ic and Ie are aminated using a base (i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc.) in a solvent (i.e., methanol (MeOH), ethanol (EtOH), water (HO), etc.) to provide compounds of formula (I).

[0377] General Process C

[0378]

[0379] Wherein X is a good leaving group, i.e. Cl, Br, -SCH3 or S(O)2CH3, and R 1 、R 2 、R c 、R d and p is as defined in formula (I).

[0380] Compounds of formula (I) can also be prepared using intermediates Ie and If as outlined in General Scheme C. Intermediates Ie and If are aminated using a base (i.e., sodium hydroxide (NaOH), potassium hydroxide (KOH), etc.) in a solvent (i.e., methanol (MeOH), ethanol (EtOH), water (HO), etc.) to provide compounds of formula (I).

[0381] General Process D

[0382]

[0383] Among them and R 1 、R c and R d As defined in formula (I).

[0384] Alternatively, compounds of formula (I) can also be prepared using intermediates Ig, Ih, Ij, Ik, and Im as outlined in General Scheme D. Intermediate Ig is olefinized using a base (i.e., potassium carbonate (KCO) and diethyl (cyanomethyl)phosphonate) in a solvent (i.e., tetrahydrofuran (THF), water (HO)), optionally at elevated temperature, to provide intermediate Ih. Ih is hydrogenated using a metal catalyst (i.e., palladium on carbon (Pd / C), platinum dioxide (PtO), etc., and hydrogen (H) gas in a solvent (i.e., ethanol (EtOH) and / or tetrahydrofuran (THF)) to provide intermediate Ij. Intermediate Ik is obtained by treating intermediate Ij with an acid (i.e., hydrochloric acid (HCl)) in a solvent (i.e., ethanol (EtOH), dichloromethane (CHCl), etc.), and then subsequently treating with a base (i.e., ammonia (NH)). Intermediates Ik and Im are cyclized using a base (eg, sodium hydroxide (NaOH), potassium hydroxide (KOH), etc.) in a solvent (eg, dimethylacetamide (DMA)), optionally at elevated temperature, to afford compounds of formula (I).

[0385] General Process E

[0386]

[0387] Among them and R 1 、R c and R d As defined in formula (I).

[0388] Alternatively, compounds of formula (I) can be prepared using intermediates In and Io as outlined in General Scheme D. Acylation of intermediates In and Io with 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).

[0389] General Program F

[0390]

[0391] Among them, L, R c 、R d 、R 1 and R 7 As defined in formula (I).

[0392] The general procedure for synthesizing compounds of general formula I (e.g., I-17 to I-30) comprises the reaction of one equivalent of the corresponding substituted 6-mercapto-2-oxo-4,5-disubstituted-1,2-dihydro-pyridine derivative with a stoichiometric amount of LR using two equivalents of DIPEA as a base and acetone as a solvent. 1 -R 7Final coupling between intermediates affords the final compounds.

[0393] 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.

[0394] General Scheme G, 6-Oxo-2-[4-(1H-tetrazol-5-yl)-phenylamino]-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile

[0395]

[0396] General Scheme H, 6-Oxo-2-[4-(1H-tetrazol-5-yl)-cyclohexylamino]-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile

[0397]

[0398] General Scheme I, 6-Oxo-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile

[0399]

[0400] General Scheme J, 6-Oxo-2-[3-(1H-tetrazol-5-yl)-azetidin-1-yl]-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile

[0401]

[0402] General Scheme K, 4-Benzyl-6-oxo-2-[2-(1H-tetrazol-5-yl)-benzylthio]-1,6-dihydro-pyrimidine-5-carbonitrile

[0403]

[0404] The mixtures of enantiomers, diastereomers, cis / trans isomers produced by the above process can be separated into their individual components by chiral salt techniques, chromatography using normal phase, reverse phase or chiral columns depending on the separation properties.

[0405] It is understood that in the descriptions and formulae shown above, unless otherwise indicated, the different 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 , m, n, p, q, r and other variables are as defined above. In addition, for synthetic purposes, the compounds and selected groups of General Schemes A to E are merely representative to illustrate the general synthetic methods of compounds of Formula (I) as defined herein.

[0406] Pharmaceutical compositions

[0407] The compounds of formula (I) or (II) may be provided in any form suitable for the intended administration, including, among others, pharmaceutically acceptable salts, solvates and prodrugs of the compounds of formula (I) or (II).

[0408] Pharmaceutically acceptable salts refer to salts of compounds of formula (I) or (II) that are considered acceptable for clinical and / or veterinary use. Typical pharmaceutically acceptable salts include those prepared by reacting compounds of formula (I) or (II) with inorganic acids or organic acids or organic or inorganic bases. Such salts are referred to as acid addition salts and base addition salts, respectively. It will be appreciated that the specific counterions that form part of any salt do not have a critical property, as long as the salt is pharmaceutically acceptable as a whole, and as long as the counterions do not bring undesirable mass to the salt as a whole. These salts can be prepared by methods known to those skilled in the art. Pharmaceutically acceptable salts are, for example, described and discussed in Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, PA, USA, 1985 and the latest version, and Encyclopedia of Pharmaceutical Technology.

[0409] Examples of pharmaceutically acceptable addition salts include acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, hydroiodic acid, metaphosphoric acid or phosphoric acid; and 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, camphorsulfuric acid, isethionic acid (isothionic), mucic acid, gentisic acid, isonicotinic acid, glucaric acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, amylopectin, benzoic acid ... and sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid; and 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. It should be understood that, as defined herein, all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid salt.

[0410] The compound of formula (I) or (II) or its pharmaceutically acceptable salt can be provided in a soluble or insoluble form together with a pharmaceutically acceptable solvent (such as water, ethanol and the like). Soluble forms can also include hydrated forms such as monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates and the like.

[0411] The compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof can be provided as prodrugs. As used herein, the term "prodrug" is intended to mean a compound that, upon exposure to certain physiological conditions, releases a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which is then able to exhibit the desired biological effect. A typical example is an unstable carbamate of an amine.

[0412] Because known prodrugs can enhance many required qualities (such as solubility, bioavailability, manufacturing etc.) of medicaments, the compounds of this invention can be delivered in prodrug form. Therefore, the present invention contemplates the prodrug of the compound currently required to be included, its delivery method and the composition containing it. " prodrug " contemplates any covalent bonding carrier that releases the active parent drug of the present invention in vivo when such prodrug is applied to an individual. The prodrug of the present invention is prepared by modifying the functional group present in the compound, in such a way that the modification is cracked into the parent compound in conventional operation or in vivo. Prodrug includes the compounds of this invention, wherein hydroxyl, amino, sulfydryl, carboxyl or carbonyl are bonded to any group, and it can be respectively cracked in vivo to form free hydroxyl, free amino, free sulfydryl (sulfhydryl), free carboxyl or free carbonyl.

[0413] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) of hydroxyl groups in the compounds of the invention and carbamates (e.g., N,N-dimethylaminocarbonyl), esters (e.g., C 1-6

[0014] Examples of the present invention include alkyl esters such as methyl, ethyl, 2-propyl, phenyl, 2-aminoethyl, and morpholinoethanol esters, N-acyl derivatives of amino groups (e.g., N-acetyl), N-Mannich bases, Schiff bases, and oximes, acetals, ketals, and enols of enaminoketone, ketone, and aldehyde functional groups, and the like. See Bundegaard, H., Design of Prodrugs, pp. 1-92, Elesevier, New York-Oxford (1985).

[0414] The compound or its pharmaceutically acceptable salt, ester or prodrug is administered orally, nasally, transdermally, pulmonary, by 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 a particular route of administration.

[0415] The dosage regimen for utilizing the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0416] Techniques for formulating and administering the disclosed compounds of the present invention can be found in Remington: the Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. 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.

[0417] In one aspect of the present invention, a pharmaceutical composition is provided, comprising at least one compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, as an active ingredient, 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 can be administered alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient in a single or multiple dose. Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

[0418] A "pharmaceutical composition" is a formulation containing a compound of the invention in a form suitable for administration to a subject. Pharmaceutical compositions can be formulated according to conventional techniques (such as those disclosed in Remington: The Science and Practice of Pharmaceuticals, 21st edition, 2000, Lippincott Williams & Wilkins) with a pharmaceutically acceptable carrier or diluent and any other known adjuvants and excipients.

[0419] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0420] "Pharmaceutically acceptable excipient" means an excipient that is suitable for use in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0421] The pharmaceutical compositions formed by combining a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent, or excipient can be readily administered in a variety of dosage forms such as tablets, powders, buccal tablets, syrups, suppositories, injectable solutions, and the like. In powders, the carrier is a finely powdered solid, such as talc or starch, which is mixed with the finely powdered active ingredient. In tablets, the active ingredient is mixed in suitable proportions with a carrier having the necessary binding properties and compacted into the desired shape and size.

[0422] The pharmaceutical composition may be specifically prepared for administration by any suitable route, such as oral and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the preferred route will depend on the general condition and age of the individual to be treated, the nature of the condition to be treated and the active ingredient selected.

[0423] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they may be prepared with coatings such as enteric coatings or they may be prepared to provide controlled release of the active ingredient, such as sustained or extended release according to methods well known in the art.

[0424] For oral administration in tablet or capsule form, the compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, may be suitably combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water, or its analogue. In addition, suitable binders, lubricants, disintegrants, flavorings, and coloring agents may be added to the mixture as appropriate. Suitable binders include, for example, lactose, glucose, starch, gelatin, gum arabic, gum tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, or its analogue. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or its analogue. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, three-starch gum, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, or its analogue. Additional excipients for capsules include macrogels or lipids.

[0425] To prepare a solid composition (such as a tablet), the active compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is mixed with one or more excipients (such as the excipients described above) and other pharmaceutical diluents (such as water) to prepare a solid preformulated composition containing 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 evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets or capsules.

[0426] Liquid compositions for oral or parenteral administration of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof include, for example, aqueous solutions, syrups, elixirs, aqueous or oily suspensions, and emulsions of edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Suitable dispensing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, alginate, gum arabic, polydextrose, sodium carboxymethylcellulose, gelatin, methylcellulose, or polyvinylpyrrolidone.

[0427] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions and sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

[0428] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluidity should be such that it is easy to inject. It must be stable under manufacturing and storage conditions and must be preserved to prevent contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol and its analogues) and a suitable mixture thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and its analogues. In many cases, it is preferred that an isotonic agent, such as sugar, a polyol (such as mannitol, sorbitol), or sodium chloride, be included in the composition. Prolonged absorption of the injectable composition can be achieved by including a delayed absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0429] The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0430] For example, sterile injectable solutions can be prepared by incorporating the required amount of active compound into a suitable solvent, optionally together with one or a combination of the ingredients listed above, followed by filtration sterilization. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle containing an alkaline dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and freeze drying, which produces a powder of the active ingredient plus any other required ingredients from its previously sterile-filtered solution. It is also contemplated that reservoir-type injectable compositions are within the scope of the present invention.

[0431] For parenteral administration, solutions containing a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol solution, or in a sterile aqueous solution may be used. If necessary, such aqueous solutions should be appropriately buffered, and the liquid diluent should first be rendered 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 purposes.

[0432] In addition to the aforementioned ingredients, compositions of compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof may contain one or more additional ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives (e.g., methylparaben (including antioxidants)), emulsifiers, and the like.

[0433] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat, ameliorate, or prevent an identified disease, disorder, or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual'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 that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is a disease or condition associated with α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0434] For any compound, the therapeutically effective amount can be estimated initially in a cell culture assay (e.g., in cells) or in an animal model (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 doses and routes suitable for administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that causes death in 50% of the group). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and route of administration.

[0435] Dosage and administration are adjusted to provide sufficient amounts of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state; the individual's general health; the individual's age, weight, and sex; diet; time and frequency of administration; drug combination; reaction sensitivities; and tolerance / response to therapy. Depending on the half-life and clearance rate of the particular formulation, long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly, or biweekly.

[0436] The suitable dosage of the compound of formula (I) or (II) or its pharmaceutically acceptable salt will depend on the age and condition of the patient, the severity of the disease to be treated and other factors known to the practicing physician. The compound can be, for example, administered orally, parenterally or topically every day or at intervals such as weekly intervals according to different administration schedules. In general, a single dose will be within the range of 0.01 to 500 mg per kilogram of body weight, preferably within the range of 0.05 to 100 mg per kilogram of body weight, more preferably within the range of 0.1 to 50 mg per kilogram of body weight, and most preferably within the range of 0.1 to 25 mg per kilogram of body weight. The compound can be administered in bolus form (i.e., a one-time administration of the entire daily dose) or twice or more a day in divided doses. Changes based on the aforementioned dosage range can be made by a physician of general technology taking into account known considerations (such as the weight, age and condition of the person being treated, the severity of the ailment and the specific route of administration).

[0437] The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof can also be prepared in the form of a pharmaceutical composition comprising one or more other active substances alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient, in single or multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients are as described above, and the one or more other active substances can be any active substance, or preferably an active substance as described in the following section "Combination Therapy".

[0438] Treatment

[0439] In another aspect, the present invention relates to a method for preventing, reducing the risk of, or ameliorating a disease or condition in which α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) plays a role, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0440] Another aspect of the present invention relates to a method for preventing, reducing the risk of, or ameliorating a disease or condition in which α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) plays a role, the method 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 a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0441] Another aspect of the present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), the method comprising administering to a subject suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0442] Another aspect of the present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD), the method comprising administering to a subject suffering from or susceptible to a disease or condition associated with ACMSD 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 of a pharmaceutically acceptable carrier, diluent, or excipient.

[0443] In another aspect, the present invention relates to a method for treating, preventing or treating nicotinamide adenine dinucleotide (NAD + ) modulates a disease or condition in which the drug modulates the effect of, reduces the risk of, or ameliorates the disease or condition, the method comprising administering to an individual in need thereof a therapeutically effective amount of one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0444] In another aspect, the present invention relates to a method for treating, preventing or treating nicotinamide adenine dinucleotide (NAD + ) A method for modulating a disease or condition in which the disease or condition is involved, reducing the risk of the disease or condition, or ameliorating the disease or condition, the method comprising administering to an individual in need thereof 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 of a pharmaceutically acceptable carrier, diluent, or excipient.

[0445] In another aspect, the present invention relates to a method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD +) level, a method for reducing the risk of, or ameliorating a disease or condition, the method comprising administering to a patient suffering from or susceptible to a disease or condition associated with NAD + A therapeutically effective amount of one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered to an individual suffering from a disease or condition associated with a decrease in the level of IL-12.

[0446] In another aspect, the present invention relates to a method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) level, a method for reducing the risk of, or ameliorating a disease or condition, the method comprising administering to a patient suffering from or susceptible to a disease or condition associated with NAD + A pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient is administered to an individual suffering from a disease or condition associated with a decrease in the level of steroid hormone.

[0447] Another aspect of the present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a condition associated with mitochondrial dysfunction, comprising administering a therapeutically effective amount of one or more compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, to a subject suffering from or susceptible to a metabolic condition. In one embodiment, the condition associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic condition, a neurodegenerative disease, an aging-related condition, a kidney condition, or a chronic inflammatory disease. In a preferred embodiment, the condition associated with mitochondrial dysfunction is a common metabolic condition, such as obesity or type II diabetes.

[0448] Another aspect of the present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a condition 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 pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the condition associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease. In a preferred embodiment, the condition associated with mitochondrial dysfunction is a common metabolic disorder, such as obesity or type 2 diabetes.

[0449] In another aspect, the present invention relates to a method for promoting oxidative metabolism, comprising administering to an individual suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, said one or more compounds increasing intracellular nicotinamide adenine dinucleotide (NAD+ ).

[0450] In another aspect, the present invention relates to a method for promoting oxidative metabolism, comprising administering to an individual 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 of a pharmaceutically acceptable carrier, diluent or excipient, wherein the one or more compounds increase intracellular nicotinamide adenine dinucleotide (NAD + ).

[0451] In yet another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or condition mediated by ACMSD inhibition, wherein the medicament comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0452] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or condition mediated by ACMSD inhibition, wherein the medicament comprises a pharmaceutical composition comprising one or more compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0453] In yet another aspect, the present invention relates to a compound for use in a method for treating, preventing, reducing the risk of, or ameliorating a disease or condition mediated by ACMSD inhibition, wherein the compound comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0454] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, preventing, reducing the risk of, or ameliorating a disease or condition mediated by ACMSD inhibition, wherein the composition comprises one or more compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0455] Another aspect of the present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0456] Another aspect of the present invention relates to the use of a pharmaceutical composition for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), wherein the pharmaceutical composition comprises one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0457] In another aspect, the present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating, preventing, or treating nicotinamide adenine dinucleotide (NAD + ) content, reduces the risk of the disease or condition, or improves the disease or condition.

[0458] In another aspect, the present invention relates to the use of a pharmaceutical composition for the manufacture of a pharmaceutical composition for the treatment, prevention, and administration of nicotinamide adenine dinucleotide (NAD + ) content, reducing the risk of the disease or condition, or improving the disease or condition, the pharmaceutical composition comprises one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0459] Another aspect of the present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a condition associated with mitochondrial dysfunction.

[0460] Another aspect of the present invention relates to the use of a pharmaceutical composition for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating conditions associated with mitochondrial dysfunction, wherein the pharmaceutical composition comprises one or more compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0461] In another aspect, the present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting oxidative metabolism.

[0462] In another aspect, the present invention relates to the use of a pharmaceutical composition for the manufacture of a medicament for promoting oxidative metabolism, wherein the pharmaceutical composition comprises one or more compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0463] Another aspect of the present invention 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 condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0464] Another aspect of the present invention 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 the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD).

[0465] In another aspect, the present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which is suitable for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) levels, reduces the risk of, or ameliorates a disease or condition associated with the present invention.

[0466] In another aspect, the present invention relates to a pharmaceutical composition suitable for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) content, reduces the risk of the disease or condition, or improves the disease or condition, the pharmaceutical composition comprises one or more compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0467] Another aspect of the present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which is useful as a medicament for treating, preventing, reducing the risk of, or ameliorating conditions associated with mitochondrial dysfunction.

[0468] Another aspect of the present invention relates to a pharmaceutical composition useful as a medicament for treating, preventing, reducing the risk of, or ameliorating conditions associated with mitochondrial dysfunction, 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.

[0469] In another aspect, the present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, which is suitable for use as an agent for promoting oxidative metabolism.

[0470] In another aspect, the present invention relates to a pharmaceutical composition suitable for use as an agent for promoting oxidative metabolism, comprising one or more compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0471] Another aspect of the present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in treating or preventing nicotinamide adenine dinucleotide (NAD + ) content, reduce the risk of, or improve a disease or condition associated with a decrease in the level of the drug.

[0472] Another aspect of the present invention relates to a pharmaceutical composition for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) content, reduce the risk of the disease or condition, or improve the disease or condition, the pharmaceutical composition comprises 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.

[0473] In another aspect, the present invention 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.

[0474] In another aspect, the present invention relates to a pharmaceutical composition for treating, preventing, reducing the risk of, or ameliorating a condition associated with mitochondrial dysfunction, 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.

[0475] Another aspect of the present invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in promoting oxidative metabolism.

[0476] Another aspect of the present invention 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 promoting oxidative metabolism.

[0477] In some embodiments, the nicotinamide adenine dinucleotide (NAD +) levels are chronic liver diseases, including, but not limited to, primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-related graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, 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 II diabetes.

[0478] In some embodiments, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[0479] In another aspect, the present invention relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or condition by inhibiting α-amino-β-carboxyadipate-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).

[0480] As used herein, "treating" or "treat" describes the management and care of a patient for the purpose of reversing, inhibiting, or combating a disease, condition, or disorder, and includes the process of administering a compound of the present invention (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 inhibit the disease, condition, or disorder.

[0481] The compounds of the present invention (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 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.

[0482] The compounds of the present invention (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 "alleviate" is intended to describe a process of reducing the severity of a sign or symptom of a disorder. Importantly, a sign or symptom can be alleviated without eliminating the sign or symptom. Preferably, the treatment is curative or ameliorative.

[0483] Clinical conditions and other uses of the compounds

[0484] The compounds of formula (I) or (II) as defined herein, or pharmaceutically acceptable forms thereof, compositions, medicaments and compounds for use, are suitable for the treatment of diseases or conditions in which α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) regulation plays a role. The compounds can be used in human or veterinary medicine, and the patient can be any mammal, especially a human. The treatment may comprise administering a therapeutically effective amount of a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, to any mammal, especially a human, suffering from a disease or condition in which α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) regulation plays a role.

[0485] The present invention also relates to a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions associated with α-amino-β-carboxyadipate-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 steatotic hepatitis (NASH) or chronic kidney disease.

[0486] The term "a disease or condition associated with alpha-amino-beta-carboxyhexanedioate-epsilon-semialdehyde decarboxylase (ACMSD) dysfunction" refers to a condition characterized by nicotinamide adenine dinucleotide (NAD + ) expression and / or activity is decreased, or through NAD + Elevated levels improve the disease.

[0487] The methods, agents, and compounds of the present invention are suitable for treating disorders associated with abnormal mitochondrial function, alleviating the symptoms of the disorders, or delaying the onset of the disorders. Disorders associated with abnormal mitochondrial function include, for example, metabolic disorders, neurodegenerative diseases, aging-related disorders, and chronic inflammatory disorders. Mitochondrial disorders also include diseases with inherited and / or acquired mitochondrial dysfunction (i.e., Charcot-Marie-Tooth disease, 2A2 mitochondrial encephalopathy lactic acidosis and stroke (MELAS), Leigh syndrome, Barth syndrome, and Leber's optic neuropathy), fatty acid oxidation disorders, hereditary deafness and blindness, and metabolic abnormalities induced by exposure to toxic chemicals and / or drugs (e.g., cisplatin-induced deafness).

[0488] Metabolic disorders include, for example, type II 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, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.

[0489] Neurodegenerative disorders include diseases such as photoreceptor degeneration (ie, retinitis pigmentosa), dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0490] Chronic inflammatory diseases include conditions such as celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), irritable bowel disease, atherosclerosis, arthritis, and psoriasis.

[0491] Age-related disorders include diseases such as cancer, dementia, cardiovascular disease (ie, atherosclerosis), hypertension, diabetes (type I or type II), arthritis, cataracts, Alzheimer's disease, macular degeneration, and osteoporosis.

[0492] Individuals may suffer from or be susceptible to metabolic disorders. Individuals 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. Normal adult glucose levels are between approximately 60 and 126 mg / dL. Normal insulin levels are approximately 7 mU / mL ± 3 mU. Hypertension can be diagnosed by consistently having a blood pressure reading of or above approximately 140 / 90. Cardiovascular disease can be diagnosed by measuring cholesterol levels. For example, an LDL cholesterol level above approximately 137 or a total cholesterol level 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 to 199 mg / dL (7.8 to 11.0 mmol) after a 75g oral glucose tolerance test over two hours. 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 below about 2.8 to 3.0 mmol / L (50 to 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) measurement. Alternatively, waist circumference (estimates fat distribution), waist-to-hip ratio (estimates fat distribution), skinfold thickness (estimates fat distribution if measured at several points), or bioimpedance (estimates % fat based on the principle that lean mass conducts electrical current better than fat mass (i.e., fat mass impedes electrical current)) can be measured. Parameters for normal, overweight, or obese individuals are as follows: underweight: BMI <18.5; normal: BMI from about 18.5 to about 24.9; overweight: BMI = about 25 to about 29.9. Overweight individuals are characterized by a waist circumference >94 cm for men or >80 cm for women and a waist-to-hip ratio ≥0.95 for men and ≥0.80 for women. Obese individuals are characterized by a BMI of 30 to 34.9, greater than 20% above "normal" weight for height, a body fat percentage >30% for women and 25% for men, and a waist circumference >102 cm (40 inches) for men or 88 cm (35 inches) for women. Individuals with severe or morbid obesity are characterized by a BMI ≥35.

[0493] The methods described herein can result in a decrease in the severity of a metabolic disorder or amelioration of one or more symptoms of a metabolic disorder. For example, symptoms of diabetes include elevated fasting blood glucose levels, blood pressure at or above 140 / 90 mm / Hg; abnormal blood lipid levels, such as high-density lipoprotein (HDL) less than or equal to 35 mg / dL, or triglycerides greater than or equal to 250 mg / dL (mg / dL = milligrams of glucose per deciliter of blood). The efficacy of the treatment is determined in conjunction with any known method for diagnosing a metabolic disorder. Amelioration of one or more symptoms of a metabolic disorder indicates that the compound provides clinical benefit.

[0494] The method of the present invention is suitable for treating renal disorders, alleviating symptoms of renal disorders, or delaying the onset of renal disorders.Renal disorders include acute kidney injury (AKI) and chronic kidney disease (CKD).

[0495] A subject may be suffering from or susceptible to acute kidney injury (AKI). Acute kidney injury may 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, resulting in azotemia). Subjects suffering from or at risk of developing acute kidney injury (AKI) are identified by methods known in the art. For example, acute kidney injury may be characterized by an increase in serum creatinine of at least 50% relative to baseline, an absolute increase in serum creatinine of at least 0.3 mg / dL relative to baseline, a decrease in glomerular filtration rate of at least 25% compared to baseline, a decrease in urine output to 0.5 ml or less per kilogram of body weight per hour for at least 6 hours, or any combination thereof. Acute kidney injury may be caused by ischemia, drugs or toxic agents (i.e., radiocontrast media, nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, or chemotherapeutic agents), viruses, and obstruction.

[0496] An individual may have or be susceptible to chronic kidney disease (CKD). Chronic kidney disease (CKD) is defined as (1) having renal impairment, as defined by structural or functional abnormalities of the kidney, for 3 months or longer, with or without a reduced glomerular filtration rate (GFR), or (2) having a glomerular filtration rate of less than 60 mL / min / 1.73 m 2 The present invention provides the method for the treatment of renal insufficiency.The GFR of CKD or the individual at risk of CKD is determined by methods known in the art.The structural or functional abnormalities are manifested as symptoms such as pathological abnormalities or markers of renal injury, including abnormalities identified in imaging studies or the composition of blood or urine.

[0497] For example, CKD can be diagnosed by testing 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 individuals with CKD. Additional markers of kidney damage may include hematuria (i.e., any detectable amount of blood in the urine), proteinuria (i.e., a protein concentration greater than about 100 mg / dL in the urine), albuminuria (i.e., an albumin concentration greater than about 100 mg / dL in the urine), an intact parathyroid hormone (PTH) concentration greater than about 150 pg / mL in the blood, or a blood phosphorus content greater than about 4.5 mg / dL. One specific marker of kidney disease is a higher than normal GFR ratio (i.e., greater than about 90 mL / min / 1.73 m 2 A GFR lower than normal is also indicative of CKD.

[0498] The method of the present invention is applicable to treating non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatosis hepatitis (NASH), alleviating its symptoms or delaying its onset. Individuals may suffer from or be susceptible to non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatosis hepatitis (NASH). Individuals suffering from non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatosis hepatitis (NASH) or at risk of suffering from non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatosis hepatitis (NASH) are identified by methods known in the art. For example, NAFLD and / or NASH can be diagnosed by liver biopsy.

[0499] As defined herein, non-alcoholic fatty liver disease (NAFLD) is a disease of fat deposition in the liver, which occurs in patients whose alcohol intake history is not enough to cause liver damage. Non-alcoholic fatty liver disease (NAFLD) can be further classified into simple fatty liver, steatosis hepatitis and cirrhosis. Non-alcoholic steatosis hepatitis (NASH) refers to the lesions associated with inflammation, liver cell necrosis, enlargement and fibrosis. The onset of non-alcoholic simple fatty liver is induced by the fat deposition in the liver cells, and this fat accumulation is defined by the balance between growth factor (influx and synthesis of fat in liver cells) and attenuation factor (metabolism of fat and its release from liver cells). Once liver cell damage occurs, in addition to this fat deposition, non-alcoholic simple fatty liver will develop into non-alcoholic steatosis hepatitis. Non-alcoholic steatosis hepatitis is progressive and can eventually develop into cirrhosis and hepatocellular carcinoma.

[0500] Combination therapy

[0501] In another aspect, the present invention comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in combination therapy. The compounds, compositions, medicaments, and compounds for use of formula (I) or (II) or a pharmaceutically acceptable salt thereof may also be used in combination with one or more other therapeutic agents. Such therapeutic agents include, but are not limited to, 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, α-glucosidase inhibitors, α-amylase inhibitors, insulin secretagogues, A2 antagonists, insulin or insulin mimetics, glycogenokinase inhibitors, GLP-1 agonists, non-thiazolidinediones, glucokinase, and 11βHSD-1 inhibitors; anti- Obesity agents such as uncoupling protein (UCP-1, UCP-2 and UCP-3) activators, β3 adrenergic receptors (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, acyl-estrogens, leptin, NPY 5 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) transporter inhibitors, CCK-A agonists, and histamine 3 (H3) antagonists / inverse agonists; cholesterol-lowering agents such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, HMG-CoA synthetase inhibitors, squalene epoxidase inhibitors, fibric acid, the bile acid-binding resin probucol, and niacin (nicotinic acid); raising NAD + Compounds such as NAD + Precursors (i.e., nicotinamide riboside (NA), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide); and inhibition of NAD + Depleting compounds, such as PARP inhibitors and CD38 inhibitors.

[0502] PPARγ agonists suitable for use in the present invention include, but are not limited to, glitazones (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, CLX-0921, 5-BTZD, and the like); 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 suitable for use in the present invention include, but are not limited to, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB 219994, 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 suitable for use in the present invention include, but are not limited to, GW501516, GW 590735, and compounds disclosed in JP 10237049, WO 02 / 14291, and WO 2018 / 125983, and pharmaceutically acceptable salts or esters thereof.

[0503] Biguanides suitable for use in the present invention include, but are not limited to, buformin, metformin, and phenformin, and pharmaceutically acceptable salts or esters thereof. Metformin is indicated for patients with non-insulin-dependent diabetes mellitus (especially patients with refractory obesity). Physician's Desk Reference )”, pp. 1080-1086 (56th edition, 2002).

[0504] Protein tyrosine phosphatase-1B (PTP-1B) inhibitors suitable for use in the present invention include, but are not limited to, A-401,674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, MC52453, and compounds disclosed in WO 02 / 26707, WO 02 / 26743, and JP 2002114768, and pharmaceutically acceptable salts or esters thereof.

[0505] Dipeptidyl peptidase IV (DPP-IV) inhibitors, such as isoleucinethiazolidide; 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 compounds disclosed in WO 03 / 00449; WO 03 / 004496; EP 1 258 476; WO 02 / 083128; WO 021062764; WO 03 / 000250; WO 03 / 002530; WO 03 / 002531; WO 03 / 002553; WO 03 / 002593; WO 03 / 000180; and WO 03 / 000181.

[0506] Sulfonylureas suitable for use in the present invention include, but are not limited to, acetohexamide, chloropropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide, and pharmaceutically acceptable salts or esters thereof. Meglitinides suitable for use in the present invention include, but are not limited to, repaglinide and nateglinide, and pharmaceutically acceptable salts or esters thereof.

[0507] Alpha glucoside hydrolase inhibitors (or glucoside inhibitors) suitable for use in the present invention include, but are not limited to, 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. Suitable α-amylase inhibitors for use in the present invention include, but are not limited to, tendamistat, trestatin, and A1-3688, and pharmaceutically acceptable salts and esters thereof, and compounds disclosed in U.S. Pat. Nos. 4,451,455, 4,623,714, and 4,273,765.

[0508] Insulin secretagogues suitable for use in the present invention include, but are not limited to, linogliride and A-4166, and pharmaceutically acceptable salts and esters thereof.

[0509] Fatty acid oxidation inhibitors suitable for use in the present invention include, but are not limited to, clomoxir and etomoxir, and pharmaceutically acceptable salts and esters thereof. A2 antagonists suitable for use in the present invention include, but are not limited to, midaglizole, isaglidole, deriglidole, idazoxan, earoxan, fluparoxan, and pharmaceutically acceptable salts and esters thereof. Insulin or insulin mimetics suitable for use in the present invention include, but are not limited to, biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-1 (73-7) (insulintropin) and GLP-1 (7-36) -NH2), and pharmaceutically acceptable salts or esters thereof.

[0510] Glucose phosphatase inhibitors suitable for use in the present invention include, but are not limited to, CP-368,296, CP-316,819, BAYR3401, and compounds disclosed in WO 01 / 94300 and WO 02 / 20530, and pharmaceutically acceptable salts or esters thereof. GLP-1 agonists suitable for use in the present invention include, but are not limited to, incretin-3 and incretin-4, and compounds disclosed in US 2003087821 and NZ 504256, and pharmaceutically acceptable salts or esters thereof.

[0511] Non-thiazolidinediones suitable for use in the present invention include, but are not limited to, JT-501 and farglitazar (GW-2570 / GI-262579) and pharmaceutically acceptable salts or esters thereof. Glucokinase activators suitable for use in the present invention include, but are not limited to, fused heteroaromatic compounds (such as those disclosed in US 2002103199) and isoindolin-1-one substituted propionamide compounds (such as those disclosed in WO 02 / 48106).

[0512] Serotonin (5HT) transport inhibitors suitable for use in the present invention include, but are not limited to, paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine. Norepinephrine (NE) transport inhibitors suitable for use in the present invention include, but are not limited to, GW 320659, despiramine, talsupram, and nomifensine. Cannabinoid receptor 1 (CB-1) antagonists / inverse agonists suitable for use in the present invention include: U.S. Patent 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. Patent No. 6,028,084, and PCT Application Nos. WO 96 / 33159, WO 98 / 33765, WO 98 / 43636, WO 98 / 43635, WO 01 / 09120, WO 98 / 31227, WO 98 / 41519, WO 98 / 37061, WO 00 / 10967, WO 00 / 10968, WO 97 / 29079, WO 99 / 02499, WO 01 / 58869, WO 02 / 076949, WO 01 / 64632, WO 01 / 64633, WO 01 / 64634, and WO 03 / 007887, and EPO application No. EP-658546. Specific CB-1 antagonists / inverse agonists suitable for use in the present invention include, but are not limited to, rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY 65-2520 (Bayer), and SLY 319 (Solvay). CCK-A agonists suitable for use in the present invention include GI 181771 and SR 146,131. Ghrelin antagonists suitable for use in the present invention include those disclosed in PCT Application Nos. WO 01 / 87335 and WO 02 / 08250.Histamine 3 (H3) antagonists / inverse agonists suitable for use in the present invention include: PCT Application No. WO 02 / 15905, and O-[3-(1H-imidazol-4-yl)propanol]carbamate (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., Pharmazie, 55: 83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000)). Specific H3 antagonists / inverse agonists suitable for use in the present invention include, but are not limited to, thioperamide, 3-(1H-imidazol-4-yl)propyl N-4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and A331440.

[0513] Melanin-concentrating hormone receptor (MCHLR) antagonists and melanin-concentrating hormone 2 receptor (MCH2R) agonists / antagonists suitable for use in the present invention include PCT patent applications WO 01 / 82925, WO 01 / 87834, WO 02 / 06245, WO 02 / 04433, and WO 02 / 51809, and Japanese patent application JP 13226269. Specific MCH1R antagonists suitable for use in the present invention include, but are not limited to, T-226296 (Takeda), SB 568849, and SNAP 7941. Neuropeptide Y1 (NPY1) antagonists suitable for use in the present invention include those disclosed in U.S. Patent No. 6,001,836 and PCT Application Nos. WO 96 / 14307, WO 01 / 23387, WO 99 / 51600, WO 01 / 85690, WO 01 / 85098, WO 01 / 85173, and WO 01 / 89528. Specific examples of NPY1 antagonists suitable for use in the present invention include, but are not limited to, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A. Neuropeptide Y2 (NPY2) agonists suitable for use in the present invention include, but are not limited to, peptide YY (PYY) and PYY3-36, peptide YY analogs, PYY agonists, and compounds disclosed in WO 03 / 026591, WO 03 / 057235, and WO 03 / 027637.Neuropeptide Y5 (NPY5) antagonists suitable for use in the present invention include, but are not limited to, compounds described in U.S. Pat. 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. Pat. Nos. 6,326,375, 6,329,395, 6,337,332, 6,335,345, European Patent Nos. EP-01010691 and EP01044970, and PCT International Patent Publication Nos. WO 97 / 19682, WO 97 / 20820, WO 97 / 20821, WO No. 97 / 20822, No. WO 97 / 20823, No. WO 98 / 27063, No. WO 00 / 107409, No. WO00 / 185714, No. WO 00 / 185730, No. WO 00 / 64880, No. WO 00 / 68197, No. WO No. 00 / 69849, No. 01 / 09120, No. 01 / 85714, No. WO 01 / 85730, No. WO 01 / 07409, No. WO 01 / 02379, No. WO 01 / 02379, No. WO 01 / 23388, No. WO No. 01 / 23389, No. WO01 / 44201, No. WO No. 01 / 62737, No. WO 01 / 62738, No. WO 01 / 09120, No. WO 02 / 20488, No. WO 02 / 22592, No. WO 02 / 48152, No. WO 02 / 49648 and No. WO 01 / 14376. Specific NPY5 antagonists suitable for use in the combinations of the present invention include, but are not limited to, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR 235,208, FR226928, 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 suitable for use in the combinations of the present invention include, but are not limited to, the compounds described in Norman et al., J. Med. Chem., 43:4288-4312 (2000). Leptin includes, but is not limited to, recombinant human leptin (PEG-OB, Hoffman LaRoche) and recombinant methionyl human leptin (Amgen).Leptin derivatives suitable for use in the present invention (e.g., truncated forms of leptin) include: Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283 and PCT International Publication Nos. WO 96 / 23513, WO 96 / 23514, WO 96 / 23515, WO 96 / 23516, WO 96 / 23517, WO 96 / 23518, WO 96 / 23519, and WO 96 / 23520.

[0514] Opioid antagonists suitable for use in the present invention include: PCT application No. WO 00 / 21509. Specific opioid antagonists suitable for use in the present invention include (but are not limited to) nalmefene. 3-methoxynaltrexone, naloxone, and naltrexone. Orexin antagonists suitable for use in the present invention include PCT Patent Application Nos. WO 01 / 96302, WO 01 / 68609, WO 02 / 51232, WO 02 / 51838, and WO 03 / 023561. Specific orexin antagonists suitable for use in the present invention include, but are not limited to, SB-334867-A. Acyl-estrogens suitable for use in the present invention include oleoyl-estrone (del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001)). Cholecystokinin-A (CCK-A) agonists suitable for use in the present invention include 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) suitable for use in the present invention include, but are not limited to, GI-181771 (GlaxoSmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer). CNTF derivatives suitable for use in the present invention include, but are not limited to, axokine (Regeneron) and PCT Application Nos. WO 94 / 09134, WO 98 / 22128, and WO 99 / 43813. Growth hormone secretagogue (GHS) agonists suitable for use in the present invention include those disclosed in U.S. Patent No. 6,358,951, U.S. Patent Application Nos. 2002 / 049196 and 2002 / 022637, and PCT Application Nos. WO 01 / 56592 and WO 02 / 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.

[0515] 5HT2c agonists suitable for use in the present invention include: U.S. Patent No. 3,914,250 and PCT Application Nos. WO 02 / 36596, WO 02 / 48124, WO 02 / 10169, WO 01 / 66548, WO 02 / 44152, WO 02 / 51844, WO 02 / 40456, and WO 02 / 40457. Specific 5HT2c agonists suitable for use in the present invention include, but are not limited to, BVT933, DPCA37215, 1K264, PNU 22394, WAY161503, R-1065, and YM 348.

[0516] Mc4r agonists suitable for use in the present invention include: PCT Application Nos. WO 99 / 64002, WO 00 / 74679, WO 01 / 991752, WO 01 / 74844, WO 01 / 70708, WO 01 / 70337, WO 01 / 91752, WO 02 / 059095, WO 02 / 059107, WO 02 / 059108, WO 02 / 059117, WO 02 / 12166, WO 02111715, WO 02 / 12178, WO 02 / 15909, WO 02 / 068387, WO 02 / 068388, WO 02 / 067869, WO 03 / 007949 and WO 03 / 009847. Specific Mc4r agonists suitable for use in the present invention include CIR86036 (Chiron), ME-10142 and ME-10145 (Melacure).

[0517] Monoamine reuptake inhibitors suitable for use in the present invention include: PCT application No. WO 01 / 27068 and No. WO 01 / 62341. Specific monoamine reuptake inhibitors suitable for use in the present invention include (but are not limited to) sibutramine (Meridia O / ): U.S. Patent Nos. 4,746,680, 4,806,570, and 5,436,272, and U.S. Patent Publication No. 2002 / 0006964.

[0518] Suitable serotonin reuptake inhibitors and releasers for use in the present invention include dexfenfluramine, fluoxetine, and other serotonin reuptake inhibitors, including but not limited to those described in U.S. Patent No. 6,365,633 and PCT Patent Application Nos. WO 01 / 27060 and WO 01 / 162341.

[0519] 11βHSD-1 inhibitors suitable for use in the present invention include, but are not limited to, BVT 3498, BVT 2733, and compounds disclosed in WO 01 / 90091, WO 01 / 90090, and WO 01 / 90092. Uncoupling protein (UCP-1, UCP-2, and UCP-3) activators suitable for use in the present invention include PCT Patent Application No. WO 99 / 00123. Specific uncoupling proteins (UCP-1, UCP-2, and UCP-3) suitable for use in the present invention include, but are not limited to, phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]benzoic acid (TTNPB), and retinoic acid.

[0520] β3 adrenergic receptor (β3) agonists suitable for use in the present invention include: U.S. Patent No. 5,705,515 and U.S. Patent No. 5,451,677, and PCT Patent Application No. WO 01 / 74782 and WO 02 / 32897. Specific β agonists suitable for use in the present invention 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.

[0521] Thyroid hormone beta agonists suitable for use in the present invention include PCT Application No. WO 02 / 15845 and Japanese Patent Application No. JP 2000256190. Specific thyroid hormone beta agonists suitable for use in the present invention include, but are not limited to, KB-2611 (KaroBioBMS). Specific fatty acid synthase (PAS) inhibitors suitable for use in the present invention include, but are not limited to, cerulenin and C75. Specific phosphodiesterase (PDE) inhibitors suitable for use in the present invention include, but are not limited to, theophylline, pentoxifylline, zaprinast, sildenafil, arnrinone, milrinone, cilostamide, rolipram, and cilomilast.

[0522] Lipase inhibitors suitable for use in the present invention include, but are not limited to, PCT Application No. WO 01 / 77094 and U.S. Patent 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 suitable for use in the present invention include, but are not limited to, tetrahydrolipstatin (orlistat / ), Triton WR1339, RHC80267, lipstatin, teasaponin, and diethylcoumarin phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, and RHC 80267.

[0523] Examples of HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, and fluvastatin. Examples of HMG-CoA synthetase inhibitors are: β-lactone derivatives disclosed in U.S. Patents 4,806,564, 4,816,477, 4,847,271, and 4,751,237; β-lactam derivatives disclosed in U.S. Patent 4,983,597 and U.S. Patent 07 / 540,992, filed June 20, 1990; and substituted oxirane analogs disclosed in European Patent Publication EP 0 411 703. Examples of squalene epoxidase inhibitors are disclosed in European Patent Publication EP 0 318 860 and Japanese Patent Publication J02 169-571A. Examples of LDL receptor gene inducer molecules are disclosed in U.S. Patent 5,182,298, filed March 18, 1991. Other cholesterol-lowering agents that may be administered include niacin, probucol, fibric acids (i.e., clofibrate and gemfibrozil), and LDL receptor gene inducers.

[0524] Examples of PARP inhibitors include, but are not limited to, iodonitrocoumarin, 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-fluoro-l-[4-(4-phenyl-3,6-dihydropyridine-l(butyl]quinazoline-2,4(lh,3h)-dione, 3-(4-chlorophenyl)quinazolidine-5-carboxamide, 2-(3'-methoxyphenyl)benzimidazole-4-carboxamide, benzamide, 3-aminobenzamide, 3-aminophthalic acid hydrazide and 1,5-dihydroxyisoquinoline.

[0525] The above-mentioned compounds that can be used in combination with the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof can be prepared and administered as described in the art, such as in the references cited above.

[0526] The above compounds are only illustrative of the ACMSD inhibitors, antidiabetic agents, antiobesity agents, cholesterol lowering agents, NAD enhancing agents, and + Compounds that inhibit NAD +While this list of compounds is not intended to be comprehensive, the methods of the present invention can employ any anti-obesity agent and any anti-diabetic agent and are not limited to any particular structural class of compounds.

[0527] As used herein, "combination therapy" includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, and at least one second agent as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, cooperative (e.g., synergistic) effects and / or pharmacokinetic or pharmacodynamic co-actions resulting from the combination of therapeutic agents, or any combination thereof. Administration of these therapeutic agents in combination is typically performed over a defined period of time (typically minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" may be, but is not generally 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 invention.

[0528] "Combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at different times and in any order, alternating and in any order, as well as the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to an individual a single capsule of each therapeutic agent with a fixed ratio or multiple single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent in the selected combination can be administered by intravenous injection, while the other therapeutic agents in 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 strictly speaking not critical.

[0529] Bioanalysis and Animal Studies

[0530] Methods for screening ACMSD1 inhibitors

[0531] The activity of the compounds as ACMSD1 inhibitors was determined in a spectrophotometric in vitro assay. A pre-assay mixture was incubated, and then a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and an ACMSD1 solution were added. The effect of ACMS concentration on enzyme activity was studied by varying the concentration of 3-hydroxyanthranilic acid (3OH-HA) in the pre-assay mixture. Kinetic parameters were calculated from the initial velocity data using Lineweaver-Burk plots.

[0532] Cell analysis methods

[0533] Mouse hepatocyte cell lines were grown and plated. Cells were maintained in culture medium at 37°C and once adhered, various concentrations of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or DMSO were added. Primary hepatocytes were harvested after approximately 24 hours.

[0534] Assay of ACMSD-1 regulation in HEK293T cells

[0535] HEK293T cells were inoculated and transfected to transiently express ACMSD. Cells were subsequently stimulated with various concentrations of compounds of formula (I) or (II) and then lysed to measure ACMSD activity in a spectrophotometric in vitro assay. The amount of total protein content in the cell lysates was determined by Bradford analysis and used to obtain standardized enzyme specific activity across all samples.

[0536] Measurement of NAD in primary human hepatocytes + content

[0537] Primary hepatocytes were treated with different concentrations of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or MEHP (control) after seeding. The compound was replaced every 24 hours, and then the cells were directly harvested and lysed for detection of NAD via LC MS / MS (liquid chromatography mass spectrometry / mass spectrometry). + content.

[0538] Modulates SOD2 activity in AML12 cells and primary murine hepatocytes

[0539] Primary hepatocytes or AML-12 cells were lysed and total protein concentration was determined using a Bradford assay. SOD2 activity was measured using a SOD assay kit at designated times after treatment with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. Absorbance was measured and, based on a standard curve and the measured protein concentration, the results were expressed as U / ml / mg protein.

[0540] Measurement of NAD in primary murine hepatocytes + content

[0541] Extraction of NAD using acidic extraction method + The samples were collected and homogenized. After pelleting the insoluble protein fraction, the samples were separated by high performance liquid chromatography (HPLC) and analyzed by mass spectrometry. The protein in the pellet was quantified by Bradford analysis and used for standardization.

[0542] RNA preparation and RT-qPCR analysis of ACMSD and SIRT1-regulated genes in cells

[0543] Cells (AML-12, Hepa-1.6, HEK-293, primary human and murine hepatocytes) were treated with various concentrations of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, and the gene expression of ACMSD, Pgc1a, Sod1, and Sod2 (MnSOD) was determined using RT-qPCR. Total RNA was extracted from the cells, treated with DNase, and used for reverse transcription (RT).

[0544] Modulates caspase 3 / 7 activity in MDCK cells

[0545] MDCK cells were cultured in basal medium to a final concentration of 10%. Cells were plated in 96 wells and 24 hours after cell plating, the culture medium was changed with fresh culture medium supplemented with 1% FBS. Cisplatin was then used to induce cell damage. Different concentrations of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof (in DMSO) were added in combination with cisplatin or added before cisplatin was added. According to standard procedures, apoptosis protease 3 / 7 activity (Promega) was determined using the luminescent signal readings on a plate reader. Each experiment / condition was performed in triplicate. Apoptosis protease activity was analyzed as a percentage effect of the cell standardization by cisplatin alone and by vehicle-treated cells.

[0546] Cytotoxicity and hERG screening

[0547] HePG2 and AML-12 cells were seeded and dose responses of compounds were performed at various concentrations. Cells were stimulated and the supernatant was used for LDH release as a measure of necrosis, while cells were lysed to measure ATP levels for determination of cell viability.

[0548] The Proxon hERG Assay Kit is stably transfected with the hERG potassium channel and a high-affinity red fluorescent hERG channel ligand and is used to determine the hERG channel affinity binding of compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof. Compounds (competitors) that bind to the hERG channel protein are identified by their ability to displace the tracer, resulting in lower fluorescence polarization.

[0549] Caenorhabditis elegans experiments - ACMSD1 silencing, lifespan analysis, mobility assessment, and GFP quantification

[0550] ACMSD1 silencing: Bacterial feeding RNAi experiments were conducted in Caenorhabditis elegans (C. elegans) to determine the effects of acmsd-1 knockdown or silencing on gene expression and survival. Clones used in bacterial feeding experiments were acmsd-1, SIR-2.1, and DAF-16. Total RNA was extracted from cells, treated with DNase, and used for reverse transcription (RT).

[0551] Worms are grown on NGM agar plates containing carbenicillin and IPTG and inoculated with bacterial cultures. After RNAi treatment, worms are transferred to culture plates containing paraquat and inoculated with RNAi bacteria. Control animals are grown on RNAi bacteria containing an empty vector (control) and subsequently transferred to culture plates containing paraquat and inoculated with RNAi bacteria. RT-qPCR and survival analysis are used to quantify the gene expression of sod-3 under mRNA content and protein content. The movement of worms is recorded on the 1st, 3rd, and 5th day of adulthood.

[0552] Study on the anti-diabetic effect in C57BL / 6J and KK-Ay mice

[0553] Mice were fed a conventional diet or a high-fat diet (HFD). The compound of formula (I) or a pharmaceutically acceptable salt thereof was administered daily, and blood and tissue were collected for RNA isolation, lipid measurement, and histology. Oxygen consumption was measured and histological analysis and transmission electron microscopy were performed. An oral glucose tolerance test and an intraperitoneal insulin tolerance test were also performed to quantify glucose and measure plasma insulin concentration.

[0554] Antidiabetic and antiobesity studies in db / db mice harboring LepR mutations

[0555] Animals were fed a high-fat diet (HFD). For subchronic intervention, animals were treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof once daily for 14 days. Blood samples were collected and the glucose concentration of each blood sample was determined. For acute intervention, an initial blood sample was collected and then a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof was administered. The dietary route was then restricted, and a second blood sample was collected. Oral glucose tolerance test was performed on mice and blood glucose concentration was determined.

[0556] For the euglycemic-hyperinsulinemic clamp analysis, animals received presensitization with continuous [3- 3 H] glucose infusion and subsequent blood samples were collected to determine plasma insulin, glucose, and [3- 3The basal endogenous glucose concentration was measured and the basal endogenous glucose rate was calculated. The mice were then gavaged with a vehicle or a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. Subsequently, the animals received [3- 3 [H] glucose infusion, resulting in a modest net increase in plasma insulin concentration. Blood glucose concentration was measured and target blood glucose was established by adjusting the rate of glucose infusion. 2-deoxy-D-[1- 14 C] glucose and blood samples were collected. Mice were then sacrificed. Gastrocnemius muscle and epididymal adipose tissue were collected and plasma [ 3 H]- and [ 14 C]-radioactivity.

[0557] Body weight was assessed and brown adipose tissue (BAT) and gonadal white adipose tissue (WAT) were dissected and weighed. Volumetric oxygen (VO2) and volumetric carbon dioxide production (VCO2) were measured and reported as the average VO2 per hour (mL / h / kg) normalized to body weight. Activity counts by infrared beam interruption and food intake were also measured.

[0558] Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in male C57BL / 6J mice

[0559] Mice were fed a "Western" HF-HSD (high fat-high sucrose diet) or a normal 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 subsequently sacrificed. Body weight and food intake were monitored weekly and total fat mass was analyzed. An intraperitoneal glucose tolerance test (IPGTT) was also performed and tail vein glucose levels were measured after glucose administration. Insulin resistance was calculated using a homeostatic model of insulin resistance. Mice were then sacrificed by taking blood samples via cardiac puncture. Plasma was obtained and tissues were collected along with the plasma for further biochemical and molecular analysis or for histological analysis.

[0560] Study on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in methionine- and choline-deficient mice

[0561] 25 g mice were fed a methionine and choline deficient diet (MCD to induce NASH) or a standard diet (as a control). Animal experiments and assessment of NAFLD and NASH were performed on C57BL / 6J mice fed a high-fat and high-sucrose diet as described above.

[0562] Study on atherosclerosis in LDL-R knockout mice fed with high cholesterol

[0563] LDL-R knockout (KO) mice were sacrificed approximately 12 weeks after initiation of the atherogenic diet, after which the heart and aorta were perfused with PBS and subsequently fixed. Atherosclerosis and biochemical parameters were measured using appropriate commercially available kits. For in vivo lipopolysaccharide (LPS) studies, mice were injected intraperitoneally with LPS, and blood was drawn from the tail vein. TNFα levels were quantified using a mouse TNFα ELISA assay. Blood cell counts were determined.

[0564] Sco2 KO / KI Studying inherited mitochondrial diseases in mice

[0565] The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof was dissolved in water and added to a standard powdered diet at an appropriate concentration. The diet was changed every three days and administered ad libitum for one month. Tissues were collected for histological analysis. For quadriceps muscle samples, the spectrophotometric activity of cI, cII, cIII, and cIV, as well as CS, was measured. NAD was extracted from the tissue using acidic and alkaline extraction methods, respectively. + , and analyzed by mass spectrometry.

[0566] Studying inherited mitochondrial diseases in gene-ablated mice

[0567] Gene-cleared and WT male mice were administered a diet (CD) or a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, admixed with CD. The mice were regularly monitored for body weight, food consumption, and physical endurance, and their motor abilities were measured. Oxygen consumption and carbon dioxide production, as well as spontaneous locomotion and feeding activity, were recorded. Tissue sections were collected and prepared from quadriceps, liver, and BAT. In situ histochemical COX and succinate dehydrogenase (SDH) activity was analyzed from frozen sections of quadriceps, ridge content in BAT and muscle was determined from electron micrographs, and citrate synthase activity was analyzed for skeletal muscle samples.

[0568] Kidney disease research

[0569] C57BL / 6J WT mice were fed a standard commercial diet and divided into four groups: control; cisplatin; a compound of formula (I) or (II) alone or a pharmaceutically acceptable salt thereof. Mice were sacrificed and tissue samples and serum were collected. Serum creatinine and BUN levels were measured and proinflammatory cytokines TNF-α, IL-1b, and IL-6 were quantified from serum or homogenates from renal tissue. Mouse kidneys were collected and stained for analysis. Lobular damage was examined and scored based on the percentage of cortical tubular necrosis. Neutrophil infiltration was quantitatively assessed on stained tissues by counting the number of neutrophils per high-power field.

[0570] Alternatively, C57BL / 6J WT mice were numbered and acclimated for a period of time and then randomly divided into different treatment groups based on their body weight. Different groups were maintained on a given diet for a period of time. Body weight measurements were obtained and food consumption was assessed. Blood was collected by retroorbital puncture under light anesthesia and used to analyze basal blood urea nitrogen (BUN).

[0571] Mice were anesthetized and placed on a surgical platform. Both kidneys were exposed via incision and the renal pedicles were closed using vascular clamps. The clamps were subsequently removed and the surgical site was sutured. Except that the occlusal clamps were not applied, the sham-operated group underwent a similar surgical procedure. Animals were monitored until they recovered from anesthesia and were returned to their breeding cages. The general clinical signs and symptoms and mortality of the animals were observed every day.

[0572] One day before termination, animals were housed independently in metabolic cages and urine was collected for the assessment of urea, creatinine, sodium, and potassium. Blood was also collected by retroorbital puncture under light anesthesia, and plasma was used to analyze blood urea nitrogen (BUN) and serum creatinine. The animals were then euthanized and organs were collected. One kidney was fixed and the other was quickly frozen and used to estimate lipid peroxidation, GSH, MPO, and SOD levels.

[0573] Study on acute kidney injury induced by ischemia / reperfusion

[0574] CD-1 (ICR) mice were treated with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof by oral gavage once daily. CD1 mice were divided into four groups: (1) juvenile mice with sham injury; (2) juvenile 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 were randomly divided into two groups: mice receiving a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, and mice receiving vehicle as a control. Serum creatinine levels were measured and BUN measurements were recorded. Renal tissue was then assessed and scored for tubular damage.

[0575] Study on cisplatin-induced acute kidney injury

[0576] C57BL6 mice were treated with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof by oral gavage once daily. The animals were allowed to recover and were sacrificed 48, 72, and 96 hours after the cisplatin injection.

[0577] Serum creatinine was measured as the primary outcome measure. Tubular damage was scored on a scale of 0 to 4 based on the percentage of tubules with necrosis, dilation, or cellular swelling: 0, less than 5%; 1, 5-25%; 2, 25-50%; 3, 50-75%; and 4, greater than 75%. All high-power fields (×400) in the cortex and outer medulla were evaluated by a pathologist in a blinded fashion.

[0578] Effects on sepsis-induced acute kidney injury

[0579] C57BL6 mice (12 to 15 weeks old) were treated with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof via IP injection following sepsis induced by cecal ligation and puncture.

[0580] Blood and kidney tissue were collected at sacrifice for measurement of primary and secondary outcomes. The primary outcome measure (at 48 hours) was serum creatinine. Secondary outcomes (at 48 hours) included markers of macrophage phenotype (IF plaques), plasma NGAL, plasma and renal markers of inflammation (IL-6, IL-18, TNF), and markers of renal injury (KIM-1, NGAL, TIMP2, and IGFBP7). Additional outcomes included cell death (IF: phospholipid binding protein V and propidium iodide; caspase 3 / 7), autophagy, biogenesis (PGC-1α, mitochondrial DNA), OXPHOS (complex I, III, and IV activity), Sirt1 and Sirt3 expression, and AMPK (total, P-AMPK, P-ACC, and HIF-1α).

[0581] With H&E and PAS staining, histological analysis was performed using standard protocols. Images were collected and analyzed using an optical microscope (IX71, Olympus, Tokyo, Japan) with DP analyzer software (DP70-BSW, Tokyo, Japan). Tubular injury in kidney sections stained with PAS 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%. Tubular injury scores will be used to assess protection against kidney injury.

[0582] Determination of the effect on FoxO1 phosphorylation level

[0583] AML-12 cells were treated with various concentrations of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The cells were then lysed and analyzed by SDS-PAGE / Western blotting. Blocking and antibody incubation were then performed, and the presence of each protein was detected using its specific antibody.

[0584] Inhibitory effect

[0585] The present invention also relates to a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting ACMSD activity. The method comprises contacting a cell with a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In related embodiments, the method further provides that the compound is present in an amount effective to produce a concentration sufficient to selectively inhibit ACMSD in the cell.

[0586] 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 pharmaceutically acceptable salts thereof are those that are capable of reducing or preferably inhibiting ACMSD and increasing NAD + Compounds that inhibit and / or activate SIRT and downstream targets of SIRT (such as PGC-1α, FoxO1 and / or SOD). Preferably, the inhibition is determined as the IC of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof relative to the ACMSD inhibition assay. 50 With respect to ACMSD inhibition, the preferred compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof have an IC of 50 At or below 1 μM, more preferably below 300 nM, for example below 100 nM, such as below 50 nM.

[0587] Exemplary Embodiments

[0588] Some embodiments of the present invention are described in Example 1, as follows:

[0589] Example I-1. A compound represented by formula (I):

[0590]

[0591] or a pharmaceutically acceptable salt or tautomer thereof,

[0592] in:

[0593] X is H, S, SR 2 NR 2 NR 2 R 2' 、O、OH、OR h , F, Br or Cl;

[0594] W is N or C;

[0595] (i) When W is N, then:

[0596] L is -(C(R 5 )2) m CH=CH(C(R5 )2) p -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0597] (ii) When W is C, then:

[0598] 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 -、 -(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(R5 )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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0599] Y 1 O, NR 4 or S(O) q ;

[0600] Each Y 2 are independently O, NH or S;

[0601] R 1 Not present or C6-C 10 Arylene or heteroarylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S, and wherein the C6-C 10 Arylene or heteroarylene optionally substituted with one to two R e replace;

[0602] R 2 is H or C1-C4 alkyl;

[0603] R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl; or

[0604] R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O and S;

[0605] R 3 is H or C1-C4 alkyl;

[0606] R 4 is H or C1-C4 alkyl;

[0607] Each R 5 is independently H or C1-C4 alkyl at each occurrence;

[0608] Each R 6 is independently H or C1-C4 alkyl at each occurrence;

[0609] R 7 is H, A, B or C;

[0610] 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 Tetrazodone, -(CH2) r Thiadiazole, -(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)2alkyl, where -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r Isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group,

[0611] B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR gR g '、-(CH2) r C(O)NR g R g '、-(CH2) r S(O)2NR g R g '、-(CH2) r C(O)NHS(O)2NR 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 ,

[0612] 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) rC(O)NHCN, -CH=CHCO2R x or -(C(R 6 )2) r C(O)NHS(O)2C1-C4alkyl, wherein the aryl and heteroaryl groups are substituted with one to three substituents each independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, halogen, and OH, and wherein the heterocycloalkyl group is substituted with one to two ═O or ═S;

[0613] R c H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x or -CO2R x ;

[0614] R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl;

[0615] Each R e is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN;

[0616] R f is absent, H or methyl;

[0617] R g is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or S(O)2N(C1-C6 alkyl)2;

[0618] R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10 aryl or a 5- to 7-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents independently selected from C1-C6 alkyl group, halogen, and -OH;

[0619] R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl group is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0620] R i (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl group is substituted with one or more NH2; (ii) (CH2CH2O) n CH2CH2OH; or (iii) C1-C6 alkyl, substituted by one or more substituents each independently selected from the group consisting of OH and a 4- to 7-membered heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, N or S;

[0621] R j is absent, H, C1-C6 alkyl or -CN;

[0622] Each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 aryl;

[0623] Each R y and R z are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0624] Each of m, p, q, r and t is independently 0, 1 or 2;

[0625] n is 0, 1, 2, or 3;

[0626] s is 1 or 2;

[0627] o is 0, 1, 2, 3 or 4; and

[0628] represents a single bond or a double bond; and

[0629] The restrictions are

[0630] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 When it is phenylene or pyridine, then R 7 Not -COOH;

[0631] When X is O; R fis H; W is C; R j is -CN; L is -SCH2-; R 1 is phenylene or pyridine; and R 7 When it is tetrazole, R c Not for H;

[0632] When X is O; R f is H; W is C; R j is -CN; L is -SC(R 5 )2 or -SCH2CH2-; R 1 If it does not exist, then R 7 Not COOH or tetrazole;

[0633] When X is O; R f is H; W is N; R j Does not exist; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH2- or -OCH2-; and R 1 When it is phenylene, then R 7 Not -COOH, -CH2COOH, and

[0634] When X is O; R f is H; W is N; R j Not present; L is -NHCH2-, -CH2NH- or -NH-C(O)-; and R 1 When it is phenylene, then R d Not a phenyl group.

[0635] Embodiment I-2. The compound according to embodiment I-1, wherein X is O, OH, OR h , F, Br or Cl.

[0636] Embodiment I-3. The compound according to embodiment I-1, wherein X is H, S, SR 2 NR 2 or NR 2 R 2' .

[0637] Embodiment I-4. A compound according to any one of embodiments I-1 to I-3, wherein R f Does not exist.

[0638] Embodiment I-5. A compound according to any one of embodiments I-1 to I-3, wherein R f is H or methyl.

[0639] Embodiment I-6. A compound according to any one of embodiments I-1 to I-5 wherein W is N.

[0640] Embodiment I-7. The compound according to embodiment I-6, wherein R j Does not exist.

[0641] Embodiment I-8. A compound according to any one of embodiments I-1 to I-5 wherein W is C.

[0642] Embodiment I-9. The compound according to embodiment I-8, wherein R j It is H, C1-C6 alkyl or -CN.

[0643] Embodiment I-10. Compounds according to embodiment I-8 or I-9, wherein R j It is -CN.

[0644] Embodiment I-11. A compound according to any one of embodiments I-1 to I-10, wherein R c is C1-C6 alkyl, -CN or halogen.

[0645] Embodiment I-12. A compound according to any one of embodiments I-1 to I-11, wherein R c is -CN or halogen.

[0646] Embodiment I-13. A compound according to any one of embodiments I-1 to I-12, wherein R c It is -CN.

[0647] Embodiment I-14. A compound according to any one of embodiments I-1 to I-13, wherein R d It is a methyl group.

[0648] Embodiment I-15. A compound according to any one of embodiments I-1 to I-13, wherein R d is an optionally substituted 5- to 10-membered aryl group.

[0649] Embodiment I-16. A compound according to any one of embodiments I-1 to I-13, wherein R d is an optionally substituted 5-membered or 6-membered heteroaryl group.

[0650] Embodiment I-17. A compound according to any one of embodiments I-1 to I-13, wherein R d is an optionally substituted 5-membered or 6-membered cycloalkyl group.

[0651] Embodiment I-18. A compound according to any one of embodiments I-1 to I-13, wherein R dis methyl, cyclohexyl, pyridyl, thiazolyl, phenyl or thienyl.

[0652] 19. A compound according to any one of embodiments I-1 to I-13, wherein R d is methyl, cyclohexyl, pyridyl, thiazolyl, thienyl or optionally substituted phenyl.

[0653] Embodiment I-20. A compound according to any one of embodiments I-1 to I-13, wherein R d It is a methyl group.

[0654] Embodiment I-21. A compound according to any one of embodiments I-1 to I-13, wherein R d It is -CF3.

[0655] Embodiment I-22. A compound according to any one of embodiments I-1 to I-13, wherein R d CR f F2.

[0656] Embodiment I-23. A compound according to any one of embodiments I-1 to I-13, wherein R d -(C(R 6 )2) r C6-C 10 Aryl, -(C(R 6 )2) r -5-membered or 6-membered heteroaryl, -(C(R 6 )2) r - 5-membered or 6-membered cycloalkyl group.

[0657] Embodiment I-24. A compound according to any one of embodiments I-1 to I-13, wherein R d -(C(R 6 )2) r C6-C 10 Aryl.

[0658] Embodiment I-25. A compound according to any one of Embodiments I-1 to I-24, wherein L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p -.

[0659] Embodiment 1-26. The compound according to embodiment 1-25, wherein Y 1 For S.

[0660] Embodiment I-27. A compound according to any one of Embodiments I-1 to I-24, wherein L is -(C(R5 )2) m NR 3 C=(O)(C(R 5 )2) p -or-(C(R 5 )2) m Y 1 (C(R 5 )2) p -cyclopropyl-.

[0661] Embodiment I-28. A compound according to any one of embodiments I-1 to I-27, wherein R 1 C6-C 10 Arylene.

[0662] Embodiment I-29. A compound according to any one of embodiments I-1 to I-27, wherein R 1 It is a heteroarylene group.

[0663] Embodiment I-30. A compound according to any one of embodiments I-1 to I-27, wherein R 1 Does not exist.

[0664] Embodiment I-31. A compound according to any one of embodiments I-1 to I-30, wherein R 7 It is A.

[0665] Embodiment I-32. Compounds according to Embodiment I-31, wherein A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r The tetrazole is optionally substituted with a C1-C6 alkyl group.

[0666] Embodiment I-33. A compound according to any one of embodiments I-1 to I-30, wherein R 7 For B.

[0667] Embodiment 1-34. Compounds according to Embodiment 1-31, wherein B is -(CH2) r C(O)NR g R g 'or -(CH2) r S(O)2NR g R g ',

[0668] Embodiment I-35. A compound according to any one of embodiments I-1 to I-30, wherein R 7 For C.

[0669] Embodiment 1-36. Compounds according to Embodiment 1-31, wherein C is -(CH2) r CN, -(CH2) s OH or -(C(R 6 )2) r C6-C 10 Aryl, wherein the aryl group is substituted with one to three substituents each independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH.

[0670] Embodiment 1-37. A compound or a pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of:

[0671]

[0672]

[0673]

[0674]

[0675]

[0676] Embodiment 1-38. A compound or a pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of:

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686] Embodiment 1-39. A pharmaceutical composition comprising the compound according to any one of Embodiments 1-1 to 1-38 or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0687] Embodiment 1-40. The pharmaceutical composition of embodiment 1-39, comprising one or more additional therapeutic agents.

[0688] Embodiment 1-41. A method of treating, preventing, or reducing the risk of a disease or condition inhibited by α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to the disease or condition a therapeutically effective amount of one or more compounds according to any one of Embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof.

[0689] Example I-42. A method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) level or a method for reducing the risk of a disease or condition, comprising administering to a patient suffering from or susceptible to a disease or condition associated with decreased NAD + administering a therapeutically effective amount of one or more compounds according to any one of Examples I-1 to I-38, or a pharmaceutically acceptable salt thereof, to an individual suffering from a disease or condition associated with decreased levels of adenomatous polyposis.

[0690] Example 1-43. The method according to any one of Examples 1-41 to 1-42, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and α1-antitrypsin deficiency.

[0691] Embodiment 1-44. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to an individual suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds according to any one of embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, said one or more compounds increasing intracellular nicotinamide adenine dinucleotide (NAD + ).

[0692] Embodiment 1-45. The method of embodiment 1-44, wherein the disorder associated with mitochondrial dysfunction is a hereditary mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[0693] Embodiment 1-46. The method of embodiment 1-45, wherein the common metabolic disorder is obesity or type II diabetes.

[0694] Embodiment 1-47. A method of promoting oxidative metabolism, comprising administering to an individual suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds according to any one of embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, wherein the one or more compounds increase intracellular nicotinamide adenine dinucleotide (NAD + ).

[0695] 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.

[0696] Embodiment I-49. A compound according to any one of embodiments I-1 to I-38 or a pharmaceutically acceptable salt thereof for use in treating or preventing nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0697] Embodiment I-50. A compound according to any one 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.

[0698] Embodiment I-51. The compound according to any one of Embodiments I-1 to I-38, or a pharmaceutically acceptable salt thereof, for use in promoting oxidative metabolism.

[0699] Embodiment 1-52. Use of a compound according to any one of Embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0700] Embodiment I-53. A use of a compound according to any one of embodiments I-1 to I-38 or a pharmaceutically acceptable salt thereof for treating or preventing nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0701] Embodiment 1-54. Use of a compound according to any one of Embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0702] Embodiment I-55. Use of the compound according to any one of Embodiments I-1 to I-38 or a pharmaceutically acceptable salt thereof for promoting oxidative metabolism.

[0703] Embodiment 1-56. Use of a compound according to any one of Embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0704] Embodiment I-57. A use of a compound according to any one of embodiments I-1 to I-38 or a pharmaceutically acceptable salt thereof for the manufacture of a method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0705] Embodiment 1-58. Use of a compound according to any one of Embodiments 1-1 to 1-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0706] Embodiment I-59. Use of the compound according to any one of Embodiments I-1 to I-38 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting oxidative metabolism.

[0707] Example 1-60. A method of treating, preventing, or reducing the risk of a disease or condition inhibited by α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to the disease or condition a therapeutically effective amount of the pharmaceutical composition of Example 1-39.

[0708] Example I-61. A method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) level or a method for reducing the risk of a disease or condition, comprising administering to a patient suffering from or susceptible to a disease or condition associated with decreased NAD + administering a therapeutically effective amount of the pharmaceutical composition according to Examples 1-39 to an individual suffering from a disease or condition associated with decreased serum leukemia.

[0709] Example 1-62. The method according to any one of Examples 1-60 to 1-61, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and α1-antitrypsin deficiency.

[0710] Example 1-63. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering a therapeutically effective amount of the pharmaceutical composition of Example 1-39 to a subject suffering from or susceptible to a metabolic disorder.

[0711] Embodiment 1-64. The method of embodiment 1-63, wherein the disorder associated with mitochondrial dysfunction is a hereditary mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[0712] Example I-65. A method as described in technical solution 64, wherein the common metabolic disorder is obesity or type II diabetes.

[0713] Embodiment 1-66. A method of promoting oxidative metabolism, comprising administering a therapeutically effective amount of the pharmaceutical composition of embodiment 1-39 to a subject suffering from or susceptible to a metabolic disorder.

[0714] Embodiment 1-67. The pharmaceutical composition according to embodiment 1-39, for use as a medicament.

[0715] Example 1-68. The pharmaceutical composition according to Example 1-39 is used for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0716] Embodiment 1-69. The pharmaceutical composition of embodiment 1-39, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0717] Embodiment I-70. The pharmaceutical composition according to embodiment I-39, which is used for promoting oxidative metabolism.

[0718] Embodiment 1-71. Use of the pharmaceutical composition according to embodiment 1-39 for treating, preventing or reducing the risk of a disease or condition associated with α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0719] Example 1-72. A use of the pharmaceutical composition according to Example 1-39 for treating, preventing, and preventing nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0720] Embodiment 1-73. Use of the pharmaceutical composition of embodiment 1-39 for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0721] Example I-74. Use of the pharmaceutical composition according to Example I-39 for promoting oxidative metabolism.

[0722] Example 1-75. Use of the pharmaceutical composition according to Example 1-39 for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0723] Example 1-76. A use of the pharmaceutical composition according to Example 1-39 for the manufacture of a pharmaceutical composition for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0724] Embodiment 1-77. Use of the pharmaceutical composition of embodiment 1-39 for the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0725] Example I-78. Use of the pharmaceutical composition according to Example I-39 for manufacturing a medicament for promoting oxidative metabolism.

[0726] Example II-1. A compound represented by formula (II):

[0727]

[0728] or a pharmaceutically acceptable salt or tautomer thereof, wherein:

[0729] X is H, S, SR 2 NR 2 NR2 R 2' 、O、OH、OR h , F, Br or Cl;

[0730] W is N or C;

[0731] (i) When W is N, then: L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0732] (ii) When W is C, then: 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 -、 -(C(R5 )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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0733] Y 1 O, NR 4 or S(O) q ;

[0734] Each Y 2 are independently O, NH or S;

[0735] R 1 Does not exist, C6-C 10 Arylene, heteroarylene or C3-C8 cycloalkylene, wherein the heteroarylene includes one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O and S, and wherein the C6-C 10 Arylene, heteroarylene and C3-C8 cycloalkylene are optionally substituted by one or two R e replace;

[0736] R 2 is H or C1-C4 alkyl;

[0737] R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl; or

[0738] R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O and S;

[0739] R 3 is H or C1-C4 alkyl;

[0740] R 4 is H or C1-C4 alkyl;

[0741] Each R 5 is independently H or C1-C4 alkyl at each occurrence;

[0742] Each R 6 is independently H or C1-C4 alkyl at each occurrence;

[0743] R 7 is H, A, B or C;

[0744] 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 Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(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)2alkyl, wherein -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6)2) r Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(C(R 6 )2) r Isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group,

[0745] B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g '、-(C(R 6 )2) r C(O)NR g R g '、-(C(R 6 )2) r S(O)2NR g R g '、-(C(R 6 )2) r C(O)NHS(O)2NR 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 ,

[0746] 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-C4alkyl, wherein the aryl and heteroaryl groups are substituted with one to three substituents each independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, halogen, and OH, and wherein the heterocycloalkyl group is substituted with one to two ═O or ═S;

[0747] R c H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x or -CO2R x ;

[0748] R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl;

[0749] Each R eis independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN;

[0750] R f is absent, H or methyl;

[0751] R g is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or S(O)2N(C1-C6 alkyl)2;

[0752] R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10 aryl or a 5- to 7-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents independently selected from C1-C6 alkyl group, halogen, and -OH;

[0753] R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl group is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0754] R i (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl group is substituted with one or more NH2; (ii) (CH2CH2O) n CH2CH2OH; or (iii) C1-C6 alkyl, substituted by one or more substituents each independently selected from the group consisting of OH and a 4- to 7-membered heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, N or S;

[0755] R j is absent, H, C1-C6 alkyl or -CN;

[0756] Each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 aryl;

[0757] Each R y and R zare independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0758] Each of m, p, q, r and t is independently 0, 1 or 2;

[0759] n is 0, 1, 2, or 3;

[0760] s is 1 or 2;

[0761] o is 0, 1, 2, 3 or 4; and

[0762] represents a single bond or a double bond; and

[0763] The restrictions are

[0764] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 When it is phenylene or pyridine, then R 7 Not -COOH;

[0765] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 is phenylene or pyridine; and R 7 When it is tetrazole, R c Not for H;

[0766] When X is O; R f is H; W is C; R j is -CN; L is -SC(R 5 )2 or -SCH2CH2-; R 1 If it does not exist, then R 7 Not COOH or tetrazole;

[0767] When X is O; R f is H; W is N; R j Does not exist; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH2- or -OCH2-; and R 1 When it is phenylene, then R 7 Not -COOH, -CH2COOH, and

[0768] When X is O; R f is H; W is N; R j Not present; L is -NHCH2-, -CH2NH- or -NH-C(O)-; and R 1When it is phenylene, then R d Not a phenyl group.

[0769] Example II-2. A compound represented by formula (I):

[0770]

[0771] or a pharmaceutically acceptable salt or tautomer thereof,

[0772] in:

[0773] X is H, S, SR 2 NR 2 NR 2 R 2' 、O、OH、OR h , F, Br or Cl;

[0774] W is N or C;

[0775] (i) When W is N, then:

[0776] L is -(C(R 5 )2) m CH=CH(C(R 5 )2) p -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5)2) p -;

[0777] (ii) When W is C, then:

[0778] 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 -、 -(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 Pyridyl (C (R 5 )2) p -or-(C(R 5 )2) m Thienyl (C (R 5 )2) p -;

[0779] Y 1 O, NR 4 or S(O) q ;

[0780] Each Y 2 are independently O, NH or S;

[0781] R 1 Not present or C6-C 10 Arylene or heteroarylene, wherein heteroarylene includes one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O and S, and wherein C6-C 10 Arylene or heteroarylene optionally substituted with one to two R e replace;

[0782] R 2 is H or C1-C4 alkyl;

[0783] R 2' is H, C1-C4 alkyl or C3-C7 cycloalkyl; or

[0784] R 2 and R 2' Together with the nitrogen atom to which it is attached, it forms a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 additional heteroatoms selected from N, O and S;

[0785] R 3 is H or C1-C4 alkyl;

[0786] R 4 is H or C1-C4 alkyl;

[0787] Each R 5 is independently H or C1-C4 alkyl at each occurrence;

[0788] Each R 6 is independently H or C1-C4 alkyl at each occurrence;

[0789] R 7 is H, A, B or C;

[0790] 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 Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r Isoxazol-3-ol, -(CH2) r P(O)(OH)OR x 、-(CH2) r S(O)2OH, -(CH2) rC(O)NHCN or -(CH2) r C(O)NHS(O)2alkyl, where -(CH2) r Tetrazole, -(CH2) r Oxadiazolone, -(CH2) r Tetrazodone, -(CH2) r Thiadiazole, -(CH2) r Isoxazol-3-ol is optionally substituted with a C1-C6 alkyl group,

[0791] B is -(C(R 6 )2) r S(O)2OC1-C4alkyl, -O(C(R 6 )2) r S(O)2OC1-C4alkyl, -Y 2 (C(R 6 )2) r C(O)NR g R g ', -Y 2 (C(R 6 )2) r S(O)2NR g R g '、-(CH2) r C(O)NR g R g '、-(CH2) r S(O)2NR g R g '、-(CH2) r C(O)NHS(O)2NR 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 xor -O(C(R 6 )2) r P(O)2OR x ,

[0792] 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-C4alkyl, wherein the aryl and heteroaryl groups are substituted with one to three substituents each independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, halogen, and OH, and wherein the heterocycloalkyl group is substituted with one to two ═O or ═S;

[0793] R c H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN, -OR x or -CO2R x ;

[0794] R d Methyl, CF3, CR f F2, -(C(R 6 )2) t C6-C 10 Aryl, -(C(R 6 )2) t -5-membered or 6-membered heteroaryl, -(C(R 6 )2) t -5-membered or 6-membered cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, or optionally substituted 5-membered or 6-membered cycloalkyl;

[0795] Each Re is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -NHR z , -OH or -CN;

[0796] R f is absent, H or methyl;

[0797] R g is H, C1-C6 alkyl, OH, -S(O)2(C1-C6 alkyl) or S(O)2N(C1-C6 alkyl)2;

[0798] R g ' is H, C1-C6 alkyl, C3-C7 cycloalkyl, a 4- to 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from N, O and S, C6-C 10 aryl or a 5- to 7-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents independently selected from C1-C6 alkyl group, halogen, and -OH;

[0799] R h is H, C1-C4 alkyl, or a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted with one or more substituents each independently selected from NH2, C1-C4 alkylamino, C1-C4 dialkylamino, and C(O)NH2; and wherein the heterocycloalkyl group is optionally substituted with one or more substituents each independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0800] R i (i)-(CH2) s OC(O)C1-C6 alkyl, wherein the alkyl group is substituted with one or more NH2; (ii) (CH2CH2O) n CH2CH2OH; or (iii) C1-C6 alkyl, substituted by one or more substituents each independently selected from the group consisting of OH and a 4- to 7-membered heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, N or S;

[0801] R j is absent, H, C1-C6 alkyl or -CN;

[0802] Each R x Each occurrence is independently H, C1-C6 alkyl or C6-C 10 aryl;

[0803] Each R y and Rz are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0804] Each of m, p, q, r and t is independently 0, 1 or 2;

[0805] n is 0, 1, 2, or 3;

[0806] s is 1 or 2;

[0807] o is 0, 1, 2, 3 or 4; and

[0808] represents a single bond or a double bond; and

[0809] The restrictions are

[0810] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 When it is phenylene or pyridine, then R 7 Not -COOH;

[0811] When X is O; R f is H; W is C; R j is -CN; L is -SCH2-; R 1 is phenylene or pyridine; and R 7 When it is tetrazole, R c Not for H;

[0812] When X is O; R f is H; W is C; R j is -CN; L is -SC(R 5 )2 or -SCH2CH2-; R 1 If it does not exist, then R 7 Not COOH or tetrazole;

[0813] When X is O; R f is H; W is N; R j Does not exist; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH2- or -OCH2-; and R 1 When it is phenylene, then R 7 Not -COOH, -CH2COOH, and

[0814] When X is O; R f is H; W is N; R j Not present; L is -NHCH2-, -CH2NH- or -NH-C(O)-; and R1 When it is phenylene, then R d Not a phenyl group.

[0815] Embodiment II-3. The compound according to embodiment II-1 or II-2, wherein X is O, OH, OR h , F, Br or Cl.

[0816] Embodiment II-4. Compounds according to embodiment II-1 or II-2, wherein X is H, S, SR 2 NR 2 or NR 2 R 2' .

[0817] Embodiment II-5. A compound according to any one of embodiments II-1 to II-4, wherein R f Does not exist.

[0818] Embodiment II-6. A compound according to any one of embodiments II-1 to II-4, wherein R f is H or methyl.

[0819] Embodiment II-7. A compound according to any one of embodiments II-1 to II-6 wherein W is N.

[0820] Embodiment II-8. The compound according to embodiment II-7, wherein R j Does not exist.

[0821] Embodiment II-9. The compound of any one of Embodiments II-1 to II-6 wherein W is C.

[0822] Embodiment II-10. The compound according to embodiment II-9, wherein R j It is H, C1-C6 alkyl or -CN.

[0823] Embodiment II-11. Compounds according to embodiment II-9 or II-10, wherein R j It is -CN.

[0824] Embodiment II-12. A compound according to any one of Embodiments II-1 to II-11, wherein R c is C1-C6 alkyl, -CN or halogen.

[0825] Embodiment II-13. A compound according to any one of Embodiments II-1 to II-12, wherein R c is -CN or halogen.

[0826] Embodiment II-14. A compound according to any one of Embodiments II-1 to II-12, wherein R c It is -CN.

[0827] Embodiment II-15. A compound according to any one of Embodiments II-1 to II-14, wherein R d It is a methyl group.

[0828] Embodiment II-16. A compound according to any one of Embodiments II-1 to II-14, wherein R d is an optionally substituted 5- to 10-membered aryl group.

[0829] Embodiment II-17. A compound according to any one of Embodiments II-1 to II-14, wherein R d is an optionally substituted 5-membered or 6-membered heteroaryl group.

[0830] Embodiment II-18. A compound according to any one of Embodiments II-1 to II-14, wherein R d is an optionally substituted 5-membered or 6-membered cycloalkyl group.

[0831] Embodiment II-19. A compound according to any one of embodiments II-1 to II-14, wherein R d is methyl, cyclohexyl, pyridyl, thiazolyl, phenyl or thienyl.

[0832] Embodiment II-20. A compound according to any one of embodiments II-1 to II-14, wherein R d is methyl, cyclohexyl, pyridyl, thiazolyl, thienyl or optionally substituted phenyl.

[0833] Embodiment II-21. A compound according to any one of embodiments II-1 to II-14, wherein R d It is a methyl group.

[0834] Embodiment II-22. A compound according to any one of embodiments II-1 to II-14, wherein R d It is -CF3.

[0835] Embodiment II-23. A compound according to any one of embodiments II-1 to II-14, wherein R d CR f F2.

[0836] Embodiment II-24. A compound according to any one of Embodiments II-1 to II-14, wherein R d -(C(R 6 )2) r C6-C10 Aryl, -(C(R 6 )2) r -5-membered or 6-membered heteroaryl, -(C(R 6 )2) r - a 5-membered or 6-membered cycloalkyl group.

[0837] Embodiment II-25. A compound according to any one of Embodiments II-1 to II-14, wherein R d -(C(R 6 )2) r C6-C 10 Aryl.

[0838] Embodiment II-26. A compound according to any one of Embodiments II-1 to II-25, wherein L is -(C(R 5 )2) m Y 1 (C(R 5 )2) p -.

[0839] Embodiment II-27. The compound according to embodiment II-26, wherein Y 1 For S.

[0840] Embodiment II-28. A compound according to any one of Embodiments II-1 to II-25, wherein 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 -cyclopropyl-.

[0841] Embodiment II-29. A compound according to any one of Embodiments II-1 to II-28, wherein R 1 C6-C 10 Arylene.

[0842] Embodiment II-30. A compound according to any one of embodiments II-1 to II-28, wherein R 1 It is a heteroarylene group.

[0843] Embodiment II-31. A compound according to any one of Embodiments II-1 to II-28, wherein R 1 Does not exist.

[0844] Embodiment II-32. A compound according to any one of Embodiments II-1 to II-31, wherein R 7 It is A.

[0845] Embodiment II-33. The compound according to embodiment II-32, wherein A is -(C(R 6 )2) r CO2R x or -(CH2) r Tetrazolyl, where -(CH2) r The tetrazole is optionally substituted with a C1-C6 alkyl group.

[0846] Embodiment II-34. A compound according to any one of Embodiments II-1 to II-31, wherein R 7 For B.

[0847] Embodiment II-35. Compounds according to Embodiment II-32, wherein B is -(CH2) r C(O)NR g R g 'or -(CH2) r S(O)2NR g R g '.

[0848] Embodiment II-36. A compound according to any one of Embodiments II-1 to II-31, wherein R 7 For C.

[0849] Embodiment II-37. Compounds according to Embodiment II-32, wherein C is -(CH2) r CN, -(CH2) s OH or -(C(R 6 )2) r C6-C 10 Aryl, wherein the aryl group is substituted with one to three substituents each independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, and OH.

[0850] Example II-38. A compound or a pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of:

[0851]

[0852]

[0853]

[0854]

[0855]

[0856] Example II-39. A compound or a pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of:

[0857]

[0858]

[0859]

[0860] Embodiment II-40. A compound or a pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of:

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872] Embodiment II-41. A pharmaceutical composition comprising the compound according to any one of Embodiments II-1 to II-40 or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

[0873] Embodiment II-42. The pharmaceutical composition of embodiment II-41, comprising one or more additional therapeutic agents.

[0874] Embodiment II-43. A method of treating, preventing, or reducing the risk of a disease or condition inhibited by α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to an individual suffering from or susceptible to the disease or condition 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.

[0875] Example II-44. A method for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) level or a method for reducing the risk of a disease or condition, comprising administering to a patient suffering from or susceptible to a disease or condition associated with decreased NAD + administering a therapeutically effective amount of one or more compounds according to any one of Examples II-1 to II-40, or a pharmaceutically acceptable salt thereof, to an individual suffering from a disease or condition associated with decreased levels of adenomatous polymorphisms (e.g., leukemia, leukemia, or rheumatoid arthritis).

[0876] Example II-45. A method according to any one of Examples II-43 to II-44, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and α1-antitrypsin deficiency.

[0877] Embodiment II-46. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to an individual suffering from or susceptible to a metabolic 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, wherein the one or more compounds increase intracellular nicotinamide adenine dinucleotide (NAD + ).

[0878] Embodiment II-47. The method of embodiment II-46, wherein the disorder associated with mitochondrial dysfunction is a hereditary mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[0879] Embodiment II-48. The method of embodiment II-47, wherein the common metabolic disorder is obesity or type II diabetes.

[0880] Example II-49. A method of promoting oxidative metabolism, comprising administering to an individual suffering from or susceptible to a metabolic disorder a therapeutically effective amount of one or more compounds according to any one of Examples II-1 to II-40, or a pharmaceutically acceptable salt thereof, wherein the one or more compounds increase intracellular nicotinamide adenine dinucleotide (NAD + ).

[0881] Embodiment II-50. The compound according to any one of Embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0882] Embodiment II-51. A compound according to any one of embodiments II-1 to II-40 or a pharmaceutically acceptable salt thereof for use in treating or preventing nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0883] Embodiment II-52. A compound according to any one 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.

[0884] Embodiment II-53. The compound according to any one of Embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for use in promoting oxidative metabolism.

[0885] Embodiment II-54. A use of a compound according to any one of Embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0886] Example II-55. A use of a compound according to any one of Examples II-1 to II-40 or a pharmaceutically acceptable salt thereof for treating or preventing nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0887] Embodiment II-56. Use of a compound according to any one 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.

[0888] Embodiment II-57. Use of the compound according to any one of Embodiments II-1 to II-40 or a pharmaceutically acceptable salt thereof for promoting oxidative metabolism.

[0889] Example II-58. Use of a compound according to any one of Examples II-1 to II-40, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0890] Example II-59. A use of a compound according to any one of Examples II-1 to II-40 or a pharmaceutically acceptable salt thereof for the manufacture of a method for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0891] Embodiment II-60. Use of a compound according to any one of Embodiments II-1 to II-40, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0892] Example II-61. Use of the compound according to any one of Examples II-1 to II-40 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting oxidative metabolism.

[0893] Example II-62. A method for treating, preventing, or reducing the risk of a disease or condition inhibited by α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or susceptible to the disease or condition a therapeutically effective amount of the pharmaceutical composition of Example II-41.

[0894] Example II-63. A method for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) level or a method for reducing the risk of a disease or condition, comprising administering to a patient suffering from or susceptible to a disease or condition associated with decreased NAD + administering a therapeutically effective amount of the pharmaceutical composition according to Example II-41 to an individual suffering from a disease or condition associated with decreased serum leukemia level.

[0895] Example II-64. A method according to any one of Examples II-62 to II-63, wherein the disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and α1-antitrypsin deficiency.

[0896] Example II-65. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering a therapeutically effective amount of the pharmaceutical composition of Example II-41 to a subject suffering from or susceptible to a metabolic disorder.

[0897] Embodiment II-66. The method of embodiment II-65, wherein the disorder associated with mitochondrial dysfunction is a hereditary mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[0898] Embodiment II-67. The method of embodiment II-66, wherein the common metabolic disorder is obesity or type II diabetes.

[0899] Example II-68. A method of promoting oxidative metabolism, comprising administering a therapeutically effective amount of the pharmaceutical composition according to Example II-41 to a subject suffering from or susceptible to a metabolic disorder.

[0900] Embodiment II-69. The pharmaceutical composition according to embodiment II-41, for use as a medicament.

[0901] Example II-70. The pharmaceutical composition according to Example II-41 is used for treating, preventing and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0902] Embodiment II-71. The pharmaceutical composition of embodiment II-41, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0903] Example II-72. The pharmaceutical composition according to Example II-41, which is used for promoting oxidative metabolism.

[0904] Example II-73. Use of the pharmaceutical composition according to Example II-41 for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyadipate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0905] Example II-74. A use of the pharmaceutical composition according to Example II-41 for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0906] Embodiment II-75. Use of the pharmaceutical composition according to embodiment II-41 for treating, preventing or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0907] Example II-76. Use of the pharmaceutical composition according to Example II-41 for promoting oxidative metabolism.

[0908] Example II-77. Use of the pharmaceutical composition according to Example II-41 for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction.

[0909] Example II-78. A use of the pharmaceutical composition according to Example II-41 for the manufacture of a pharmaceutical composition for treating, preventing, and treating nicotinamide adenine dinucleotide (NAD + ) levels or reduce the risk of a disease or condition associated with the disease or condition.

[0910] Example II-79. Use of the pharmaceutical composition according to Example II-41 for the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[0911] Example II-80. Use of the pharmaceutical composition according to Example II-41 for the manufacture of a medicament for promoting oxidative metabolism.

[0912] Examples

[0913] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present invention will become apparent from different examples. The examples provided illustrate different components and methods applicable to practicing the present invention. In general, the present invention extends to any novel feature or any novel feature combination disclosed in the specification (including the accompanying claims and drawings). The examples do not limit the claimed invention. Therefore, the features, wholes, characteristics, compounds or chemical moieties described in conjunction with a particular aspect, embodiment or example of the present invention should be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. Based on the present invention, those skilled in the art can identify and adopt other components and methods applicable to practicing the present invention. In addition, unless otherwise indicated, any feature disclosed herein can be replaced by alternative features for the same or similar purposes.

[0914] The invention will now be described, by way of example only, with reference to the following examples:

[0915] example

[0916] Compound preparation

[0917] General methods and materials

[0918] All chemicals were purchased from Sigma-Aldrich, Alfa Aesar. Recorded at 200 and 400 MHz 1 H NMR spectra were recorded at 100.6 and 50.3 MHz using deuterated solvents as indicated below. 13 C NMR spectrum. TLC was performed on aluminum-backed silica plates (silica gel 60F254). All reactions were carried out under a nitrogen atmosphere using distilled solvents. All test compounds were found to have a purity of >95% as determined by HPLC analysis. HPLC-grade water was obtained from a serial Milli-Ro / Milli-Q device. 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 syringe with a 20 μL stainless steel loop.

[0919] The abbreviations used in the following examples and elsewhere in this document are:

[0920] Ac2O acetic anhydride

[0921] AcOH acetic acid

[0922] AIBN Azobisisobutyronitrile

[0923] atm atmospheric pressure

[0924] br broad peak

[0925] DIPEA N,N-Diisopropylethylamine

[0926] DCM dichloromethane

[0927] DME dimethoxyethane

[0928] DMF N,N-dimethylformamide

[0929] DMSO dimethyl sulfoxide

[0930] BPO Benzoyl Peroxide

[0931] EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0932] ESI electrospray ionization

[0933] EtOAc

[0934] EtO2 diethyl ether

[0935] EtOH

[0936] EtO - Na + Sodium ethoxide

[0937] Et3NH + Cl - Triethylamine hydrochloride

[0938] h hour

[0939] HPLC high-performance liquid chromatography

[0940] LCMS liquid chromatography mass spectrometry

[0941] m multiplet

[0942] MeI iodomethane

[0943] MeOH methanol

[0944] MHz Megahertz

[0945] min

[0946] MS molecular sieves

[0947] MTBE 2-methoxy-2-methylpropane

[0948] MW microwave

[0949] NBS N-bromosuccinamide

[0950] NMR Nuclear Magnetic Resonance

[0951] PET petroleum ether

[0952] ppm parts per million

[0953] p-TSA p-toluenesulfonic acid

[0954] rt room temperature

[0955] TLC thin layer chromatography

[0956] Example 1: Intermediate 1.4.4-Oxo-6-thiophen-2-yl-2-thione-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile

[0957]

[0958] 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 KCO (1.57 g, 11.44 mmol). Stirring was continued overnight under reflux. After cooling, the formed slightly yellow solid was collected, dissolved with hot water and filtered again. The aqueous phase was acidified to pH 1, the precipitate was filtered and dried under reduced pressure. The title compound 1.4 (1 g, 4.25 mmol) was obtained as a slightly yellow solid. Yield 49%. 1 H NMR (200MHz, DMSO-d6) δ7.22 (m, 1H), 7.68 (m, 1H), 7.85 (d, J = 4.8Hz, 1H), 8.05 (s, 1H).

[0959] Example 2: Intermediate 2.2. Sodium 6-oxo-4-trifluoromethyl-1,6-dihydro-pyrimidine-2-thiolate

[0960]

[0961] Under N2 atmosphere, sodium (0.35 g, 16.29 mmol) was dissolved in pure EtOH (25 mL). To the resulting solution were added ethyl trifluoroacetoacetate 2.1 (1.59 mL, 10.86 mmol) and thiourea 1.2 (0.91 g, 11.94 g). The mixture was stirred and refluxed for 4 h. After cooling at room temperature, the resulting precipitate was collected by vacuum filtration and washed with cold EtOH (2 x 5 mL) to afford (1.34 g, 6.14 mmol) of intermediate 2.2. Yield: 38%. MS-ESI (-) m / z: 194.8 [MH].

[0962] Example 3: Intermediate 3.3. 2-Mercapto-6-oxo-4-phenyl-1,6-dihydro-pyridine-3-carbonitrile

[0963]

[0964] To a stirred solution of KOH (0.58 g, 10.41 mmol) in pure EtOH (20 mL) was 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 and refluxed for 3 hours. It was then cooled at room temperature and concentrated under reduced pressure. The crude product was poured into H2O (20 mL) and washed with AcOEt (2×15 mL). The organic phase was acidified to pH=2 by adding 37% aqueous HCl solution, and the resulting precipitate was collected by filtration under vacuum and washed with H2O (2×5 mL). The solid was then triturated with AcMe to give intermediate 3.3 (0.49 g, 2.14 mmol) as a slightly yellow solid. Yield 21%. MS-ESI (-) m / z: 227.3 [MH] -

[0965] Example 4: Intermediate 4.2.4-Benzyl-2-mercapto-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile

[0966]

[0967] 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. A white solid was collected and dissolved in water. The pH was adjusted to 3 by adding 3N 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 light yellow solid. Yield: 20%. 1 H NMR (200MHz, DMSO-d6) δ3.93 (s, 2H), 7.26-7.41 (m, 5H), 13.15 (brs, 1H).

[0968] Example 5: Intermediate 5.2. 2-Mercapto-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridine-3-carbonitrile

[0969]

[0970] To a stirred solution of KOH (0.28 g, 5.04 mmol) in pure EtOH (10 mL) was added 3-oxo-3-thiophen-2-yl-propionic acid ethyl ester 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 hours. It was then cooled at room temperature, and the formed precipitate was collected by filtration under vacuum and washed with EtOH (2×5 mL) to give intermediate 5.2 (0.17 g, 0.72 mmol) as a slightly yellow solid. Yield 12%. MS-ESI (-) m / z: 233.3 [MH] - .

[0971] Example 6: Intermediate 6.4. 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydro-pyridine-3,5-dicarbonitrile

[0972]

[0973] Step 1: 2-Cyano-3-thiophen-2-yl-acrylic acid ethyl ester (6.1)

[0974] To a solution of thiophene-2-carboxaldehyde 1.3 (1 g, 8.9 mmol) and 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 under vacuum. The crude product was dissolved in water and extracted with EtOAc (3 × 50 mL). The organic phase was collected, washed with brine and dried over anhydrous Na2SO4. The title intermediate 6.1 (1.3 g, 6.27 mmol) was obtained as a white solid. Yield 70%.

[0975] Step 2: 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydro-pyridine-3,5-dicarbonitrile (6.2)

[0976] 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. After cooling, a red precipitate was 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) δ7.24-7.27(m,1H),7.53-7.55(m,1H),7.94-7.95(m,1H),13.0(brs,1H).

[0977] Example 7: Intermediate 7.1. Potassium 3-cyano-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridine-2-thiol

[0978]

[0979] To a stirred solution of KOH (0.91 g, 16.29 mmol) in pure 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 and refluxed for 7 hours. It was then cooled and allowed to stand overnight at room temperature. The large amount of precipitate thus formed 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 [MH] -

[0980] Example 8: Intermediate 8.3. (3-Bromomethyl-phenyl)-acetic acid ethyl ester

[0981]

[0982] Step 1: m-Tolyl-ethyl acetate (8.2)

[0983] To a solution of 8.1 (15 g, 99.88 mmol) in EtOH (pure) (400 mL) was added HCl (concentrated) (0.3 mL, 9.9 mmol) and stirring was continued at reflux for 4 h. The volatiles were removed under reduced pressure. The crude product was dissolved in DCM (200 mL), dried over Na2SO4 and evaporated under reduced pressure. The title compound 8.2 (17 g, 95.39 mmol) was obtained as a colorless oil. Yield 96%. 1 H NMR (200MHz, CDCl3) δ1.28 (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+).

[0984] Step 2: (3-Bromomethyl-phenyl)-ethyl acetate (8.3)

[0985] 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 CH 3 CN (300 mL). Stirring was continued for 4 h under reflux. Volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc (300 mL) and a saturated aqueous solution of NaHCO 3 (300 mL). The organic phase was collected and dried over Na 2 SO 4. The crude product was purified by flash chromatography (dry loading) using 2% to 4% PET / Et 2 O elution for the product. The title compound 8.3 (10 g, 38.89 mmol) was obtained as a slightly yellow oil. Yield 66%. 1 H NMR (200MHz, CDCl3) δ1.27(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).

[0986] Example 9: Intermediate 9.3.3-Bromomethyl-benzamide

[0987]

[0988] Step 1: 3-Methyl-benzamide (9.2)

[0989] 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, 200 W for 20 minutes. After cooling, the resulting white precipitate was collected and dried under reduced pressure to afford the title compound 9.2 (870 mg, 6.4 mmol) as white crystals. Yield: 50%. GC-MS (m / z): 135.1 (M+).

[0990] Step 2: 3-Bromomethyl-benzamide (9.3)

[0991] 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. Volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (300 mL) and a saturated aqueous solution of 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 slightly yellow solid. Yield: 53%.

[0992] Example 10: Intermediate 10.4.3'-Bromomethyl-3,5-difluoro-4-methoxy-biphenyl

[0993]

[0994] Step 1: 3,5-Difluoro-4-methoxy-3'-methyl-biphenyl (10.3)

[0995] To a solution of compound 10.1 (0.18 mL, 1.33 mmol) in DME (15 mL) was added tetrapalladium (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 for 4 h under reflux. The solvent was removed under reduced pressure. The crude residue was dissolved 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. The pure title compound 10.3 (282 mg, 1.22 mmol) was obtained as a colorless oil and used in the next step without further purification. Yield 91%. 1 H NMR (400MHz, CDCl3) δ2.43 (s, 3H), 4.04 (s, 3H), 7.14 (d, J = 9.3, 2H), 7.32-7.33 (m, 4H).

[0996] Step 2: 3'-Bromomethyl-3,5-difluoro-4-methoxy-biphenyl (10.4)

[0997] To a solution of intermediate 10.3 (260 mg, 1.1 mmol) in CH3CN (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 NaHCO 3(ss) The organic phase was washed with brine and dried over Na2SO4. The crude product was purified by flash chromatography using PET / Et2O as eluent to afford the title compound 10.4 (250 mg, 0.77 mmol) as a yellow oil in 72% yield. 1 H NMR (400MHz, CDCl3) δ4.06 (d, J = 3.7 Hz, 3H), 4.55 (s, 2H), 7.14 (d, J = 6.2 Hz, 1H), 7.16 (d, J = 6.1 Hz, 1H), 7.41-7.47 (m, 3H), 7.54 (s, 1H).

[0998] Example 11: Intermediate 11.2. (3-Bromomethyl-phenyl)-acetic acid

[0999]

[1000] 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 overnight at reflux. The solvent was removed under reduced pressure. The reaction was dissolved in water, extracted with EtOAc (3×20 mL), washed with brine, and dried over Na2SO4. The crude product was purified by flash chromatography eluting with CHCl2 / MeOH (3% for 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+).

[1001] Example 12: Intermediate 12.2. [3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid

[1002]

[1003] Step 1: [3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (12.1)

[1004] 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 overnight at room temperature. 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, eluting with CHCl / MeOH (10% for the product) and tearing with a mixture of EtO / acetone, the title intermediate 12.1 (200 mg, 0.52 mmol) was obtained as a pure slightly yellow solid. Yield 25%. 1 H NMR (400MHz, DMSO-d6) δ3.49 (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); 13C NMR(100MHz,DMSO-d6)δ34.3,40.9,88.5,116.8,127.6,128.9,129.1,129.8 ,130.4,131.9,135.2,135.8,137.0,139.9,159.1,161.6,165.7,172.9.HPLC 95.8%.

[1005] Step 2: [3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (12.2)

[1006] 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 afford the title intermediate 12.2 (250 mg, 0.62 mmol) as a slightly yellow solid. Yield: 79%. 1 H NMR (400MHz, DMSO-d6) δ3.53(s,2H),4.50(s,2H),7.16(d,J=7.5Hz,1H),7.27(t,J=7.4 Hz,1H),7.36-7.39(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) δ35.1,40.9,97.7,115.5,127.6,128.8,129,130.2,130.4,133.3,135.7,136,137,138.6,160.3,163.2,172.9,174.

[1007] Example 13: Intermediate 13.3.[3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid

[1008]

[1009] Step 1: 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (13.2)

[1010] 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 overnight at reflux. The volatiles were then removed under reduced pressure. The crude product was dissolved in water, washed with EtOAc, acidified to pH 1 and extracted with EtOAc (3 x 50 mL). It was shredded with hot acetone to afford the title intermediate 13.2 (45 mg, 0.12 mmol) as a slightly yellow solid. Yield 12%. 1 H NMR (400MHz, DMSO-d6) δ4.62(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)δ33.9,88.7,116.5,128.8,129.3,129.9,130.2,131.5, 132.1,133.7,135.4,137.9,139.7,159.0,161.2,165.3,167.4. HPLC: 97.2%

[1011] Step 2: 3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (13.3)

[1012] 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% for the product) to give intermediate 13.3 (120 mg, 0.3 mmol) as a slightly yellow solid. Yield 79%. 13 C NMR (100MHz, DMSO-d6) δ33.8,88.7,116.5,128.8,129.3,129.9,130.2,131.4,132.1,133.7,135.5,137.9,139.6,159,161.1,165.2,167.3;

[1013] Example 14: Intermediate 14.2.3-Bromomethyl-benzonitrile

[1014]

[1015] 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 under reflux for 16 h and the reactants were then allowed to warm to room temperature. The resulting solid was collected, washed with CCl4, and dried under reduced pressure. The title compound 14.2 (2.84 g, 14.5 mmol) was obtained as a white solid. Yield 85%. GC-) 196.9 (M+).

[1016] Example 15: Intermediate 15.1. 2-(3-Bromomethyl 1-phenyl)-ethanol

[1017]

[1018] To a solution of intermediate 11.2 (500 mg, 2.17 mmol) in THF (10 mL) was added dropwise BH3-THF (1 M in THF, 2.8 mL) 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 / H2O (1:1 v:v, 15 mL) and washed with a saturated aqueous solution of 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. The crude product was purified by flash chromatography (eluting with DCM / MeOH) to give the title intermediate 15.1 (400 mg, 1.85 mmol) as a white solid. Yield 85%. GC / MS (m / z) 214 (M+).

[1019] Example 16: Intermediate 16.2.2 (3-Bromomethyl-phenyl)-acetonitrile

[1020]

[1021] 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 CH 3 CN (15 mL). Stirring was continued under reflux for 4 h. Volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and a saturated aqueous solution of NaHCO 3 (100 mL). The organic phase was collected and dried over Na 2 SO 4. After flash chromatography (eluting with PET / EtOAc), the title compound 16.2 (250 mg, 1.18 mmol) was obtained as a slightly yellow solid. Yield 50%.

[1022] Example 17: Intermediate 17.3. 5-(3-Bromomethyl-phenyl)-2-methyl-2H-tetrazole

[1023]

[1024] Step 1: 5-m-Tolyl-2H-tetrazole (17.1)

[1025] 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 at 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 3N HCl and extracted with EtOAc (3×20 mL). The organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The title compound 17.1 (1.22 g, 7.6 mmol) was obtained as a white solid. Yield 89%. 1 H NMR (200MHz, DMSO-d6) δ2.39 (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+).

[1026] Step 2: 2-Methyl-5-m-tolyl-2H-tetrazolyl (17.2)

[1027] 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 at reflux for 6 h. The solvent was then removed under reduced pressure and the resulting residue was dissolved in EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified to give the title intermediate 17.2 (500 mg, 2.87 mmol) as a white solid. Yield 46%. 1 H NMR (400MHz, CDCl3) δ4.37(s,3H),7.26-7.39(m,1H),7.35-7.39(m,1H),7.91-7.96(m,2H).

[1028] Step 3: 5-(3-Bromomethyl-phenyl)-2-methyl-2H-tetrazole (17.3)

[1029] To a suspension of compound 17.2 (200 mg, 1.15 mmol) in CH3CN (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 dissolved in water, extracted with EtOAc (3×20 mL), washed with brine and dried over Na2SO4. The crude product was purified by flash chromatography eluting with CH2Cl2 / MeOH (7% for 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) δ4.41 (s, 3H), 4.56 (s, 2H), 7.46-7.52 (m, 1H), 8.07-8.09 (m, 1H), 8.19 (s, 1H).

[1030] Example 18: Intermediate 18.1.5-(3-Bromomethyl-phenyl)-1H-tetrazole

[1031]

[1032] To a suspension of compound 17.1 (300 mg, 1.87 mmol) in CH3CN (15 mL) was added AIBN (31 mg, 0.18 mmol) and NBS (333 mg, 1.87 mmol). Stirring was continued overnight at reflux. The solvent was removed under reduced pressure. The reaction was dissolved in water, extracted with EtOAc (3×20 mL), washed with brine, and dried over Na2SO4. The crude product was purified by flash chromatography eluting with CH2Cl2 / MeOH (7% for product) to give the title compound 18.1 (150 mg, 0.62 mmol) as a light yellow solid. Yield 34%.

[1033] Example 19: Intermediate 19.5.3-Bromomethyl-benzenesulfonamide

[1034]

[1035] Step 1: 3-Chlorosulfonyl-benzoic acid (19.2)

[1036] 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, dissolved in EtOAc and washed with water (3×20 mL). The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure. The title intermediate 19.2 (1.19 g, 5.39 mmol) was obtained as a white solid. Yield 65%. 1HNMR (400MHz, DMSO-d6) δ7.45(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).

[1037] Step 2: 3-sulfamoyl-benzoic acid (19.3)

[1038] To a low temperature solution of 25% NH4OH (10 mL) was added intermediate 19.2 (1.10 g, 5.39 mmol) in batches. Stirring was continued for 2 h at room temperature 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) δ7.50(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).

[1039] Step 3: 3-Hydroxymethyl-benzenesulfonamide (19.4)

[1040] At 0 ° C, BH3-THF complex (14 mL, 14.01 mmol) was added dropwise to a stirred solution of intermediate 19.3 (940 mg, 4.67 mmol) and stirring was continued at room temperature for 4 h. The reaction mixture was then cooled to 0 ° C and quenched by dropwise addition of MeOH. After 15 min, 3N HCl solution (37 mL) 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 phase was 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) δ4.51 (s, 2H), 7.34 (s, 2H), 7.5 (d, J = 5Hz, 2H), 7.68 (t, J = 5.2Hz, 1H), 7.8 (s, 1H).

[1041] Step 4: 3-Bromomethyl-benzenesulfonamide (19.5)

[1042] To a stirred suspension of intermediate 19.4 (200 mg, 1.07 mmol) in DCM (3.5 mL) was added PBr 3 and stirring was continued at 20 ° C for 16 h. Water was then 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 Na 2 SO 4 to give the title intermediate 19.5 (120 mg, 0.47 mmol) as a colorless oil. Yield 45%. 1 H NMR (400MHz, CDCl3) δ4.53 (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).

[1043] Example 20: Intermediate 20.2.4-Benzyl-2-mercapto-6-oxo-1,6-dihydro-pyridine-3-carbonitrile

[1044]

[1045] 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). Subsequently, the pH was 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 light yellow solid. Yield 40%. 1 H NMR (400MHz, DMSO-d6) δ3.63(s,2H),5.81(s,1H),7.17-7.36(m,5H),13.1(brs,1H).

[1046] Example 21: [3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-ethyl acetate (Compound I-1)

[1047]

[1048] 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 continued stirring under gentle reflux for 16 h. The solvent was then removed under reduced pressure. The crude product was dissolved in water and the resulting aqueous solution was neutralized with 3N HCl solution. The resulting light 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) δ1.15(d,J=7.03Hz,3H),3.62(s,2H),4.03(q,J=7.16Hz,2H),4.55(s,2H),7. 17(d,J=7.1Hz,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)δ14.4,34.2,60.7,88.6,116.6,127.8,129.1,129.1,129.9, 130.3,132.1,135.2,135.5,137.1,139.7,159.1,161.1,165.3,171.4. HPLC>97.9%.

[1049] Example 22: 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzamide (Compound I-2)

[1050]

[1051] To a stirred suspension of intermediate 1.4 (182 mg, 0.78 mmol) and intermediate 9.3 (200 mg, 0.65 mmol) in CH 3 CN (20 mL) was added K 2 CO 3 (119 mg, 0.86 mmol) and stirring was continued for 16 h under gentle reflux. The volatiles were removed under reduced pressure. The crude product was dissolved in water, and the resulting aqueous mixture was acidified to pH 3 with 3N HCl solution and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4 to give the title compound I-2 (120 mg, 0.24 mmol) as a slightly yellow solid after trituration with hot Et 2 O. Yield 42%. 1H NMR (400MHz, DMSO-d6) δ4.61(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)δ34.5,88.1,117.1,127.3,129.1,129.3,130.4,132.5 ,132.5,135.5,135.9,137.7,140.2,159.4,161.6,165.7,168.4.HPLC>94.2%.

[1052] Example 23: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}thio)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (Compound I-3)

[1053]

[1054] Step 1: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}thio)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (22.1)

[1055] 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 and dried over NaSO to afford intermediate 22.1 (180 mg, 0.0.38 mmol) as a light yellow powder after flash chromatography eluting with CHCl / MeOH (4% for the product). Yield 55%. 1 H NMR (400MHz, DMSO-d6) δ3.93 (s, 3H), 4.60 (s, 2H), 7.34-7.43 (m, 4H), 7.5 (d, J = 4.3Hz, 1H), 7. 60(d,J=7.5Hz,1H),7.84(s,1H),8.0(d,J=4.9Hz,1H),8.29(d,J=4.9Hz,1H),13.9(brs,1H).

[1056] Step 2: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}thio)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (Compound I-3)

[1057] To a stirred suspension of intermediate 22.1 (170 mg, 0.36 mmol) in DCM (25 mL) was added a 1M solution of BBr in DCM (0.72 mL, 0.72 mmol) and the mixture was stirred at reflux for 16 h. The reaction mixture was quenched by adding MeOH and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography using DCM / MeOH (5% for the product). After grinding with hot EtO, the title compound I-3 (90 mg, 0.2 mmol) was obtained as a white solid. Yield 42%. 1 HNMR (400MHz, DMSO) δ4.59(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)δ88.7,110.3( 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%.

[1058] Example 24: [3-(5-Cyano-4-methoxy-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-4)

[1059]

[1060] 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 KCO (60 mg, 0.43 mmol) and stirring was continued at room temperature for 16 h. The reaction mixture was 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. The crude product was purified by flash chromatography (eluting with DCM / MeOH, using 1.5% for the product) to give the title compound I-4 (45 mg, 0.11 mmol) as a white solid. Yield 58%; 1 H NMR(400MHz,DMSO-d6)δ3.56(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)δ34.2,40.3,52.1,88.5,116.6,127.8,129,129.1,129.8, 130.3,132,135.1,135.3,137.1,139.8,159.1,161.4,165.5,171.8. HPLC>97.1%.

[1061] Example 25: [3-(4-Bromo-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-5)

[1062]

[1063] To a stirred solution of intermediate 12.2 (30 mg, 0.051 mmol) in AcOH (3.0 mL) was added HBr (36% solution in AcOH, 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 H2O (3×10 mL), brine (10 mL), dried over Na2SO4, 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 give 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. 1H-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, 1 30.1,133.1,133.6,134.6,136.6,138.7,155.8,159.7,174.3,177.1. HPLC>95%.

[1064] Example 26: [3-(5-Cyano-4-cyclopropylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-6)

[1065]

[1066] 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, poured into water, and the resulting aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine and dried over Na2SO4. After being torn apart with Et2O, the title compound I-6 (80 mg, 0.2 mmol) was obtained as a white solid. Yield 39%. 1 H NMR(400MHz,DMSO-d6)δ0.73(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)δ6.6,6.6,25,34.3,40.8,79.7,116.7,127.3,128.5,128.6,129 .2,130.1,130.7,133.2,135.4,138.3,140.1,158.7,162.8,172.8,172.8.HPLC>99.3%.

[1067] Example 27: [3-(4-Amino-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-7)

[1068]

[1069] [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 white solution was stirred at room temperature for 72 h. The mixture was then poured into AcOEt (15 mL), washed with HCl 3 M (5 mL), aqueous NaHCO solution (10 mL), brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash chromatography (CHCl / MeOH / AcOH, 99:1:0.1 to 90:10:0.1) to give 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) δ3.53(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)δ34.3,40.9,78.9,116.9,127.6,128.6,128.7,129.3 ,130.4,130.8,133.4,135.5,138.3,140.4,159.1,163.7,173.HPLC>97.9%.

[1070] Example 28: [3-(5-Cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-8)

[1071]

[1072] 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, delivery solvent: THF, flow rate: 1.0 mL / min). The resulting reaction mixture (approximately 5 mL) was diluted with EtOAc (15 mL), washed with 3M 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, eluting with H2O / MeOH 80 / 20 to 10 / 90) to give the title compound I-8 as a white powder. Yield: 34%. MS / MS ESI(+): 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).

[1073] Example 29: [3-(5-Cyano-4-methylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-9)

[1074]

[1075] To a stirred solution of intermediate 12.2 (100 mg, 0.25 mmol) in DMF (3 mL) was added a solution of 33% MeNH2 (0.03 mL, 0.27 mmol) in ethanol and stirring was continued at room temperature for 16 h. The reaction mixture was quenched with brine, poured into water, acidified to pH 6 by adding 3M HCl solution, and then extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine and dried over Na2SO4 to give the title compound I-9 (80 mg, 0.2 mmol) as a white solid. Yield 80%. 1H NMR (400MHz, DMSO-d6) δ2.93(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 ),7.27-7.29(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)δ28.6,34.5,40.9,79.6,116.9,127.4,128.6,128.7,129.3, 130.2,130.7,133.3,135.5,138.3,140.3,158.5,161.9,172.9,173.1. HPLC>98.1%.

[1076] Example 30: 3-(5-Cyano-4-methylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-benzoic acid (Compound I-10)

[1077]

[1078] To a stirred solution of intermediate 13.3 (90 mg, 0.23 mmol) in DMF (3 mL) was added a solution of 33% MeNH2 (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, acidified to pH 6 by adding 3M HCl solution, and then 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% for the product) to give the title compound I-10 (45 mg, 0.12 mmol) as a white solid. Yield 51%. 1 H NMR (400MHz, DMSO-d6) δ2.94(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). 13C NMR (100MHz, DMSO-d6) δ28.6,34.2,79.8,116.8,128.3,129.1,129.2,130,130. 7,131.3,133.3,133.5,139.3,140.2,158.5,161.9,167.4,172.9. HPLC>95.1%.

[1079] Example 31: 2-(3-Cyano-benzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-11)

[1080]

[1081] 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, acidified to pH 6 by adding 3M HCl solution, and then 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 to give the title compound I-11 (50 mg, 0.17 mmol) as a white solid. Yield 17%. 1 H NMR (400MHz, DMSO-d6) δ4.60(s,2H),7.35(d,J=4.8Hz,1H),7.54(t,J=7.8Hz,1H),7.74(d,J=7.7Hz,1 H), 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)δ33.2,88.8,111.8,116.5,118.9,130,130.2,131.6 ,132.1,132.8,134.1,135.4,139.3,139.6,159,161.2,165.1.HPLC>99.1%.

[1082] Example 32: 2-[3-(2-Hydroxy-ethyl)-benzylsulfanyl]-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (Compound I-12)

[1083]

[1084] 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 h. The solvent was removed under reduced pressure. The resulting mixture was poured into water, acidified to pH 6 by adding 3M HCl solution, and then extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4. 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%. 1 H NMR(400MHz,DMSO-d6)δ2.47,(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)δ34.3,62.3,62.3,88.3,116.9,126.8,128.5,128.8,1 29.8,129.9,131.8,135.1,136.9,139.9,140.3,159,162,165.9. HPLC>96.1%.

[1085] Example 33: 2-(3-Cyanomethyl-benzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-13)

[1086]

[1087] 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 h. The solvent was then removed under reduced pressure. The resulting mixture was poured into water, acidified to pH 6 by adding 3M HCl solution, and then extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4. The crude product was purified by flash chromatography eluting with DCM / MeOH (2.5% for the product) to give the title compound I-13 (300 mg, 0.82 mmol) as a yellow solid. Yield 96%. 1 H NMR (400MHz, DMSO-d6) δ4.01 (s, 2H), 4.52 (s, 2H), 7.24 (d, J = 7.49Hz, 1H), 7.31-7.36 (m,2H),7.43-7.45(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)δ22.6,33.9,87.9,117.5,119.5,127.5,128.5,128.9,129 .6,129.6,131.3,131.9,134.5,138.6,140.3,159.1,164.1,166.7.HPLC>97.7%.

[1088] 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)

[1089]

[1090] 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 h. 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 slightly yellow solid. Yield 58%. 1H NMR (400MHz, DMSO-d6) δ4.40(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). 13 C NMR (100MHz, DMSO-d6) δ33.9,40.5,88.7,116.5,125.7,127.2,127.5,129.9,130,131.3,132.1,135.4,138.6,139.7,159.1,161.1,164.2,165.2. HPLC>99.3%.

[1091] Example 35: [3-(5-Cyano-4-morpholin-4-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-15)

[1092]

[1093] To a stirred suspension of intermediate 12.2 (100 mg, 0.25 mmol) in CH 3 CN (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 dissolved 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 Na 2 SO 4 to give the title compound I-15 (80 mg, 0.18 mmol) as a white solid. Yield 71%. 1 H NMR(400MHz, CDCl3)δ3.60(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) δ35.1,40.6,47.7,47.7,66.5,66.5,80.6,118.4,127.7,128.3, 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%.

[1094] Example 36: [3-(5-Cyano-4-piperazin-1-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-16)

[1095]

[1096] 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).

[1097] To a stirred suspension of intermediate 12.2 (250 mg, 0.62 mmol) and KCO (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 dissolved in water and the aqueous mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine and dried over NaSO. The crude product was purified by flash chromatography eluting with DCM / MeOH (4% for the product) to give the title intermediate 35.1 (60 mg, 0.11 mmol) as a slightly yellow solid. Yield 18%.

[1098] Step 2. [3-(5-Cyano-4-piperazin-1-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (I-16)

[1099] 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 dissolved 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 Na2SO4. After shredding with hot Et2O, the title compound I-16 (20 mg, 0.044 mmol) was obtained as a white solid. Yield 37%. 1 H NMR(400MHz,DMSO-d6)δ2.83(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). 13C NMR(100MHz,DMSO-d6)δ34.6,41.2,45.5,45.5,48.4,48.4,118.7,127.2,128.6,1 28.7,129.2,130.1,131.8,133.7,135.8,138.1,140.1,161.5,162.4,172,173.1. HPLC>90.9%.

[1100] 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).

[1101]

[1102] To a stirred suspension of compound I-1 (300 mg, 0.73 mmol) and KCO (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 h. The resulting mixture was poured into water and then extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and dried over NaSO to give the title compound I-17 (298 mg, 0.7 mmol) as a slightly yellow solid. Yield 96%. 1 H NMR (400MHz, DMSO-d6) δ0.14(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)δ14.4,31.1,36.1,40.5,60.6,87.5,116.5,127.9,129.1,1 29.2,130,130.4,132.1,135.3,135.4,136.2,139.5,157.1,160.1,166.4,171.3. HPLC>95.1%.

[1103] Example 38. 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-benzenesulfonamide (Compound I-18)

[1104]

[1105] 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 dissolved in water and then extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4. After trituration with hot Et2O, the title compound I-18 (50 mg, 0.12 mmol) was obtained as a slightly yellow solid. Yield 28%. 1 H NMR (400MHz, DMSO-d6) δ4.65(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) δ33.7,88.6,116.6,125.2,126.1,129.7,129.9,132,132.5,135.4,138.4,139.7,144.8,159.1,161.4,165.3. HPLC>95.1%.

[1106] Example 39: [3-(3-Cyano-6-oxo-4-phenyl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-19)

[1107]

[1108] 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 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-19 (60 mg, 0.16 mmol) was obtained as a light brown powder. Yield 37%. 1H NMR (400MHz, DMSO-d6) δ3.55(s,2H),4.5(s,2H),6.51(s,1H),7.16(d,J=7.4Hz,1H),7. 27(t,J=7.7Hz,1H),7.37(m,2H),7.51-7.53(m,3H),7.55-7.56(m,2H),12.17(brs,2H); 13 C NMR(100MHz,DMSO-d6)δ33.5,40.6,95.9,108,116.2,127.6,128.3,128.3,128.5,128.5, 128.9,128.9,130,130.3,135.4,135.9,137.5,155.9,162.1,164.9,172.7; HPLC: 96.88%.

[1109] Example 40: [3-(3-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-20)

[1110]

[1111] 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 light brown powder. Yield 42%. 1 H NMR (400MHz, DMSO-d6) δ3.55 (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)δ33.6,40.6,93.8,104.5,116.5,127.6,128.6,128.6,128.7, 128.7, 129.5, 130.3, 130.3, 135.4, 136.6, 137.4, 147.4, 165.1, 172.7; HPLC: 96.5%.

[1112] Example 41: [3-(3,5-Dicyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-21)

[1113]

[1114] 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 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-21 (110 mg, 0.27 mmol) was obtained as a light brown powder. Yield 35%. 1 H NMR (400MHz, DMSO-d6) δ3.56(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 CNMR(100MHz,DMSO-d6)δ33.3,40.6,85.8,93.1,115.5,127.8,128,128,128.6,130.5, 130.9,131.4,131.4,132.9,135.3,137.4,,150.8,159.8,166.9,172.8,; ​​HPLC: 97.5%.

[1115] 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)

[1116]

[1117] 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 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-22 (90 mg, 0.27 mmol) was obtained as a slightly yellow powder. Yield 38%. 1 H NMR (400MHz, DMSO-d6) δ4.6 (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) δ33.2,86.2,93.4,115.7,124.9,126.2,128.1,128.2,129. 8,131.2,131.6,131.6,132.5,133,139.5,151.1,155.8,160.1,166.8; HPLC: 96.7%

[1118] Example 43: [3-(4-Benzyl-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-23)

[1119]

[1120] 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 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-23 (100 mg, 0.25 mmol) was obtained as a slightly yellow 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%.

[1121] Example 44: (5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydro-pyrimidin-2-ylsulfanyl)-acetic acid (Compound I-24)

[1122]

[1123] 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. 0.3 equivalents of DIPEA and chloroacetic acid were then added to complete the reaction. 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 10% to 80% H2O / MeOH. Compound I-24 (210 mg, 0.71 mmol) was obtained as a slightly yellow powder. Yield 83%. 1 H NMR (400MHz, DMSO-d6) δ4.0 (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); 13 C NMR (100MHz, DMSO-d6) δ33.4,88.5,116.5,129.8,132.3,135.6,139.5,159,161.1,165.2,169.3; HPLC: 99.6%.

[1124] Example 45: 6-Oxo-2-(1H-tetrazol-5-ylmethylsulfanyl)-4-thiophen-2-yl-1,6-dihydro-pyrimidine-5-carbonitrile (Compound I-25)

[1125]

[1126] 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 5-chloromethyl-1H-tetrazole (101 mg, 0.85 mmol). Stirring was continued overnight at room temperature. 0.3 equivalents of DIPEA and 5-chloromethyl-1H-tetrazole were then added to complete the reaction. 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 10% to 80% H2O / MeOH. Compound I-25 (120 mg, 0.37 mmol) was obtained as a slightly yellow powder. Yield 44%. 1H NMR (400MHz, DMSO-d6) δ4.82(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%.

[1127] Example 46: 2-(1H-tetrazol-5-ylmethylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (Compound I-26)

[1128]

[1129] 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 Na 2 SO 4. Compound I-26 (60 mg, 0.19 mmol) was obtained as a white powder. Yield 35%. 1 HNMR(400MHz,DMSO-d6)δ4.69(s,2H),6.67(s,1H),15.1(brs,1H); 13 C NMR(100MHz,DMSO-d6)δ23.1,107.7,120.6(q,J CF =2.7Hz),152,154.3,163.9,164.8; HPLC: 97.9%

[1130] Example 47: (6-Oxo-4-trifluoromethyl-1,6-dihydro-pyrimidin-2-ylsulfanyl)-acetic acid (Compound I-27)

[1131]

[1132] 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 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 Na 2 SO 4 . The crude product of the reaction was purified by reverse flash chromatography, eluting the product with 5 to 65% H 2 O / MeOH. Compound I-27 (125 mg, 0.49 mmol) was obtained as a white powder. Yield 58%. 1 H NMR (400MHz, DMSO-d6) δ3.96 (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%.

[1133] Example 48: [3-(6-Oxo-4-trifluoromethyl-1,6-dihydro-pyrimidin-2-ylsulfanylmethyl)-phenyl]-acetic acid (Compound I-28)

[1134]

[1135] 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 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 Na 2 SO 4 . The crude product of the reaction was purified by reverse flash chromatography using 5 to 80% H 2 O / MeOH elution for the product. Compound I-28 (100 mg, 0.29 mmol) was obtained as a white powder. Yield 45%. 1 H NMR (400MHz, DMSO-d6) δ3.54(s,2H),4.52(s,2H),6.87(s,1H),7.16(d,J=7.3H z, 1H), 7.26 (t, J = 7.4Hz, 1H), 7.33-7.35 (m, 2H), 12.18 (brs, 1H); HPLC: 98.1%.

[1136] Example 49: 2-[3-(1H-tetrazol-5-yl)-benzylsulfanyl]-6-trifluoromethyl-3H-pyrimidin-4-one (Compound I-29)

[1137]

[1138] 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 overnight at room temperature. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3N HCl. A white solid was collected and characterized as the title compound. Compoun...

Claims

1. A compound represented by formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is O or OR h ; W is N; L is -SCH2; R 1 Does not exist, C6-C 10 Arylene, heteroarylene, wherein the heteroarylene includes one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O and S, and wherein the C6-C 10 Arylene and heteroarylene groups are optionally substituted with one or two R e replace; Each R 6 is independently H or C1-C4 alkyl at each occurrence; R 7 is A; A is -(C(R 6 )2) r Tetrazole, -(C(R 6 )2) r Oxadiazolone, -(C(R 6 )2) r Tetrazodone, -(C(R 6 )2) r Thiadiazole, -(C(R 6 )2) r Isoxazol-3-ol; R c is H, halogen or -CN; R d -(C(R 6 )2) t -C6-C 10 Aryl or -(C(R 6 )2) t -5-membered or 6-membered heteroaryl; Each R e Each occurrence is independently C1-C6 alkyl, chloro, bromo, -NHR z , -OH or -CN; R f is H; R h is H; R j for non-existence; R z is H, C1-C6 alkyl or C1-C6 haloalkyl; Each r is independently 0, 1 or 2; each t is independently 1 or 2; and Indicates a single bond or a double bond.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c For H.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c It is -CN.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R d -(C(R 6 )2) r -C6-C 10 Aryl or -(C(R 6 )2) r -5-membered or 6-membered heteroaryl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R d -CH2-C6-C 10 Aryl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 C6-C 10 Arylene.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a heteroarylene group.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Does not exist.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is -(CH2) r Tetrazole.

10. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

11. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 12 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, comprising one or more additional therapeutic agents.

14. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating, preventing or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction, wherein the disease or condition is selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome (Sjögren's syndrome), sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha-1 antitrypsin deficiency.

15. The use according to claim 14, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

16. The pharmaceutical composition according to claim 12, for use as a medicament.

17. Use of the pharmaceutical composition according to claim 12 for the manufacture of a medicament for treating, preventing or reducing the risk of a disease or condition associated with α-amino-β-carboxyhexanedioate-ε-semialdehyde decarboxylase (ACMSD) dysfunction, wherein the disease or condition is selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomas (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, non-alcoholic fatty liver disease (NAFLD), liver transplantation-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, disease), Gaucher's disease, hemochromatosis, and alpha-1-antitrypsin deficiency.

18. The use according to claim 17, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

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