RU2841136C2 - α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE INHIBITORS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (II):

or a pharmaceutically acceptable salt or tautomer thereof, where: X is O or OH; W is N; L is -(C(R⁵)₂)_mY¹(C(R⁵)₂)_p-; Y¹ is S; R¹ is absent or represents C₆-C₁₀ arylene; each R⁵ in each occurrence is independently H; each R⁶ in each occurrence is independently H; R⁷ is A or C; A is -(C(R⁶)₂) r tetrazole, C is -(C(R⁶)₂)_rC₆-C₁₀ aryl, wherein said aryl is substituted with one to three substitutes, each independently selected from halogen and OH; R^c is H or -CN; R^d is CF₃, -(C(R⁶)₂)_tC₆-C₁₀ aryl; R^f is H; R^j is absent; each m, p, q and r is independently 0, 1 or 2; each t is 1 or 2; and is a single bond or a double bond, which are capable of inhibiting decarboxylase activity of semialdehyde α-amino-β-carboxymuconic acid (ACMSD). Present application also describes pharmaceutical compositions, use of said compounds as a medicinal agent.

EFFECT: compounds are suitable for preventing and/or treating diseases and disorders associated with disorders of NAD⁺ biosynthesis, for example, metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, renal diseases and diseases associated with aging.

54 cl, 1 tbl, 98 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/769,959, filed November 20, 2018, the entire contents of which are incorporated herein by reference.

AREA OF TECHNOLOGY

[0002] The present disclosure relates to compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD). The compounds of the present disclosure can be used in methods for preventing and/or treating diseases and disorders associated with impaired NAD ⁺ biosynthesis, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with aging.

LEVEL OF TECHNOLOGY

[0003] ACMSD is an essential enzyme for tryptophan metabolism and regulates the biosynthesis of NAD ⁺ from tryptophan. ACMSD is a zinc-dependent amidohydrolase that is involved in the homeostasis of picolinic acid (PA), quinolinic acid (QA), and NAD ⁺ . ACMSD is located at a branching point in the biosynthesis pathway of NAD ⁺ from tryptophan and determines the final transformation of the amino acid, i.e., conversion to PA, complete oxidation in the citric acid cycle, or conversion to NAD ⁺ via QA synthesis.

[0004] ACMSD has been isolated from human liver, kidney, and brain tissues. There are two isoforms, ACMSD1 and ACMSD2, resulting from differential transcriptional splicing of the ACMSD gene, but only ACMSD1 has enzymatic activity. ACMSD1 directs ACMS (β-amino-ω-carboxymuconic acid semialdehyde) into the acetyl-CoA cascade, and upon inhibition of ACMSD1, ACMS is non-enzymatically converted to quinolinic acid (QA), resulting in the formation of NAD ⁺ and an increase in intracellular NAD ⁺ levels.

[0005] Elevated NAD ⁺ levels have been shown to protect against neurodegeneration, improve muscle function and oxidative metabolism in mice, and extend lifespan in worms. However, decreased NAD ⁺ levels have been linked to a number of pathophysiological conditions including type 2 diabetes (T2D), hyperlipidemia (elevated cholesterol and TAG), mitochondrial disease, neutropenia, cancer, and kidney disease.

[0006] Thus, inhibition of ACMSD represents a novel approach to increasing NAD ⁺ levels and altering the pathophysiology of disease associated with defects in NAD ⁺ biosynthesis.

ESSENCE OF THE INVENTION

[0007] The object of the embodiments of this disclosure is to provide a new series of compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), and said compounds are useful for the prevention and/or treatment of diseases and disorders associated with impaired NAD ⁺ biosynthesis, such as metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with aging.

[0008] The compounds of formula (I) or (II) described herein can be used to treat a disease or disorder in which ACMSD plays a role. Described herein are methods for treating a disease or disorder associated with abnormalities in NAD ⁺ biosynthesis by administering to subjects suffering from or predisposed to developing said disease or disorder a therapeutically effective amount of one or more compounds that increase intracellular NAD ⁺ through inhibition of ACMSD1 in an amount sufficient to activate sirtuins (SIRT) and downstream targets of SIRT such as PGC-1α, FoxO1, and/or superoxide dismutase (SOD). The methods according to the present disclosure can be used to treat NAD ⁺ dependent diseases through inhibition of ACMSD. Inhibition of ACMSD may provide a new approach to the prevention and treatment of metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, diseases associated with aging, and other ACMSD-dependent diseases or diseases characterized by impaired NAD ⁺ synthesis.

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

and its pharmaceutically acceptable salts and tautomers, where:

X is H, S, SR ² , NR ² , NR ² R ^2' , O, OH, OR ^h , F, Br or Cl;

W represents N or C;

(i) if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

(ii) if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

Y ¹ represents O, NR ⁴ or S(O) _q ;

each Y ² independently represents O, NH or S;

R ¹ is absent or is C ₆ -C ₁₀ arylene or heteroarylene, said heteroarylene comprising one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene or heteroarylene is optionally substituted with one or two R ^e ;

R ² is H or C ₁ -C ₄ alkyl;

R ^2' is H, C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; or

R ² and R ^2' together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O and S;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is H or C ₁ -C ₄ alkyl;

each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl;

each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl;

R ⁷ is H, A, B or C;

A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol, -(CH ₂ ) _r P(O)(OH)OR ^x , -(CH ₂ ) _r S(O) ₂ OH, -(CH ₂ ) _r C(O)NHCN or -(CH ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol optionally substituted with C ₁ -C ₆ alkyl,

B represents -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NR ^g R ^g' , -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ ^Rx , -(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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x ,

C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups;

R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x or -CO ₂ R ^x ;

R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;

each R ^e at each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN;

R ^f is absent, is H or methyl;

R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ ;

R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH;

R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

R ⁱ is (i) -(CH ₂ ) _s OC(O)C ₁ -C ₆ alkyl, wherein said alkyl is substituted with one or more NH ₂ ; (ii) (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH; or (iii) C ₁ -C ₆ alkyl substituted with one or more substituents each independently selected from OH and 4-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N or S;

R ^j is absent, represents H, C ₁ -C ₆ alkyl, or -CN;

each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl;

each R ^y and R ^z independently represents H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each m, p, q, r, and t is independently equal to 0, 1, or 2;

n is 0, 1, 2 or 3;

s is 1 or 2;

o is equal to 0, 1, 2, 3 or 4; And

represents a single bond or a double bond; and

provided that

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; then R ⁷ is not -COOH;

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; and R ⁷ is tetrazole; then R ^c is not H;

if X is O; R^frepresents H; W represents C; R^jrepresents -CN; L represents -S-C(R⁵)₂or -SCH₂CH₂-; R¹absent; then R⁷does not represent COOH or tetrazole;

if X is O, R ^f is H; W is N; R ^j is absent; R ^d is methyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH ₂ - or -OCH ₂ -; and R ¹ is phenylene; then R ⁷ is not -COOH, -CH ₂ COOH, or ; And

if X is O, R ^f is H, W is N, R ^j is absent, L is -NHCH ₂ -, -CH ₂ NH-, or -NH-C(O)-, and R ¹ is phenylene, then R ^d is not phenyl.

[0010] The present description provides a compound represented by formula (II):

and its pharmaceutically acceptable salts and tautomers, where:

X is H, S, SR ² , NR ² , NR ² R ^2' , O, OH, OR ^h , F, Br or Cl;

W represents N or C;

(i) if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

(ii) if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

Y ¹ represents O, NR ⁴ or S(O) _q ;

each Y ² independently represents O, NH or S;

R ¹ is absent or represents C ₆ -C ₁₀ arylene, heteroarylene or C ₃ -C ₈ cycloalkylene, wherein said heteroarylene contains one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene, heteroarylene and C ₃ -C ₈ cycloalkylene are optionally substituted with one or two R ^e ;

R ² is H or C ₁ -C ₄ alkyl;

R ^2' is H, C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; or

R ² and R ^2' together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O and S;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is H or C ₁ -C ₄ alkyl;

each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl;

each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl;

R ⁷ is H, A, B or C;

A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol, -(C(R ⁶ ) ₂ ) _r P(O)(OH)OR ^x , -(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r C(O)NHCN or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol are optionally substituted with C ₁ -C ₆ alkyl,

B represents -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ R ^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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x ,

C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups;

R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x or -CO ₂ R ^x ;

R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;

each R ^e at each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN;

R ^f is absent, is H or methyl;

R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ ;

R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH;

R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

R ⁱ is (i) -(CH ₂ ) _s OC(O)C ₁ -C ₆ alkyl, wherein said alkyl is substituted with one or more NH ₂ ; (ii) (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH; or (iii) C ₁ -C ₆ alkyl substituted with one or more substituents each independently selected from OH and 4-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N or S;

R ^j is absent, represents H, C ₁ -C ₆ alkyl, or -CN;

each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl;

each R ^y and R ^z independently represents H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each m, p, q, r, and t is independently equal to 0, 1, or 2;

n is 0, 1, 2 or 3;

s is 1 or 2;

o is equal to 0, 1, 2, 3 or 4; And

represents a single bond or a double bond; and

provided that

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; then R ⁷ is not -COOH;

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; and R ⁷ is tetrazole; then R ^c is not H;

if X is O; R^frepresents H; W represents C; R^jrepresents -CN; L represents -S-C(R⁵)₂or -SCH₂CH₂-; R¹absent; then R⁷does not represent COOH or tetrazole;

if X is O, R ^f is H; W is N; R ^j is absent; R ^d is methyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH ₂ - or -OCH ₂ -; and R ¹ is phenylene; then R ⁷ is not -COOH, -CH ₂ COOH, or ; And

if X is O, R ^f is H, W is N, R ^j is absent, L is -NHCH ₂ -, -CH ₂ NH-, or -NH-C(O)-, and R ¹ is phenylene, then R ^d is not phenyl.

[0011] In another aspect of the present disclosure, there is provided 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.

[0012] In another aspect, the present disclosure provides a compound of formula (I) or (II) for use as a medicament. In another aspect of the present description, there is provided a pharmaceutical composition comprising a compound of formula (I) or (II) for use as a medicine.

[0013] In another aspect, the present disclosure provides a method of treating a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II). In another aspect, the present disclosure provides a method of preventing a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II). In another aspect of the present disclosure, there is provided a method for reducing the risk of a disease or disorder by inhibiting α-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II).

[0014] In another aspect, the present disclosure provides a method of treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of formula (I) or (II). In another aspect, the present disclosure provides a method of preventing a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of formula (I) or (II). In another aspect of the present disclosure, there is provided a method for reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of formula (I) or (II).

[0015] In another aspect, the present disclosure provides a method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II) that results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ). In another aspect, the present disclosure provides a method of preventing a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II) that results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ). In another aspect of the present disclosure, there is provided a method for reducing the risk of a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II), which results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[0016] In another aspect of the present disclosure, there is provided a method for accelerating oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II) that results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[0017] In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in treating a disease or disorder by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in preventing a disease or disorder by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in reducing the risk of a disease or disorder by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD).

[0018] In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels. In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in preventing a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels. In another aspect, the present disclosure provides a compound of formula (I) or (II) for use in reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels.

[0019] In another aspect, the present disclosure provides a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ), for use in treating a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ), for use in preventing a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ), for use in reducing the risk of a disorder associated with mitochondrial dysfunction.

[0020] In another aspect of the present disclosure, there is provided a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ), for use in accelerating oxidative metabolism.

[0021] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for treating a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for preventing a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for reducing the risk of a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[0022] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for preventing a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels.

[0023] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) for the treatment of a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) for the prevention of a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) for reducing the risk of a disorder associated with mitochondrial dysfunction.

[0024] In another aspect of the present disclosure, there is provided the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) to accelerate oxidative metabolism.

[0025] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for the manufacture of a medicament for treating a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) for the manufacture of a medicament for preventing a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD). In another aspect, the present disclosure 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 disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[0026] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ). In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for preventing a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ). In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) in the manufacture of a medicament for reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ).

[0027] In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) in the manufacture of a medicament for treating a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) in the manufacture of a medicament for preventing a disorder associated with mitochondrial dysfunction. In another aspect, the present disclosure provides the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) in the manufacture of a medicament for reducing the risk of a disorder associated with mitochondrial dysfunction.

[0028] In another aspect of the present disclosure, there is provided the use of a compound of formula (I) or (II) that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) in the manufacture of a medicament for accelerating oxidative metabolism.

[0029] In some aspects, the compounds of the present invention can be administered alone or in combination with other compounds, including other ACMSD-modulating compounds or other therapeutic agents.

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. As used herein, the singular forms "a" and "an" include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present invention, suitable methods and materials are now described. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not an admission of prior art to the claimed disclosure. In case of conflict, the present description, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0031] Other features and advantages of the present invention will become apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0032] All references, including patents or patent applications, cited in this specification are herein incorporated by reference. The authors of the present description do not consider any references to constitute prior art. In addition, they do not consider any information from the prior art to constitute part of the common knowledge in this field.

[0033] It should be understood that in the present description, unless otherwise indicated, the following terms have the meanings indicated below. If a term is not described, then the standard meaning of the term, known to those skilled in the art, should be followed.

[0034] As used herein, the terms "including," "comprising," and "including" are used in an open, non-limiting sense. As used in the description and claims of the present invention, the words "include" and "comprise," as well as variations of these words, such as "including" and "includes," mean "including, but not limited to," and do not exclude other groups, additives, components, integers, or steps. As used in the description and claims of the present invention, the singular forms include the plural forms unless the context otherwise requires. In particular, when a term is used in the singular, it should be understood that the present description contemplates the term in the plural as well as in the singular unless the context otherwise requires.

[0035] The singular terms used in this description refer to one or more (i.e., at least one) grammatical object of the description. For example, "element" may mean one element or more than one element.

[0036] The term "and/or" as used herein may mean either "and" or "or" unless otherwise specified.

[0037] To provide a more concise description, certain quantitative expressions provided herein do not have the qualification "about." It should be understood that, whether or not the term "about" is used, each quantity provided herein refers to the actual given value and also refers to an approximation of the given value that is reasonably expected based on general knowledge in the art, including equivalents and approximations arising from experimental and/or measurement conditions for the given value. When a yield is provided as a percentage, the yield stated refers to the mass of the substance for which the yield is given, relative to the maximum amount of the same substance that can be obtained under the specified stoichiometric conditions. Concentrations expressed as percentages refer to mass fractions unless otherwise stated.

[0038] The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eight carbon atoms (C _1-8 alkyl), more preferably from one to six carbon atoms (C _1-6 alkyl), in particular from one to four carbon atoms (C _1-4 alkyl), including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl, isohexyl, heptyl and octyl. In a preferred embodiment, "alkyl" is a C _1-4 alkyl group, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl. Accordingly, the term "alkylene" means the corresponding diradical (-alkyl-).

[0039] The term "cycloalkyl" or "carbocycle" as used herein refers to a cyclic alkyl group, preferably comprising three to ten carbon atoms ( _C3-10 cycloalkyl or _C3-10 carbocycle), for example three to eight carbon atoms ( _C3-8 cycloalkyl or _C3-10 carbocycle), preferably three to six carbon atoms ( _C3-6 cycloalkyl or _C3-10 carbocycle), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Furthermore, the term "cycloalkyl" as used herein may also include polycyclic groups such as, for example, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, decalinyl and adamantyl. Accordingly, the term "cycloalkylene" means the corresponding diradical (-cycloalkyl-). Alkyl and cycloalkyl groups may be optionally substituted with 1-4 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.

[0040] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain or cyclic hydrocarbons containing one or more double bonds, including dienes, trienes and polyenes. Typically, an alkenyl group contains from two to eight carbon atoms (C _2-8 alkenyl), for example from two to six carbon atoms (C _2-6 alkenyl), in particular from two to four carbon atoms (C _2-4 alkenyl), and contains 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. Accordingly, the term "alkenylene" means 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, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo and -CN.

[0041] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including diynes, triynes and polyynes. Typically, an alkynyl group contains from two to eight carbon atoms (C _2-8 alkynyl), for example from two to six carbon atoms (C _2-6 alkynyl), in particular from two to four carbon atoms (C _2-4 alkynyl), and contains at least one triple bond. Examples of preferred alkynyl groups include ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl, or 1,3-butadiynyl; 1-, 2-, 3-, 4- or 5-hexynyl, or 1,3-hexadiynyl, or 1,3,5-hexatriinyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1,3-octadiynyl, or 1,3,5-octatriynyl, or 1,3,5,7-octatetraynyl. Accordingly, the term "alkynylene" means 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, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, carbamoyl, oxo and -CN.

[0042] The terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine. Thus, a trihalomethyl group is, for example, a trifluoromethyl group or a trichloromethyl group. Preferably, the terms "halo" and "halogen" mean fluorine or chlorine.

[0043] The term "haloalkyl" as used herein refers to an alkyl group as described 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, etc.

[0044] The term "alkoxy" as used herein refers to the group "alkyl-O-" wherein alkyl is as described above.

[0045] The term "hydroxyalkyl" as used herein refers to an alkyl group (as described above herein) that is substituted one or more times with a hydroxy group. Examples of hydroxyalkyl groups include HO- _CH2- , HO- _CH2 - _CH2- , and _CH3 -CH(OH)-.

[0046] The term "oxy" in this context refers to the "-O-" group.

[0047] The term "oxo" in this context refers to the group "=O".

[0048] The term "amine" as used herein refers to primary (R- _NH2 , R≠H), secondary ((R) ₂ -NH, (R) ₂ ≠H), and tertiary ((R) ₃ -N, R≠H) amines. A substituted amine means an amine in which at least one of the hydrogen atoms is replaced by a substituent.

[0049] The term "carbamoyl" as used herein refers to the group " _H2N (C=O)-".

[0050] The term "aryl" as used herein, unless otherwise specified, includes carbocyclic aromatic ring systems derived from an aromatic hydrocarbon by removal of a hydrogen atom. Additionally, aryl includes bi-, tri- and polycyclic ring systems. Examples of preferred aryl moieties include phenyl, naphthyl, indenyl, indanyl, fluorenyl, biphenyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, pentalenyl, azulenyl and biphenylenyl. Preferred "aryl" is phenyl, naphthyl or indanyl, particularly phenyl, unless otherwise specified. Any aryl used may be optionally substituted. Accordingly, the term "arylene" means the corresponding diradical (-aryl-). Aryl groups may be optionally substituted with 1 to 4 substituents. Examples of substituents on aryl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0051] The term "heteroaryl" in this context refers to aromatic groups containing one or more heteroatoms selected from O, S and N, preferably from one to four heteroatoms and more preferably from one to three heteroatoms. Furthermore, heteroaryl includes bi-, tri- and polycyclic groups, wherein at least one ring of said group is aromatic and at least one of said rings contains a heteroatom selected from O, S and N. Heteroaryl also includes ring systems substituted with one or more oxo moieties. Examples of preferred heteroaryl moieties include N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydrobenzo[b]thiophenyl, xanthenyl, isoindanyl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, pteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl, azaindolyl, pyrazolinyl, 1,2,3-oxadiazol-5(4H)-one and pyrazolidinyl. Non-limiting examples of partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-octalene. Accordingly, the term "heteroarylene" means the corresponding diradical (-heteroaryl-). Heteroaryl groups may be optionally substituted with 1-4 substituents. Examples of substituents on heteroaryl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0052] The term "heterocyclyl" as used herein refers to cyclic non-aromatic groups containing one or more heteroatoms selected from O, S and N, preferably from one to four heteroatoms and more preferably from one to three heteroatoms. Heterocyclyl further includes bi-, tri- and polycyclic non-aromatic groups, and at least one of said rings contains a heteroatom selected from O, S and N. Heterocyclyl also includes ring systems substituted with one or more oxo moieties. Examples of heterocyclic groups are oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanyl, furanyl, thiolanyl, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridinyl, oxanyl, 2H-pyranyl, 4H-pyranyl, thianyl, 2H-thiopyranyl, pyridazinyl, 1,2-diazinanyl, pyrimidinyl, 1,3-diazinanyl, pyrazinyl, piperazinyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-diazinanyl, 1,4-oxazinyl, morpholino, thiomorpholino, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, 4H-chromenyl, 1H-isochromenyl, cinnolyl, quinazolinyl, quinoxalinyl, phthalazinyl, purinyl, naphthyridinyl, pteridinyl, indolizinyl, 1H-pyrrolizinyl, 4H-quinolizinyl and aza-8-bicyclo[3.2.1]octane. Accordingly, the term "heterocyclylene" means the corresponding diradical (-heterocyclyl-). Heterocyclyl groups may be optionally substituted with 1-4 substituents. Examples of substituents on heterocyclyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyclyl, hydroxyl, and -CN.

[0053] The term "N-heterocyclic ring" as used herein refers to a heterocyclyl or heteroaryl ring as defined above having at least one nitrogen atom and bonded via the nitrogen atom. Examples of such N-heterocyclic rings 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, morpholino, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, etc.

[0054] In the present description, the structural formula of a compound in some cases illustrates a specific isomer for convenience, but the present description includes all isomers, such as geometric isomers, optical isomers based on an asymmetric carbon atom, stereoisomers, tautomers, and the like. Accordingly, it should be understood that the definition of compounds of formula (I) or (II) includes each and all individual isomers corresponding to formula (I) or (II), including cis-trans isomers, stereoisomers and tautomers, as well as racemic mixtures and pharmaceutically acceptable salts thereof. Accordingly, the definition of compounds of formula (I) or (II) is intended to also cover all R- and S -isomers of the chemical structure in any ratio, for example, with enrichment (i.e., enantiomeric excess or diastereomeric excess) of one of the possible isomers and a corresponding lesser content of the other isomers. In addition, the compounds represented by formula (I) or (II) may exhibit polymorphism. It should be noted that any crystalline form, mixture of crystalline forms, or anhydride or hydrate thereof is included within the scope of the present description. In addition, the so-called metabolite, which is formed by decomposition of the proposed compound in vivo , is included within the scope of the present description.

[0055] "Isomerism" refers to compounds that have the same molecular formula but differ in the bonding sequence of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are insuperimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture".

[0056] A carbon atom bonded to four non-identical substituents is called a "chiral center."

[0057] "Chiral isomer" means a compound with at least one chiral center. Compounds containing more than one chiral center may exist either as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Substituents attached to the chiral center in question are classified according to the Cahn, Ingold, and Prelog sequence rule . (Cahn et al ., Angew. Chem. Inter. Edit. 1966, 5, 385; correction 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. 1964, 41, 116).

[0058] Diastereoisomers, i.e., non-superimposable stereochemical isomers, can be separated by standard techniques such as chromatography, distillation, crystallization, or sublimation. Optical isomers can be prepared by separating racemic mixtures by standard techniques, such as forming diastereomeric salts by treatment with an optically active acid or base. Examples of suitable acids include, but are not limited to, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid. A mixture of diastereomers can be separated by crystallization followed by liberation of the optically active bases from said salts. An alternative method for separating optical isomers involves the use of a chiral chromatographic column optimally selected to maximize the separation of enantiomers. Another accessible method involves the synthesis of covalent diastereoisomeric molecules by reacting compounds of formula (I) or (II) with an optically pure acid in activated form or with an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation and then hydrolyzed to give an enantiomerically pure compound. Optically active compounds of formula (I) can likewise be prepared by using optically active starting materials and/or by employing a chiral catalyst. These isomers can be in the form of a free acid, a free base, an ester or a salt. Examples of chiral separation techniques are presented in the book Chiral Separation Techniques, A Practical Approach, 2nd ed., G. Subramanian, Wiley-VCH, 2001.

[0059] "Geometric isomer" means diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in the name by the prefixes cis and trans, or Z and E, which indicate that these groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0060] In addition, the structures and other compounds discussed herein include all atropisomers. "Atropisomers" are a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropisomers owe their existence to restricted rotation, caused by the difficulty of rotating large groups about a central bond. Such atropisomers usually exist as a mixture, but recent advances in chromatography technology have made it possible in some cases to separate mixtures of two atropisomers.

[0061] A "tautomer" is one of two or more structural isomers that are in equilibrium and readily convertible from one isomeric form to another. Such conversion results in the formal migration of a hydrogen atom accompanied by movement of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric forms in solution. In the solid form, one tautomer usually predominates. In solutions in which tautomerism is possible, a chemical equilibrium of the tautomers is achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0062] Among the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, the electrons and the hydrogen atom are simultaneously displaced. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule to form a cyclic (ring) form, as seen in glucose.

[0063] Common tautomeric pairs include: ketone-enol, amide-nitrile, lactam-lactim, amide-imido acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. It should be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are included within the scope of the present disclosure, and the naming of compounds does not exclude any tautomeric form.

[0064] The term "crystalline polymorphs", "polymorphs" or "crystalline forms" means crystalline structures in which the compound (or its salt or solvate) can crystallize in different crystal packing structures, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline form, optical and electrical properties, stability and solubility. The solvent used for recrystallization, the rate of crystallization, the storage temperature and other factors can determine the predominance of one crystalline form. Crystalline polymorphs of the disclosed compounds can be obtained by crystallization under various conditions.

[0065] Furthermore, the compounds of the present disclosure, such as salts of such compounds, may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0066] "Solvate" means solvent addition forms that contain a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the solid crystalline state to form 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 alkoxide. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance in which the water retains its molecular state as _H2O .

[0067] As used herein, a "subject" or "subject in need thereof" is a subject suffering from a disease or disorder associated with β-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD) or β-amino-carboxymuconate-semialdehyde decarboxylase inhibition (ACMSD). A "subject" includes a mammal. A mammal may be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, a wild bird, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. Preferably, the mammal is a human.

[0068] The present description includes all isotopes of atoms occurring in the disclosed compounds. Isotopes include those atoms that have the same atomic number but a different mass number. As a general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

Connections

[0069] The present description relates to compounds of formula (I):

and their pharmaceutically acceptable salts and tautomers, wherein the substituents are as described herein.

[0070] This description relates to compounds of formula (II):

and their pharmaceutically acceptable salts and tautomers, wherein the substituents are as described herein.

[0071] In some embodiments of formula (I) or (II), when W is N, then the present description pertains to compounds of formula (I-I):

(I-1)

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

[0072] In some embodiments of formula (I) or (II), when W is C, then the present description pertains to compounds of formula (I-2):

(I-2)

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

[0073] In some embodiments of formula (I) or (II), when R ¹ is phenyl, then the present description pertains to compounds of formula (I-3):

(I-3)

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

[0074] In some embodiments of formula (I) or (II), if R ¹ is absent, then the present description pertains to compounds of formula (I-4):

(I-4)

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

[0075] As described above, X is H, S, ^SR2 , ^NR2 , ^{NR2R2 '} , O, OH, ^ORh , F, Br, or Cl. In some embodiments, X is O, OH, ^ORh , F, Br, or Cl. In some embodiments, X is H, S, ^SR2 , ^NR2 , or ^{NR2R2 '} . In some embodiments, X is H. In some embodiments, X is S. In some embodiments, X is ^SR2 . In some embodiments, X is ^NR2 . In some embodiments, X is ^{NR2R2 '} . In some embodiments, X is O. In some embodiments, X is OH. In some embodiments, X is ^ORh . In some embodiments, X is F. In some embodiments, X is Br. In some embodiments, X is Cl.

[0076] As described above, R ² is H or C ₁ -C ₄ alkyl. In some embodiments, R ² is H. In some embodiments, R ² is C ₁ -C ₄ alkyl. In some embodiments, R ² is -CH ₃ .

[0077] As described above, R ^2' is H, C ₁ -C ₄ alkyl, or C ₃ -C ₇ cycloalkyl. In some embodiments, R ^2' is H. In some embodiments, R ^2' is C ₁ -C ₄ alkyl. In some embodiments, R ^2' is C ₃ -C ₇ cycloalkyl.

[0078] As described above, R ² and R ^2' , together with the nitrogen atom to which they are attached, form a 3-7-membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O, and S. In some embodiments, R ² and R ^2', together with the nitrogen atom to which they are attached, form a 6-membered heterocycloalkyl ring.

[0079] As described above, R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl. In some embodiments, R ^h is H. In some embodiments, R ^h is C ₁ -C ₄ alkyl, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ . In some embodiments, R ^h is a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl.

[0080] As described above, R ^f is absent, H, or methyl. In some embodiments, R ^f is absent. In some embodiments, R ^f is H. In some embodiments, R ^f is methyl.

[0081] As described above, W is N or C. In some embodiments, W is N. In some embodiments, W is C.

[0082] As described above, R ^j is absent, H, C ₁ -C ₆ alkyl, or -CN. In some embodiments, R ^j is absent. In some embodiments, R ^j is H. In some embodiments, R ^j is C ₁ -C ₆ alkyl. In some embodiments, R ^j is -CN.

[0083] In some embodiments, W is N and R ^j is absent. In some embodiments, W is C and R ^j is H, C ₁ -C ₆ alkyl, or -CN. In some embodiments, W is C and R ^j is -CN.

[0084] As described above, R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x , or -CO ₂ R ^x . In some embodiments, R ^c is H. In some embodiments, R ^c is C ₁ -C ₆ alkyl. In some embodiments, R ^c is C ₁ -C ₆ haloalkyl. In some embodiments, R ^c is halogen. In some embodiments, R ^c is -CN. In some embodiments, R ^c is -OR ^x . In some embodiments, R ^c is -CO ₂ R ^x .

[0085] As described above, R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl. In some embodiments, R ^x is H. In some embodiments, R ^x is C ₁ -C ₆ alkyl. In some embodiments, R ^x is C ₆ -C ₁₀ aryl.

[0086] As described above, R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl.

[0087] In some embodiments, R ^d is methyl. In some embodiments, R ^d is CF ₃ . In some embodiments, R ^d is CR ^f F ₂ . In some embodiments, R ^d is -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl. In some embodiments, R ^d is -CH ₂ C ₆ -C ₁₀ aryl. In some embodiments, R ^d is -CH ₂ C ₆ aryl. In some embodiments, R ^d is -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl. In some embodiments, R ^d is -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl. In some embodiments, R ^d is optionally substituted C ₆ -C ₁₀ aryl. In some embodiments, R ^d is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R ^d is an optionally substituted 5- or 6-membered cycloalkyl.

[0088] As described above, R ^f is absent, H, or methyl. In some embodiments, R ^f is absent. In some embodiments, R ^f is H. In some embodiments, R ^f is methyl.

[0089] As described above, t is 0, 1, or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0090] As described above, if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -.

[0091] In some embodiments, W is N and L is -(C(R⁵)₂)_mCH=CH(C(R⁵)₂)_p- In some embodiments, W is N and L is. In some embodiments, W is N and L is -(C(R⁵)₂)_mY¹(C(R⁵)₂)_p- In some embodiments, W is N and L is -(C(R⁵)₂)_mY¹(C(R⁵)₂)_p-cyclopropyl-. In some embodiments, W is N and L is -(C(R⁵)₂)_mY¹CH=CH-. In some embodiments, W is N and L is -(C(R⁵)₂)_mNR³C=(O)(C(R⁵)₂)_p- In some embodiments, W is N and L is -(C(R⁵)₂)_mphenyl(C(R⁵)₂)_p- In some embodiments, W is N and L is -(C(R⁵)₂)_mpyridinyl(C(R⁵)₂)_p- In some embodiments, W is N and L is -(C(R⁵)₂)_mthiophenyl(C(R⁵)₂)_p- In some embodiments, W is N and L is -(C(R⁵)₂)_mY¹(C(R⁵)₂)_p, such as -SCH₂- or -NHCH₂- In some embodiments, W is N and L is -SCH₂- In some embodiments, W is N and L is -NHCH₂-.

[0092] As described above, if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -.

[0093] In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m CH=CH(C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _o -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is . In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m Y ¹ CH=CH-. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m C=(O)(CH ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p -. In some embodiments, W is C and L is -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -.

[0094] As described above, Y ¹ is O, NR ⁴ , or S(O) _q . In some embodiments, Y ¹ is O. In some embodiments, Y ¹ is NR ⁴ . As described above, R ⁴ is H or C ₁ -C ₄ alkyl. In some embodiments, R ⁴ is H. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl.

[0095] In some embodiments, Y ¹ is S(O) _q . As described above, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, Y ¹ is S. In some embodiments, q is 1. In some embodiments, q is 2.

[0096] As described above, each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl. In some embodiments, R ⁵ is H. In some embodiments, R ⁵ is C ₁ -C ₄ alkyl.

[0097] As described above, R ³ is H or C ₁ -C ₄ alkyl. In some embodiments, R ³ is H. In some embodiments, R ³ is C ₁ -C ₄ alkyl.

[0098] As described above, each m and p is independently 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0099] As described above, o is 0, 1, 2, 3, or 4. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[00100] As described above, R ¹ is absent or is a C ₆ -C ₁₀ arylene or heteroarylene, wherein said heteroarylene comprises one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene or heteroarylene is optionally substituted with one or two R ^e . In some embodiments, R ¹ is absent. In some embodiments, R ¹ is a C ₆ -C ₁₀ arylene that is optionally substituted with one or two R ^e . In some embodiments, R ¹ is a heteroarylene, wherein said heteroarylene comprises one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and is optionally substituted with one or two R ^e . In some embodiments of formula (II), R ¹ is C ₃ -C ₈ cycloalkylene, such as C ₄ cycloalkylene, C ₅ cycloalkylene, C ₆ cycloalkylene, C ₇ cycloalkylene, or C ₈ cycloalkylene.

[00101] As described above, each R ^e in each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN.

[00102] As described above, R ⁷ is H, A, B, or C. In some embodiments, R ⁷ is H. In some embodiments, R ⁷ is A. In some embodiments, R ⁷ is B. In some embodiments, R ⁷ is C.

[00103] As described above for formula (I), A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol, -(CH ₂ ) _r P(O)(OH)OR ^x , -(CH ₂ ) _r S(O) ₂ OH, -(CH ₂ ) _r C(O)NHCN or -(CH ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein said -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol are optionally substituted with C ₁ -C ₆ alkyl.

[00104] As described above for formula (II), A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol, -(C(R ⁶ ) ₂ ) _r P(O)(OH)OR ^x , -(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r C(O)NHCN, or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein said -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol are optionally substituted with C ₁ -C ₆ alkyl. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r tetrazole. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r oxadiazolone. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r tetrazolone. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r thiadiazolol. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r P(O)(OH)OR ^x . In some embodiments, A is -(C(R ⁶ ) ₂ ) _r S(O) ₂ OH. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r C(O)NHCN. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ alkyl.

[00105] In some embodiments, A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x . In some embodiments, A is -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x . In some embodiments, A is -(CH ₂ ) _r tetrazole. In some embodiments, A is -(CH ₂ ) _r oxadiazolone. In some embodiments, A is -(CH ₂ ) _r tetrazolone. In some embodiments, A is -(CH ₂ ) _r thiadiazolol. In some embodiments, A is -(CH ₂ ) _r isoxazol-3-ol. In some embodiments, A is -(CH ₂ ) _r P(O)(OH)OR ^x . In some embodiments, A is -(CH ₂ ) _r S(O) ₂ OH. In some embodiments, A is -(CH ₂ ) _r C(O)NHCN. In some embodiments, A is -( _CH2 ) _rC (O)NHS(O) _2alkyl . _In some embodiments, said -( _CH2 ) _rtetrazole , -(CH2)roxadiazolone, -( _CH2 ) _rtetrazolone , -( _{CH2 ) rthiadiazolol} , -( _CH2 ) _risoxazol -3-ol are optionally substituted with _C1 - _C6 alkyl. In some embodiments _, A is -(C( ^R6 ) ₂ ⁾ _rCO2Rx or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r COOH or -(CH ₂ ) _r tetrazole, wherein said -(CH ₂ ) _r tetrazole is optionally substituted with C ₁ -C ₆ alkyl. In some embodiments, A is -COOH, -CH ₂ COOH, -tetrazole, or -(CH ₂ )tetrazole, wherein said tetrazole and -(CH ₂ ) _r tetrazole are optionally substituted with C ₁ -C ₆ alkyl.

[00106] As described above for formula (I), B is -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NR ^g R ^g' , -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ ^Ri , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ R ^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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x .

[00107] As described above for formula (II), B is -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ R ^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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x . In some embodiments, B is -(C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' . In some embodiments, B is -(C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' . In some embodiments, B is -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' .

[00108] In some embodiments, B is - (C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl. In some embodiments, B is -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl. In some embodiments, B is -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' . In some embodiments, B is -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' . In some embodiments, B is -(CH ₂ ) _r C(O)NR ^g R ^g' . In some embodiments, B is -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' . In some embodiments, B is -( _CH2 ) _rC (O)NHS(O) _2NRgRg ^' . In some embodiments, B is -(C( ^R6 ) ₂ ) ^rCO2Ri . In ^some embodiments, B is -(C( ^R6 ) _{2 ) rNH2CO2Rx} . _{In some} embodiments, B is - ₍ C( ^R6 ) ₂ ) _rP (O)( ^ORx ) ² . In some embodiments, B is -O(C( ^R6 ) ₂ ) _rP (O)( ^ORx ) _{2 .} In some embodiments, B is -(C( ^R6 ) ₂ ) _rS (O) _2OH . In some embodiments, B is -O(C( ^R6 ) ₂ ) _rS (O) _2OH . In some embodiments, B is -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x . In some embodiments, B is -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x .

[00109] As described above, C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents, each of which is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups.

[00110] In some embodiments, C is -(CH ₂ ) _r CN. In some embodiments, C is -(CH ₂ ) _s OH. In some embodiments, C is halogen. In some embodiments, C is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl. In some embodiments, C is -(C(R ⁶ ) ₂ ) _r SC ₆ -C ₁₀ aryl. In some embodiments, C is -(C(R ⁶ ) ₂ ) _r heteroaryl. In some embodiments, C is -O(C(R ⁶ ) _{2 ) r} heterocycloalkyl. In some embodiments ^{, C is -O(C(R 6} _{) 2} ) _r OH. In some embodiments ^, C is -OR ^y . In some embodiments, C is -(C(R ⁶ ) ₂ ) _r C(O)NHCN. In some embodiments, C is -CH=CHCO ₂ R ^x . In some embodiments, C is -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl. In the above description, aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups.

[00111] As described above, each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl. In some embodiments, R ⁶ is H. In some embodiments, R ⁶ is C ₁ -C ₄ alkyl.

[00112] As described above, each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl. In some embodiments, R ^x is H. In some embodiments, R ^x is C ₁ -C ₆ alkyl. In some embodiments, R ^x is C ₆ -C ₁₀ aryl.

[00113] As described above, each Y ² is independently O, NH, or S. In some embodiments, Y ² is O. In some embodiments, Y ² is NH. In some embodiments, Y ² is S.

[00114] As described above, each r is 0, 1, or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[00115] As described above, s is 1 or 2. In some embodiments, s is 1. In some embodiments, s is 2.

[00116] As described above, R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ .

[00117] As described above, R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH.

[00118] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^c is CN;

c) R ^d is a 5- or 6-membered heteroaryl such as thiophenyl;

d) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

e) R ¹ is phenylene;

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

[00119] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^d is CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

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

[00120] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^c is CN;

c) R ^d is a 5- or 6-membered heteroaryl such as thiophenyl;

d) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

e) R ¹ is absent;

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

[00121] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^d is CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is absent;

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

[00122] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is C;

b) R ^d is -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl or -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl);

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

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

[00123] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is C;

b) R ^d is -CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

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

[00124] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^c is CN;

c) R ^d is a 5- or 6-membered heteroaryl such as thiophenyl;

d) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

e) R ¹ is phenylene;

f) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00125] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^d is CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

e) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00126] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^c is CN;

c) R ^d is a 5- or 6-membered heteroaryl, such as thiophenyl;

d) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

e) R ¹ is absent;

f) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00127] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is N;

b) R ^d is CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is absent;

e) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00128] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is C;

b) R ^d is -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl or -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl);

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

e) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00129] In some embodiments of the present disclosure, a compound of formula (I) is provided having one, two, or three of the following features:

a) W is C;

b) R ^d is -CF ₃ ;

c) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p , such as -SCH ₂ -;

d) R ¹ is phenylene;

e) R ⁷ is A, such as -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole.

[00130] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Ia) having at least one of the following features:

(Ia),

and its pharmaceutical salts and tautomers, where

a) R ^d is a 5- or 6-membered heteroaryl;

b) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

c) R ⁷ is A or C;

d) X, R ^d , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, R ^d is thiophenyl. In some embodiments, L is -SCH ₂ - or -NHCH ₂ -. In some embodiments, R ⁷ is C. In some embodiments, C is -(C(R ⁶ ) ₂ ) _r C ₆ - C ₁₀ aryl substituted with one to three substituents each independently selected from C ₁ - C ₆ alkyl, C ₁ - C ₆ haloalkyl, halogen, and OH. In some embodiments, R ⁷ is A. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole, wherein said -(CH ₂ ) _r tetrazole is optionally substituted with C ₁ - C ₆ alkyl. In some embodiments, A is -(C(R ⁶ ) ₂ ) _r COOH or -(CH ₂ ) _r tetrazole, wherein said -(CH ₂ ) _r tetrazole is optionally substituted with C ₁ -C ₆ alkyl. In some embodiments, A is -COOH, -CH ₂ COOH, -tetrazole, or -(CH ₂ )tetrazole, wherein said tetrazole and -(CH ₂ ) _r tetrazole are optionally substituted with C ₁ -C ₆ alkyl. In some embodiments, formula (Ia) has one, two, three, or four features (a) through (d).

[00131] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Ib) having at least one of the following features:

(Ib),

and its pharmaceutical salts and tautomers, where

a) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

b) R ⁷ is A;

c) X, R ^c , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments _, A is -(C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 )rtetrazole, wherein said -( _CH2 ) _rtetrazole is optionally substituted ^with _C1 - _C6 alkyl. In some embodiments _, A is -(C(R6) ² ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted _{with C1} - _C6 alkyl. In some embodiments, formula (Ib) has one, two, or three of features (a)-(c).

[00132] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Ic) having at least one of the following features:

(Ic),

and its pharmaceutical salts and tautomers, where

a) R ^d is a 5- or 6-membered heteroaryl;

b) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

c) R ⁷ is A;

d) X, R ^d , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, ^Rd is thiophenyl. In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments, A is -(C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 ) _rtetrazole , wherein said -( ^CH2 ) _rtetrazole is optionally substituted _{with C1} - _C6 alkyl. In some embodiments, A is -(C( _R6 ⁾ ₂ ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted with _C1 - _C6 alkyl. In some embodiments, formula (Ic) has one, two, three, or four features (a)-(d).

[00133] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Id) having at least one of the following features:

(Id),

and its pharmaceutical salts and tautomers, where

a) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

b) R ⁷ is A;

c) X, R ^d , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments _, A is -(C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 )rtetrazole, wherein said -( _CH2 ) _rtetrazole is optionally substituted ^with _C1 - _C6 alkyl. In some embodiments _, A is -(C(R6) ² ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted _{with C1} - _C6 alkyl. In some embodiments, formula (Id) has one, two, or three of features (a)-(c).

[00134] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Ie) having at least one of the following features:

(Ie),

and its pharmaceutical salts and tautomers, where

a) R ^d is -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl or -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl);

b) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

c) R ⁷ is A.

d) X, R ^d , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments _, A is - ⁽ C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 )rtetrazole, wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -(C( ^R6 ) ₂ ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted with _C1 - _{C6 alkyl} . In some embodiments, formula (Ie) has one, two, three, or four features (a)-(d).

[00135] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (If) having at least one of the following features:

(If),

and its pharmaceutical salts and tautomers, where

a) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

b) R ⁷ is A;

c) X, R ^c , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments _, A is - ⁽ C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 )rtetrazole, wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -(C( ^R6 ) ₂ ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted with _C1 - _C6 alkyl. In some embodiments _, ^Rc is CN. In some embodiments, the formula (If) has one, two, or three features (a)-(c).

[00136] In some embodiments, with some of the features described above for formula (I), provided herein is a compound of formula (Ig) having at least one of the following features:

(Ig),

and its pharmaceutical salts and tautomers, where

a) L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p ;

b) R ⁷ is A;

c) X, R ^d , R ^f , R ^j , A, R ⁵ , Y ¹ , m and p are as defined for formula (I).

In some embodiments, L is _-SCH2- or _-NHCH2- . In some embodiments _, A is -(C( ^R6 ) ₂ ) _rCO2Rx or -( _CH2 )rtetrazole, wherein said -( _CH2 ) _rtetrazole is optionally substituted ^with _C1 - _C6 alkyl. In some embodiments _, A is -(C(R6) ² ) _rCOOH or -( _CH2 ) _rtetrazole , wherein said -( _CH2 ) _rtetrazole is optionally substituted with _C1 - _C6 alkyl. In some embodiments, A is -COOH, _-CH2COOH , -tetrazole, or -( _CH2 )tetrazole, wherein said tetrazole and -( _CH2 ) _rtetrazole are optionally substituted _{with C1} - _C6 alkyl. In some embodiments, formula (Ig) has one, two, or three of features (a)-(c).

[00137] In some embodiments, the compound of formula (I) is a compound selected from:

Connection No. Structure I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30 I-31 I-32 I-33 I-34 I-35 And I-36

or a pharmaceutically acceptable salt or tautomer thereof.

[00138] In some embodiments, the compound of formula (I) or (II) is a compound selected from:

I-37 I-38 I-39 I-40 And I-41 I-42 I-43 I-44 I-45 I-46 I-47 I-48 I-49 I-50 And I-51

[00139] In some embodiments, the compound of formula (I) is a compound or a pharmaceutically acceptable salt or tautomer thereof selected from:

And

or a pharmaceutically acceptable salt or tautomer thereof.

[00140] In some embodiments, the compound of formula (I) or (II) is a compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from:

And

[00141] It should be understood that such references are intended to cover not only the above general formulae, but also each and every embodiment, etc., discussed in the following description. It should also be understood that, unless otherwise indicated, such references also cover isomers, mixtures of isomers, pharmaceutically acceptable salts, solvates, and prodrugs of the compounds of formula (I) or (II).

Methods for obtaining compounds

[00142] The compounds of the present disclosure (e.g., the compounds of formula (I)) can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized by the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof understood by 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 standard techniques, such as extraction, crystallization, distillation, chromatography, etc.

[00143] The compounds according to the present description can be synthesized according to the following steps, presented in the general schemes A - F, which include different sequences of assembly of intermediates Ia-Ih and Ij-Io. The starting materials are either commercially available or prepared by known methods described in the literature or in accordance with the illustration. Suitable steps that can be used in the steps for obtaining the proposed compounds are known to those skilled in the art. The method presented below is given as a non-limiting example of the preparation of the proposed compounds.

General scheme A

where R ¹ , R ^c , R ^d and L are as defined for formula ( I ).

[00144] A general method for preparing compounds of formula (I) using intermediates Ia and Ib is shown in general scheme A. Coupling of Ia with Ib using a base, i.e. potassium carbonate ( _K2CO3 ), in _a solvent, i.e. acetonitrile ( _CH3CN ), optionally at elevated temperature, provides the desired compound of formula (I). Bases that can be used include, but are not limited to, _sodium carbonate ( _Na2CO3 ), _potassium carbonate ( _K2CO3 ), N,N-diisopropylethylamine (DIPEA), and triethylamine. The solvents used for the coupling reaction can be polar or non-polar solvents. For example, the solvent can be acetonitrile ( _CH3CN ), acetone, or dimethyl sulfoxide (DMSO).

General scheme B

^where X is a suitable leaving group, i.e. Cl, Br, _-SCH3 or S(O) _2CH3 , and _R1 , ^R2 , ^Rc , ^Rd and p are as defined for formula ( I ).

[00145] Alternatively, compounds of formula (I) can be prepared using intermediates Ic and Id as shown in general scheme B. Amination of intermediate Ic with Ie using a base, i.e. sodium hydroxide (NaOH), potassium hydroxide (KOH), etc. in a solvent, i.e. methanol (MeOH), ethanol (EtOH), water (H ₂ O), etc., yields compounds of formula (I).

General scheme C

^where X is a suitable leaving group, i.e. Cl, Br, _-SCH3 or S(O) _2CH3 , and _R1 , ^R2 , ^Rc , ^Rd and p are as defined for formula ( I ).

[00146] Compounds of formula (I) can also be prepared using intermediates Ie and If as shown in general scheme C. Amination of intermediate Ie with If using a base, i.e. sodium hydroxide (NaOH), potassium hydroxide (KOH), etc. in a solvent, i.e. methanol (MeOH), ethanol (EtOH), water (H ₂ O), etc., yields compounds of formula (I).

General scheme D

where R ¹ , R ^c and R ^d are as defined for formula (I).

[00147] Alternatively, compounds of formula (I) can also be prepared using intermediates Ig, Ih, Ij, Ik and Im as shown in general scheme D. Olefination of intermediate Ig with a base, i.e. potassium carbonate ( _K2CO3 ) and diethyl ( _cyanomethyl )phosphonate in a solvent, i.e. tetrahydrofuran (THF), water ( _H2O ), optionally at elevated temperature, provides intermediate Ih. Hydrogenation of compound Ih using a metal catalyst, i.e. palladium on carbon (Pd/C), platinum dioxide ( _PtO2 ), etc., and hydrogen gas ( _H2 ) in a solvent, i.e. ethanol (EtOH) and/or tetrahydrofuran (THF) provides intermediate Ij. The intermediate Ik is prepared by treating the intermediate Ij with an acid, i.e. hydrochloric acid (HCl) in a solvent, i.e. ethanol (EtOH), dichloromethane (CH ₂ Cl ₂ ), etc., followed by treatment with a base, i.e. ammonia (NH ₃ ). Cyclization of the intermediate Ik and Im with a base, i.e. sodium hydroxide (NaOH), potassium hydroxide (KOH), etc. in a solvent, i.e. dimethylacetamide (DMA), optionally at elevated temperature, provides compounds of formula (I).

General scheme E

where R ¹ , R ^c and R ^d are as defined for formula (I).

[00148] Alternatively, compounds of formula (I) can be prepared using intermediates In and Io as shown in general scheme D. Acylation of intermediate In with Io using a base, i.e. sodium hydroxide (NaOH), potassium hydroxide (KOH), etc. in a solvent, i.e. methanol (MeOH), ethanol (EtOH), water (H ₂ O), etc., results in the formation of compounds of formula (I).

General method F

where L, R ^c , R ^d , R ¹ and R ⁷ are as defined for formula (I).

[00149] A proposed general method for synthesizing compounds (e.g., I-17-I-30) having the general formula I comprises final coupling between one equivalent of an appropriately substituted 6-mercapto-2-oxo-4,5-disubstituted-1,2-dihydropyridine derivative with a stoichiometric amount of intermediates LR ¹ -R ⁷ using two equivalents of DIPEA as a base and acetone as a solvent, to yield the final compound.

[00150] Alternatively, some compounds of formula (I) or (II) can be prepared according to the schemes presented below, and compounds of formula (I) or (II), in general, can be prepared based on the schemes presented below.

General scheme G. 6-oxo-2-[4-(1H-tetrazol-5-yl)phenylamino]-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile

General scheme H . 6-oxo-2-[4-(1H-tetrazol-5-yl)cyclohexylamino]-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile

General scheme I. 6-oxo-2-[4-(1H-tetrazol-5-yl)piperidin-1-yl]-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile

General scheme J . 6-oxo-2-[3-(1H-tetrazol-5-yl)azetidin-1-yl]-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile

General scheme K . 4-benzyl-6-oxo-2-[2-(1H-tetrazol-5-yl)-benzylsulfanyl]-1,6-dihydropyrimidine-5-carbonitrile

[00151] The mixture of enantiomers, diastereomers, cis/trans isomers resulting from the process described above can be separated into individual components by chiral salt technology, chromatography using a normal-phase, reversed-phase or chiral column, depending on the nature of the separation.

[00152] It should be understood that in the present description and the formula presented above, the various groups R ¹ , R ² , X, L, Y, ^Ra , R ^b , R ^c , R ^d , ^Re , ^{R f ,} R x , R ^y , R ^z , m, n, p, q, r and other variables are as defined herein above, except where otherwise indicated. In addition, the compounds in the general schemes AE are merely illustrative of the synthesis, and the radicals are chosen to illustrate the general procedure for synthesizing compounds of formula (I), the definition of which is presented herein.

Pharmaceutical compositions

[00153] The compound of formula (I) or (II) may be presented in any form suitable for the intended administration, particularly including pharmaceutically acceptable salts, solvates and prodrugs of the compound of formula (I) or (II).

[00154] Pharmaceutically acceptable salts refer to salts of compounds of formula (I) or (II) that are considered suitable for clinical and/or veterinary use. Typical pharmaceutically acceptable salts include salts prepared by reacting compounds of formula (I) or (II) with an inorganic or organic acid, or with an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively. It is to be understood that the specific counterion forming part of any salt does not have any special composition, so long as said salt is pharmaceutically acceptable as a whole, and so long as said counterion does not impart undesirable properties to the salt as a whole. Such salts can be prepared by methods known in the art. Pharmaceutically acceptable salts are, for example, those described and discussed in Remington, Pharmaceutical Sciences, 17th ed., Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, PA, USA, 1985, and later editions, as well as in the Encyclopedia of Pharmaceutical Technology.

[00155] Examples of pharmaceutically acceptable addition salts include acid addition salts formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric or phosphoric acid; and with organic acids, such as succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphoric, isothionic, mucinous, gentisic, isonicotinic, saccharic, glucuronic, pyrosulose, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinylic, alginic and galacturonic acid; and arylsulfonic acids, such as benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid; and base addition salts formed with alkali metals and alkaline earth metals, and with organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internal salts. It is to be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) of said salts as described herein.

[00156] The compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, may be presented in soluble or insoluble form together with a pharmaceutically acceptable solvent such as water, ethanol, etc. Soluble forms may also include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc.

[00157] The compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, may be in the form of a prodrug. The term "prodrug" in this context means a compound which, when exposed to certain physiological conditions, releases the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, which can then exert the desired biological action. A typical example is a labile amine carbamate.

[00158] Since prodrugs are known to enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturability, etc.), the compounds of the present disclosure can be delivered in prodrug form. Thus, the present disclosure includes prodrugs of the compounds claimed herein, methods of delivering them, and compositions containing them. "Prodrugs" include any covalently bonded carriers that release the active parent drug compound of the present disclosure in vivo upon administration of such prodrug to a subject. Prodrugs as used herein are prepared by modifying functional groups present in the compound such that said modifications are cleaved, either by routine manipulation or in vivo , to yield the parent compound. Prodrugs include compounds according to the present description in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group is linked to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxyl, or free carbonyl group, respectively.

[00159] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyl functional groups, esters (e.g., C _1-6 alkyl esters, such as methyl esters, ethyl esters, 2-propyl esters, phenyl esters, 2-aminoethyl esters, morpholinoethanol esters, etc.) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups in the compounds of the present invention description, etc. See Bundegaard, H., Design of Prodrugs , pp. 1-92, Elesevier, New York - Oxford (1985).

[00160] The disclosed compounds or pharmaceutically acceptable salts, esters or prodrugs thereof are administered orally, nasally, transdermally, pulmonarily, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain modes of administration.

[00161] The dosage regimen using the proposed compounds is selected in accordance with various factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the pathological condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof used. Experienced physicians and veterinarians can readily determine and prescribe an effective amount of the compound necessary to prevent, counteract or arrest the progression of the pathological condition.

[00162] Techniques for formulating and administering dosage forms of the compounds of the present disclosure are provided in Remington : the Science and Practice of Pharmacy , ^19th edition, Mack Publishing Co., Easton, Pa. (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used for pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The subject compounds are contained in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

[00163] In one aspect, the present disclosure provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described herein, and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers. The compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, can be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in single or multiple doses. Suitable pharmaceutically acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

[00164] A "pharmaceutical composition" is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. Pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, in accordance with conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, ^21st ed., 2000, Lippincott Williams & Wilkins.

[00165] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers and/or dosage forms that are medically suitable for use in contact with the tissues of the human and animal body without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

[00166] "Pharmaceutically acceptable excipient" means an excipient useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise unacceptable, and includes an excipient acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable excipient" as used herein and in the claims includes one or more than one such excipient.

[00167] Pharmaceutical compositions obtained by combining a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described herein, with pharmaceutically acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injection solutions, and the like. In powders, the carrier is a finely divided solid such as talc or starch, in admixture with a finely divided active component. In tablets, the active component is mixed in a suitable ratio with a carrier having the necessary binding properties and compressed to the desired shape and size.

[00168] The pharmaceutical compositions may be specially formulated 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 of administration will depend on the general condition and age of the subject being treated, the nature of the pathological condition being treated and the active ingredient selected.

[00169] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, troches, powders and granules. If appropriate, they may be prepared with coatings such as enteric coatings, or they may be prepared so as to provide controlled release of the active ingredient, such as sustained or extended release, according to methods generally known in the art.

[00170] For oral administration in the form of a tablet or a capsule, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof described herein can be suitably combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like. In addition, suitable binders, lubricants, disintegrants, flavoring agents and coloring agents can be added to the mixture as appropriate. Suitable binders include, for example, lactose, glucose, starch, gelatin, gum arabic, gum tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Disintegrating agents include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, sodium croscarmellose or the like. Additional excipients for capsules include macrogels or fats.

[00171] To prepare solid compositions such as tablets, the active compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is mixed with one or more excipients, such as those described above, and with other pharmaceutical diluents, such as water, to obtain a solid preformulation composition containing a homogeneous mixture of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The term "homogeneous" is to be understood as meaning that the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is uniformly dispersed in the composition so that said composition can be readily subdivided into equally effective unit dosage forms such as tablets or capsules.

[00172] Liquid compositions of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for oral or parenteral administration include, for example, aqueous solutions, syrups, elixirs, aqueous or oily suspensions and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone.

[00173] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted to obtain sterile injection solutions or dispersions immediately before use.

[00174] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyhydric alcohol (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. The required fluidity can be maintained, for example, by coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by surfactants. Prevention of contamination by microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, for example, sugars, polyhydric alcohols such as mannitol, sorbitol and sodium chloride. Prolonged absorption of injection compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[00175] The preparation of all of the above solutions under sterile conditions is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[00176] For example, sterile injectable solutions can be prepared by incorporating the required amount of the active compound in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile liquid vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying, which yield a powder of the active component and any additional desired ingredient from a previously sterile-filtered solution. Injectable depot compositions are also contemplated as being within the scope of the present disclosure.

[00177] 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, or sterile aqueous solution can be used. Said aqueous solutions should be suitably buffered, if necessary, and the liquid diluent initially rendered isotonic with a sufficient amount of saline or glucose. Said particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Oil solutions are suitable for intra-articular, intramuscular, and subcutaneous injections.

[00178] In addition to the above ingredients, compositions of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may contain one or more additional ingredients such as diluents, buffers, flavoring agents, coloring agents, surfactants, thickeners, preservatives, such as methyl hydroxybenzoate (including antioxidants), emulsifying agents, etc.

[00179] The term "therapeutically effective amount" as used herein refers to that amount of a pharmaceutical agent that provides treatment, alleviation, or prevention of a stated disease, disorder, or pathological condition, or exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount for a subject depends on the subject's body weight, size, and health status; the nature and severity of the pathological condition; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutically effective amount for a given situation can be determined by routine experimentation, in accordance with the experience and judgment of the clinician. In a preferred aspect, the disease or disorder being treated is a disease or disorder associated with β-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00180] For any compound, the therapeutically effective amount can be initially estimated using cell culture assays, such as in cells, or in animal models, typically rats, mice, rabbits, dogs, or pigs. The animal model can also be used to determine a suitable concentration range and route of administration. The information obtained can then be used to determine suitable doses and routes of administration for humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical techniques in cell cultures or in experimental animals, such as to determine ED₅₀(the dose that is therapeutically effective in 50% of the population) and LD₅₀(the dose that is lethal to 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and can be expressed as the LD ratio₅₀/ED₅₀. Pharmaceutical compositions demonstrating high therapeutic indices are preferred. The dose may vary within the indicated range depending on the dosage form used, the patient's susceptibility and the route of administration.

[00181] The dose and administration are adjusted to provide a sufficient level of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, drug combination(s), allergic reactions, and tolerance/response to treatment. Long-acting pharmaceutical compositions may be administered once every 3-4 days, once a week, or once every two weeks, depending on the half-life and clearance rate of the particular dosage form.

[00182] A suitable dose of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof depends on the age and condition of the patient, the severity of the disease being treated and other factors well known to the practitioner. The compound can be administered, for example, orally, parenterally or locally, according to various dosage regimens, for example daily or at intervals such as weekly intervals. Typically, a single dose is from 0.01 to 500 mg/kg body weight, preferably from about 0.05 to 100 mg/kg body weight, more preferably from 0.1 to 50 mg/kg body weight and most preferably from 0.1 to 25 mg/kg body weight. The compound may be administered as a bolus (i.e., the entire daily dose is administered at one time) or in divided doses two or more times a day. An experienced physician may vary the above dosage ranges, taking into account known factors such as the weight, age and condition of the patient to be treated, the severity of the disease and the particular route of administration.

[00183] The compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof may also be prepared in a pharmaceutical composition containing one or more additional active substances, alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in the form of one or more doses. Suitable pharmaceutically acceptable carriers, diluents and excipients are described above, and the one or more additional active substances may be any active substances or, preferably, an active substance described below in the section "Combination therapy".

Treatment methods

[00184] In another aspect, the present disclosure relates to a method for preventing, reducing the risk of, or ameliorating a disease or disorder in which amino-carboxymuconate-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 pharmaceutically acceptable salts thereof.

[00185] Another aspect of the present disclosure relates to a method for preventing, reducing the risk of, or ameliorating a disease or disorder in which amino-carboxymuconate-semialdehyde decarboxylase (ACMSD) plays a role, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[00186] Another aspect of the present disclosure relates to a method of treating, preventing, reducing the risk of, or ameliorating a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof.

[00187] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder associated with ACMSD, a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[00188] In another aspect, the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder in which nicotinamide adenine dinucleotide (NAD ⁺ ) modulation 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 pharmaceutically acceptable salts thereof.

[00189] In another aspect, the present disclosure relates to a method of treating, preventing, reducing the risk of, or ameliorating a disease or disorder in which nicotinamide adenine dinucleotide (NAD ⁺ ) modulation plays a role, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[00190] In another aspect, the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof.

[00191] In another aspect, the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with reduced NAD ⁺ levels, 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.

[00192] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof. In one embodiment, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease. In a preferred embodiment, the disorder associated with mitochondrial dysfunction is a general metabolic disorder such as obesity or type II diabetes.

[00193] Another aspect of the present disclosure relates to a method for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing 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 of a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease. In a preferred embodiment, the disorder associated with mitochondrial dysfunction is a general metabolic disorder such as obesity or type II diabetes.

[00194] In another aspect, the present disclosure relates to a method of accelerating oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, which results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00195] In another aspect, the present disclosure relates to a method for accelerating oxidative metabolism comprising administering to a subject suffering from or susceptible to developing 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 of a pharmaceutically acceptable carrier, diluent, or excipient, which results in an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00196] In another aspect, the present disclosure relates to a method of manufacturing a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or pathological condition that may be mediated by inhibition of ACMSD, said medicament comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[00197] In another aspect, the present disclosure relates to a method for the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or pathological condition that may be mediated by inhibition of ACMSD, said medicament comprising 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.

[00198] In another aspect, the present disclosure relates to a compound for use in a method of treating, preventing, reducing the risk of, or ameliorating a disease or condition that may be mediated by inhibition of ACMSD, said compound comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[00199] In another aspect, the present disclosure relates to a pharmaceutical composition for use in a method of treating, preventing, reducing the risk of, or ameliorating a disease or pathological condition that may be mediated by inhibition of ACMSD, said 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.

[00200] Another aspect of the present disclosure relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[00201] Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, in the manufacture of a medicament for the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[00202] In another aspect, the present disclosure relates to the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00203] In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00204] Another aspect of the present disclosure relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00205] Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, in the manufacture of a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00206] In another aspect, the present disclosure relates to the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for accelerating oxidative metabolism.

[00207] In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, in the manufacture of a medicament for accelerating oxidative metabolism.

[00208] Another aspect of the present disclosure relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[00209] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, for use in the manufacture of a medicament for the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder by inhibiting β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD).

[00210] In another aspect, the present disclosure relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00211] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00212] Another aspect of the present disclosure relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00213] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, for use as a medicament for treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00214] In another aspect, the present disclosure relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use as a medicament for accelerating oxidative metabolism.

[00215] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, for use as a medicament for accelerating oxidative metabolism.

[00216] Another aspect of the present disclosure relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder associated with decreased levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00217] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, for use in the treatment, prevention, reduction in the risk of, or amelioration of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00218] In another aspect, the present disclosure relates to a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00219] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient, for use in treating, preventing, reducing the risk of, or ameliorating a disorder associated with mitochondrial dysfunction.

[00220] Another aspect of the present disclosure relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in accelerating oxidative metabolism.

[00221] Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient, for use in accelerating oxidative metabolism.

[00222] In some embodiments, the disease or disorder associated with decreased nicotinamide adenine dinucleotide (NAD ⁺ ) levels is a chronic liver disease, including, but not limited to, primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration, congenital fibrosis liver, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha-1 antitrypsin deficiency. In one embodiment, the general metabolic disorder is obesity or type II diabetes.

[00223] In some embodiments, the disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, an aging-related disorder, a renal disorder, or a chronic inflammatory disease.

[00224] In another aspect, the present disclosure relates to a method of treating, preventing, reducing the risk of, or ameliorating a disease or disorder by inhibiting β-amino-carboxymuconate-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).

[00225] As used herein, "treating" or "treating" describes the management and monitoring of a patient with the purpose of reversing, slowing down, or combating a disease, condition, or disorder, and includes administering a compound as described herein (i.e., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof to reverse said disease, condition, or disorder, eliminate said disease, condition, or disorder, or slow the progression of said disease, condition, or disorder.

[00226] A compound according to the present description (i.e., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate 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 occurrence of symptoms or complications of a disease, condition, or disorder.

[00227] A compound of the present description (i.e., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof may also be used to alleviate one or more symptoms of a specified disease, condition, or disorder. As used herein, the term "alleviate" describes a process by which the severity of a sign or symptom of a disorder is reduced. It is important to note that a sign or symptom may be alleviated, but not eliminated. Preferably, the treatment results in complete recovery or alleviation.

Clinical conditions and other uses of compounds

[00228] The compounds of Formula (I) or (II), or pharmaceutically acceptable forms thereof, compositions, medicaments and compounds for use as defined herein, are suitable for the treatment of a disease or disorder in which modulation of α-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD) plays a role. These compounds can be used in both human and veterinary medicine, and the patient can be any mammal, in particular a human. The treatment can comprise administering to any mammal, in particular a human, suffering from a disease or disorder in which modulation of α-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD) plays a role, a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, as defined herein.

[00229] The present invention also relates to a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, as defined herein, for use in a disease or disorder associated with α-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD), such as obesity, type II diabetes and its complications ( e.g. , diabetic retinopathy and nephropathy), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or chronic kidney disease.

[00230] The term "disease or disorder associated with α-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD)" means any disease characterized by decreased expression and/or activity of nicotinamide adenine dinucleotide (NAD+) in at least some cases of said disease, or a disease that is ameliorated by increasing NAD ⁺ levels.

[00231] The methods, drugs and compounds for use in accordance with the present invention are suitable for treating, alleviating symptoms or delaying the onset of a disorder associated with aberrant mitochondrial function. Disorders associated with aberrant mitochondrial function include, for example, metabolic disorders, neurodegenerative disorders, disorders associated with aging and chronic inflammatory disorders. Mitochondrial disorders also include diseases with inherited and/or acquired mitochondrial dysfunction (i.e., Charcot-Marie-Tooth disease type 2A2, mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS), Leigh syndrome, Barth syndrome, and Leber optic neuropathy), fatty acid oxidation disorders, inherited forms of deafness and blindness, and metabolic disorders induced by exposure to toxic chemicals and/or drugs ( e.g. , cisplatin-induced deafness).

[00232] Metabolic disorders include, for example, type II diabetes, obesity, hyperglycemia, impaired glucose tolerance, 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.

[00233] Neurodegenerative disorders include diseases such as photoreceptor degeneration ( i.e., retinitis pigmentosa), dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[00234] Chronic inflammatory diseases include conditions such as celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), irritable bowel disease, atherosclerosis, arthritis, and psoriasis.

[00235] Aging-related disorders include diseases such as cancer, dementia, cardiovascular disease ( e.g. , arteriosclerosis), hypertension, diabetes mellitus (type I or type II), arthritis, cataracts, Alzheimer's disease, macular degeneration, and osteoporosis.

[00236] A subject may have or be predisposed to developing a metabolic disorder. Subjects suffering from or at risk of developing a metabolic disorder are identified by methods known in the art. For example, diabetes can be diagnosed by measuring fasting blood glucose or insulin, or by means of a glucose tolerance test. A normal glucose level in an adult is approximately 60-126 mg/dL. A normal insulin level is approximately 7 mU/mL+3 mU. Hypertension can be diagnosed by blood pressure readings that are consistently at or above approximately 140/90. Cardiovascular disease can be diagnosed by measuring cholesterol levels. For example, an LDL cholesterol level greater than approximately 137 or a total cholesterol level greater than approximately 200 indicates cardiovascular disease. Hyperglycemia can be diagnosed by blood glucose levels above approximately 10 mmol/L (180 mg/dL). Impaired glucose tolerance can be diagnosed by glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol) after a 2-hour 75 g oral glucose tolerance test. Insulin resistance can be diagnosed by fasting serum insulin levels above approximately 60 pmol/L. Hypoglycemia can be diagnosed by blood glucose levels below approximately 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/ ^m2 (or lb/ ⁱⁿ² x 704.5). Alternatively, waist circumference (an estimate of fat distribution), waist-to-hip ratio (an estimate of fat distribution), skinfold thickness (when measured at multiple sites, an estimate of fat distribution), or bioimpedance (based on the principle that lean mass conducts current better than fat mass ( i.e. fat mass "resists" the current), an estimate of body fat%) may be measured. Parameters for individuals with normal weight, overweight, or obesity are as follows: underweight: BMI<18.5; normal: BMI from about 18.5 to about 24.9; overweight: BMI=from 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, a body weight-for-height ratio greater than 20% above the "normal" range, a body fat percentage greater than 30% for women and 25% for men, and a waist circumference greater than 102 cm (40 in) for men or 88 cm (35 in) for women. Severely or morbidly obese individuals are characterized by a BMI greater than 35.

[00237] The methods described herein may provide a reduction in the severity or alleviation 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 mmHg; abnormal blood fat levels, such as a high-density lipoprotein (HDL) level of less than or equal to 35 mg/dL, or a triglyceride level of greater than or equal to 250 mg/dL (mg/dL = milligrams of glucose per deciliter of blood). Efficacy of treatment is determined in combination with any known diagnostic method for a metabolic disorder. Alleviation of one or more symptoms of a metabolic disorder indicates that the compound has a beneficial clinical effect.

[00238] The methods of the present invention are suitable for treating, alleviating symptoms of, or delaying the onset of kidney disease. Kidney diseases include acute kidney injury (AKI) and chronic kidney disease (CKD).

[00239] A subject may have or be susceptible to developing 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 ability of the kidneys to remove nitrogen-containing 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% from baseline, an absolute increase in serum creatinine of at least 0.3 mg/dL from baseline, a decrease in glomerular filtration rate of at least 25% from baseline, a decrease in urine output to 0.5 mL per kilogram of body weight or less 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 a chemotherapeutic agent), viruses, and obstruction.

[00240] A subject may have or be susceptible to developing chronic kidney disease (CKD). Chronic kidney disease (CKD) is defined as either (1) the presence of kidney injury as defined by structural or functional abnormalities of the kidney for 3 months or longer, with or without a decrease in glomerular filtration rate (SFR), or (2) an SFR below 60 mL/min/1.73 ^m2 for 3 months or longer, with or without kidney injury. Subjects suffering from or at risk for developing chronic kidney disease (CKD) are identified by methods known in the art. Structural or functional abnormalities are manifested as symptoms, such as either pathological abnormalities or markers of kidney injury, including abnormalities detected in imaging studies, or blood or urine composition.

[00241] For example, CKD can be diagnosed by testing for a specific marker. 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., urine protein concentrations greater than about 100 mg/dL), albuminuria (i.e., urine albumin concentrations greater than about 100 mg/dL), blood intact parathyroid hormone (PTH) concentrations greater than about 150 pg/mL, or blood phosphate levels greater than about 4.5 mg/dL. One of the specific markers of kidney disease is an SCF rate above normal ( i.e. SCF above approximately 90 ml/min/1.73 ^m2 ), however, a SCF below normal also indicates CKD.

[00242] The methods of the present invention are suitable for treating, alleviating symptoms of, or delaying the onset of non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH). A subject may have or be predisposed to developing non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH). Subjects suffering from or at risk of developing non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH) are identified by methods known in the art. For example, NAFLD and/or NASH can be diagnosed by liver biopsy.

[00243] Non-alcoholic fatty liver disease (NAFLD), as defined herein, is a disease of fat deposition in the liver that occurs in patients whose history of alcohol consumption is not long enough to cause liver damage. Non-alcoholic fatty liver disease (NAFLD) can be further classified into simple fatty liver disease, steatohepatitis, and cirrhosis. Non-alcoholic steatohepatitis (NASH) refers to a pathology associated with inflammation, necrosis, ballooning, and fibrosis of liver cells. The onset of non-alcoholic simple fatty liver disease is induced by fat deposition in the liver cells, and this fat accumulation is determined by the balance between up-regulating factors (fat influx and synthesis in the liver cells) and down-regulating factors (fat catabolism and release from the liver cells). Once liver cell damage occurs in addition to this fat deposition, non-alcoholic simple fatty liver disease progresses to non-alcoholic steatohepatitis. Nonalcoholic steatohepatitis is progressive and may ultimately progress to cirrhosis and hepatocellular carcinoma.

Combination treatment

[00244] According to another aspect, the present invention includes a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in combination therapy. The compound, compositions, medicaments and compounds for use according to Formula (I) or (II), or a pharmaceutically acceptable salt thereof, can also be advantageously 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, dual PPAR/γ agonists, agonists PPARδ, biguanides, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, dipeptidyl peptidase IV (DPP-IV), sulfonylureas, meglitinides, alpha-glucoside hydrolase inhibitors, alpha-amylase inhibitors, insulin secretagogues, A2 antagonists, insulin or insulin mimetics, glycogen phosphorylase inhibitors, GLP-1 agonists, non-thiazolidinediones, glycokinase and 11 HSD-1 inhibitor; anti-obesity agents such as uncoupling protein activators (UCP-1, UCP-2, and UCP-3, 3-adrenergic receptor (3) agonists, thyroid hormone 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 factors (CNTh), cholecystokinin-A (CCK-A) agonists, opioid antagonists, orexin antagonists, acylestrogen, leptin, NPY 5 antagonists, neuropeptide Y5 (NPY5) antagonists, neuropeptide Y2 agonists (NPY2), melanin-concentrating hormone receptor (MCHLR) and melanin-concentrating hormone receptor 2 (MCH2R) antagonists, MCH1R antagonists, neuropeptide Y1, ghrelin antagonists, cannabinoid receptor 1 (CB-1), serotonin (5HT) transport inhibitors, CCK-A agonists, and histamine 3 (H3) antagonists/inverse agonists; cholesterol-lowering agents such as 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors, fibric acids, bile acid binding resins, probucol, and niacin (nicotinic acid); compounds that increase NAD levels⁺, such as NAD precursors⁺(those.nicotinamide ribose (NA), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide); and compounds that inhibit NAD uptake⁺, such as PARP inhibitors and CD38 inhibitors.

[00245] PPARy agonists suitable for the present invention include, but are not limited to, glitazones (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, CLX-09D21, 5-BTZD, etc.); GW-0207, LG-100641, LY-300512, LY-519818, R483 (Roche), T131 (Tularik), and the compounds described in W097/27857, 97/28115, 97/28137, and 97/27847; and pharmaceutically acceptable salts or esters thereof. Dual PPAR/γ agonists suitable for 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 the present invention include, but are not limited to, GW 501516, GW 590735 and the compounds described in JP 10237049, WO 02/14291 and WO 2018/125983; and pharmaceutically acceptable salts or esters thereof.

[00246] Biguanides suitable for the present invention include, but are not limited to, buformin, metformin, and phenformin, and pharmaceutically acceptable salts or esters thereof. Metformin (Glucophage®) is indicated for patients with non-insulin-dependent diabetes mellitus, particularly patients with refractory obesity. Physician's Desk Reference pp. 1080-1086, (56th ed. 2002).

[00247] Protein tyrosine phosphatase-1B (PTP-1B) inhibitors suitable for the present invention include, but are not limited to, A-401,674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, MC52453 and the compounds described in WO 02/26707, WO 02/26743, JP 2002114768, and pharmaceutically acceptable salts or esters thereof.

[00248] Dipeptidyl peptidase IV (DPP-IV) inhibitors such as isoleucine thiazolidide; NVP-DPP728; P32/98; and LAP 237, P 3298, TSL 225, valine pyrrolidide, TMC-2A/2B/2C, CD-26 inhibitors, FE 999011, P9310/K364, VIP 0177, DPP4, SDZ 274A444; and the compounds described 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.

[00249] Sulfonylureas suitable for the present invention include, but are not limited to, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, glicidone, glizolamide, tolazamide, and tolbutamide, and pharmaceutically acceptable salts or esters thereof. Meglitinides suitable for the present invention include, but are not limited to, repaglinide and nateglinide, and pharmaceutically acceptable salts or esters thereof.

[00250] Alpha-glucoside hydrolase inhibitors (or glucoside inhibitors) suitable for the present invention include, but are not limited to, acarbose, adiposin, camiglibose, emiglitate, miglitol, voglibose, pradimycin-Q, salbostatin, CKD-711, MDL-25,637, MDL-73,945, and MOR 14, and pharmaceutically acceptable salts or esters thereof, and the compounds described in U.S. Patent Nos. 4,062,950, 4,174,439, 4,254,256, 4,701,559, 4,639,436, 5,192,772, 4,634,765, 5,157,116, 5,504,078, 5,091,418, 5,217,877 and 5,091,524. Alpha-amylase inhibitors suitable for the present invention include, but are not limited to, tendamistat, trestatin and A1-3688, and pharmaceutically acceptable salts and esters thereof, and the compounds described in U.S. Patent Nos. 4,451,455, 4,623,714 and 4,273,765.

[00251] Insulin secretagogues suitable for the present invention include, but are not limited to, linogliride and A-4166, and pharmaceutically acceptable salts and esters thereof.

[00252] Fatty acid oxidation inhibitors suitable for the present invention include, but are not limited to, clomoxir and etomoxir, and pharmaceutically acceptable salts and esters thereof. A2 antagonists suitable for the present invention include, but are not limited to, midaglyzole, isaglydol, deriglydol, idazoxan, earoxan, fluparoxan, and pharmaceutically acceptable salts and esters thereof. Insulin or insulin mimetics suitable for the present invention include, but are not limited to, biota, LP-100, novarapide, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), insulin Lys-Pro, GLP-1 (73-7) (insulintropin) and GLP-1 (7-36)-NH2), and pharmaceutically acceptable salts or esters thereof.

[00253] Glycogen phosphorylase inhibitors suitable for the present invention include, but are not limited to, CP-368, 296, CP-316,819, BAYR3401, and the compounds described in WO 01/94300 and WO 02/20530, and pharmaceutically acceptable salts or esters thereof. GLP-1 agonists suitable for the present invention include, but are not limited to, exendin-3 and exendin-4, and the compounds described in US 2003087821 and NZ 504256, and pharmaceutically acceptable salts or esters thereof.

[00254] Non-thiazolidinediones suitable for the present invention include, but are not limited to, JT-501 and farglitazar (GW-2570/GI-262579), and pharmaceutically acceptable salts or esters thereof. Glycokinase activators suitable for the present invention include, but are not limited to, fused heteroaromatic compounds such as those described in US 2002103199, and isoindolin-1-one-substituted propionamide compounds such as those described in WO 02/48106.

[00255] Serotonin (5HT) transport inhibitors suitable for the present invention include, but are not limited to, paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine. Norepinephrine (NE) transport inhibitors suitable for 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 the present invention include those disclosed in: 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, W098/43636, W098/43635, 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. Particular CB-1 antagonists/inverse agonists suitable for 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 the present invention include GI 181771 and SR 146131. Ghrelin antagonists suitable for the present invention include those described in PCT Application Nos. WO 01/87335 and WO 02/08250. Histamine 3 (H3) antagonists/inverse agonists suitable for the present invention include: those described in PCT Application No. WO 02/15905 and O-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3 receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al. Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)) and proxyfan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000)). Specific H3 antagonists/inverse agonists suitable for the present invention include, but are not limited to, thioperamide, 3-(1H-imidazol-4-yl)propyl N-4-pentenyl)carbamate, clobenpropite, iodophenpropite, imoproxifan, GT2394 (Gliatech), and A331440.

[00256] Melanin-concentrating hormone receptor (MCHLR) antagonists and melanin-concentrating hormone 2 receptor (MCH2R) agonists/antagonists suitable for the present invention include those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809, and Japanese Patent Application No. JP 13226269. Specific MCH1R antagonists suitable for the present invention include, but are not limited to, T-226296 (Takeda), SB 568849, and SNAP 7941. Neuropeptide Y1 (NPY1) antagonists suitable for the present invention include those disclosed in 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 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 the present invention include, but are not limited to, peptide YY (PYY) and PYY3_36, peptide YY analogs, PYY agonists, and the compounds described in WO 03/026591, WO 03/057235, and WO 03/027637. Neuropeptide Y5 (NPY5) antagonists suitable for the present invention include, but are not limited to, the compounds described in U.S. Patent Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,337,332, 6,329,395, and 6,340,683, U.S. Patent Nos. 6,326,375, 6,329,395, 6,337,332, 6,335,345, European Patents EP-01010691 and EP 01044970, and PCT International Patent Application Publications WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, wo 01/09120, wo 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648 and WO 01/14376. Specific NPY5 antagonists useful 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 useful in the combinations of the present invention include, but are not limited to, the compounds described in Norman et al., J. Med. Chem. 43:42884312 (2000). Leptin includes, but is not limited to, recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant human methionyl leptin (Amgen). Leptin derivatives (e.g., truncated forms of leptin) useful herein include those disclosed in: Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283 and PCT International Publications WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519 and WO 96/235.

[00257] Opioid antagonists useful in the present disclosure include those described in: PCT Application No. WO 00/21509. Particular opioid antagonists suitable for the present invention include, but are not limited to, nalmefene (Revex), 3-methoxynaltrexone, naloxone, and naltrexone. Orexin antagonists suitable for the present invention include those described in: PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838, and WO 03/023561. Particular orexin antagonists suitable for the present invention include, but are not limited to, SB-334867-A. Acyl estrogens suitable for 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 the present invention include those described in U.S. Patent No. 5,739,106. Specific CCK-A agonists include, but are not limited to, AR-R 15849, GI181771, JMv-180, A-71378, A-71623, and SR146131. Specific ciliary neurotrophic factors (CNTh) suitable for the present invention include, but are not limited to, GI-181771 (GlaxoSmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, PD 149164 (Pfizer). CNTF derivatives suitable for the present invention include, but are not limited to, axokine (Regeneron) and those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813. Growth hormone secretagogue (GHS) agonists suitable for the present invention include those described in: U.S. Patent No. 6,358,951 and 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-692429, and L-163255.

[00258] 5HT2c agonists suitable for the present invention include those described in: 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. Particular 5HT2c agonists suitable for the present invention include, but are not limited to, BVT933, DPCA37215, 1K264, PNU 22394, WAY161503, R-1065, and YM 348.

[00259] Mc4r agonists suitable for the present invention include those disclosed in: 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 the present invention include CIR86036 (Chiron), ME-10142 and ME-10145 (Melacure).

[00260] Monoamine reuptake inhibitors suitable for the present invention include those described in: PCT Application Nos. WO 01/27068 and WO 01/62341. Particular monoamine reuptake inhibitors suitable for the present invention include, but are not limited to, sibutramine (Meridia O/Reductil), described in U.S. Patent Nos. 4,746,680, 4,806,570, and 5,436,272 and U.S. Patent Publication No. 2002/0006964.

[00261] Serotonin reuptake inhibitors and releasers suitable for 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.

[00262] An HSD-1 inhibitor suitable for the present invention includes, but is not limited to, BVT 3498, BVT 2733, and those compounds described in WO 01/90091, WO 01/90090, WO 01/90092. Uncoupling protein (UCP-1, UCP-2, and UCP-3) activators suitable for the present invention include those described in PCT Patent Application No. WO 99/00123. Particular uncoupled protein (UCP-1, UCP-2 and UCP-3) activators suitable for 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-naphthalenyl)-1-propenyl]benzoic acid (TTNPB) and retinoic acid.

[00263] β-adrenergic receptor (β) agonists suitable for the present invention include those disclosed in: U.S. Patent No. 5,705,515 and U.S. Patent No. 5,451,677, and PCT Patent Applications Nos. WO 01/74782 and WO 02/32897. Specific agonists suitable for 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, Trecadrin, Zeneca D7114, and SR 59119A.

[00264] Thyroid hormone agonists suitable for the present invention include those disclosed in PCT Application No. WO 02/15845 and Japanese Patent Application No. JP 2000256190. Specific thyroid hormone agonists suitable for the present invention include, but are not limited to, KB-2611 (KaroBioBMS). Specific fatty acid synthase (PAS) inhibitors suitable for the present invention include, but are not limited to, cerulenin and C75. Specific phosphodiesterase (PDE) inhibitors suitable for the present invention include, but are not limited to, theophylline, pentoxifylline, zaprinast, sildenafil, arnrinone, milrinone, cilostamide, rolipram, and cilomilast.

[00265] Lipase inhibitors suitable for the present invention include, but are not limited to, those disclosed in 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 useful in the present disclosure include, but are not limited to, tetrahydrolipstatin (orlistat/Xenical), Triton WR1339, RHC80267, lipstatin, tizaponin (teasaponin), and diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B and RHC 80267.

[00266] Examples of HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, and fluvastatin. Examples of HMG-CoA synthase inhibitors include the beta-lactone derivatives described in U.S. Patents 4,806,564, 4,816,477, 4,847,271, and 4,751,237; the beta-lactam derivatives described in U.S. Patent No. 4,983,597 and U.S. Ser. No. 07/540,992, filed June 20, 1990; and substituted oxacyclopropane analogues described in European Patent Publication EP 0 411 703. Examples of squalene epoxidase inhibitors are described in European Patent Publication EP 0 318 860 and Japanese Patent Publication J02 169-571A. Examples of LDL receptor gene inducer molecules are described in U.S. Patent 5,182,298, filed March 18, 1991. Other cholesterol-lowering agents that can be administered include niacin, probucol, fibric acids ( i.e., clofibrate and gemfibrozil), and LDL receptor gene inducers.

[00267] Examples of PARP inhibitors include, but are not limited to, iodonitocoumarin, 5-iodo-6-nitrocoumarin, 3,4-dihydro-5-methylisoquinolinone, 4-amino-l,8-naphthalimide, 3-methoxybenzamide, 8-hydroxy-2-methyl-3-hydroquinazolin-4-one, 2-{3-[4-(4-fluorophenyl)-3,6-dihydro-l(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)quinoxaline-5-carboxamide, 2-(3'-methoxyphenyl)benzirnidazole-4-carboxam, benzamide, 3-aminobenzamide, 3-aminophthalhydrazide and 1,5-dihydroxyisoquinoline.

[00268] The above-mentioned compounds, which can be used in combination with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be prepared and administered as described in the art, for example in the documents cited above.

[00269] The above compounds are merely illustrative of ACMSD inhibitors, antidiabetic agents, antiobesity agents, cholesterol-lowering agents, compounds that increase NAD ⁺ levels, compounds that inhibit NAD ⁺ consumption that can be used in the compositions of the present invention. Since this list of compounds is not exhaustive, any antiobesity agent and any antidiabetic agent can be used in the methods of the present invention and are not limited to any particular structural class of compounds.

[00270] As used herein, the term "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 a second agent as part of a specific treatment regimen that provides a beneficial effect as a result of the combined action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, a combined, e.g. , synergistic effect and/or a pharmacokinetic or pharmacodynamic co-effect, or any combination thereof, due to the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out over a certain period of time (usually minutes, hours, days, or weeks, depending on the combination selected). The term "combination therapy" may, but typically does not, encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and randomly provide the combinations of the present invention.

[00271] The term "combination therapy" includes sequential administration of the therapeutic agents, wherein each therapeutic agent is administered at different times and in any order, or alternately and in any order, as well as substantially simultaneous administration of the therapeutic agents or at least two therapeutic agents. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule of a fixed ratio of each therapeutic agent or multiple separate capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be accomplished by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of a selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence of administration of the therapeutic agents is not strictly critical.

Biological analysis and research in animals

ACMSD1 inhibition screening method

[00272] The activity of the compounds as ACMSD1 inhibitors was determined in an in vitro spectrophotometric assay. The assay premix was incubated and then the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the ACMSD1 solution were added. The effect of ACMS concentration on enzyme activity was examined by varying the concentration of 3-hydroxyanthranilic acid (3OH-HA) in the assay premix. Kinetic parameters were calculated from the initial rate data using a Lineweaver-Burk plot.

Cellular Analysis Methods

[00273] Mouse hepatocyte cell lines were grown and seeded. The cells were maintained in culture at 37°C, and after cell adhesion, various concentrations of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or DMSO were added. After approximately 24 hours, primary hepatocytes were harvested.

Determination of ACMSD-1 modulation in HEK293T cells.

[00274] HEK293T cells were seeded and transfected to transiently express ACMSD. The cells were then stimulated with various concentrations of the compound of Formula (I) or (II) and then lysed to measure ACMSD activity in an in vitro spectrophotometric assay. Total protein content in cell lysates was determined by the Bradford assay and used to determine specific enzyme activity normalized across all samples.

Determination of NAD content ⁺ in primary human hepatocytes

[00275] After seeding, primary hepatocytes were treated with various concentrations of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or MEHP (control). The compound was replaced every 24 hours, and then the cells were directly harvested and lysed for determination of NAD ⁺ content by LC-MS/MS (liquid chromatography-mass spectrometry/mass spectroscopy).

Modulation of SOD2 activity in AML12 cells and primary mouse hepatocytes

[00276] Primary hepatocytes or AML-12 cells were lysed and total protein concentration was determined using the Bradford assay. SOD2 activity was determined at the indicated time points after treatment with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, using the SOD Assay Kit. Absorbance was determined and the results were expressed as U/mL/mg protein according to the standard curve and the measured protein concentration.

Determination of NAD content ⁺ in primary mouse hepatocytes

[00277] NAD ⁺ was extracted using an acid extraction method, and samples were collected and homogenized. After precipitation of insoluble protein portions by centrifugation, samples were separated by high performance liquid chromatography (HPLC) and analyzed by mass spectrometry. Proteins in the pellet were quantified by the Bradford assay and used for normalization.

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

[00278] Cells (AML-12, Hepa-1.6, HEK-293, primary human and mouse hepatocytes) were treated with various concentrations of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the expression of the ACMSD, Pgc1a , Sod1 , and Sod2 (MnSOD) gene was determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Total RNA was extracted from the cells, and the extracted RNA was treated with DNase and used for reverse transcription (RT).

Modulation of caspase 3/7 activity in MDCK cells

[00279] MDCK cells were cultured in basal medium to a final concentration of 10%. Cells were seeded in 96 wells and 24 hours after cell seeding, the medium was replaced with fresh medium supplemented with 1% FBS. Cisplatin was then used to induce cell injury. Various concentrations of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof (in DMSO), were added in combination with cisplatin or before the addition of cisplatin. Caspase 3/7 activity (Promega) was determined according to standard methods using fluorescent signal reading on a plate reader. Each experiment/condition was performed in triplicate. Caspase activity was analyzed as a percent effect normalized to cells treated with cisplatin alone and vehicle.

Cytotoxicity and hERG screening

[00280] HePG2 and AML-12 cells were seeded and the dose-response relationship for the compound at various concentrations was determined. The cells were stimulated and the supernatant was used to release lactate dehydrogenase (LDH) as a measure of necrosis during cell lysis to determine ATP levels to determine cell viability.

[00281] The Predictor hERG assay kit was stably transfected with the hERG potassium channel and a high affinity red fluorescent ligand of the hERG channel and used to determine the affinity binding of the hERG channel by compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. Compounds that bind to the hERG channel protein (competing compounds) were identified by their ability to displace the indicator, resulting in lower fluorescence polarization.

C. elegans experiments - ACMSD1 silencing, lifespan assays, motility assessment and GFP quantification

[00282] ACMSD1 Silencing: Bacterial feeder RNAi experiments to determine the effects of down-regulation or silencing of acmsd-1 on gene expression and survival were performed in the nematode Caenorhabditis elegans ( C. elegans ). The clones used for bacterial feeding experiments were acmsd-1, SIR-2.1, and DAF-16. Total RNA was extracted from the cells, and the extracted RNA was treated with DNase and used for reverse transcription (RT).

[00283] Worms were grown on NGM agar plates supplemented with carbenicillin and IPTG and plated with bacterial cultures. Following RNAi treatment, worms were transferred to paraquat-containing plates and plated with RNAi bacteria. Control animals were grown on RNAi bacteria containing empty vector (control) and then transferred to paraquat-containing plates and plated with RNAi bacteria. Quantification of sod-3 gene expression at mRNA and protein levels was performed using RT-qPCR and survival assays. Worm movement was recorded at days 1, 3, and 5 of adulthood.

Antidiabetic activity studies in C57BL/6J and KK-Ay mice

[00284] Mice were fed a normal diet or a high-fat diet (HFD). The compound of Formula (I) or a pharmaceutically acceptable salt thereof was administered daily, and blood and tissues were collected for RNA extraction, lipid measurements, and histology. Oxygen consumption was measured, 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 concentrations.

Antidiabetic and antiobesity studies in LepR mutant db/db mice

[00285] Animals were fed a high fat diet (HFD). For subchronic interventions, animals were treated once daily with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for 14 days. Blood samples were collected and the glucose concentration in each blood sample was determined. For acute interventions, baseline blood samples were collected and then compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, were administered. Food access was then restricted and a second blood sample was collected. Mice were subjected to an oral glucose tolerance test and blood glucose concentrations were determined.

[00286] For the euglycemic hyperinsulinemic clamp test, animals received a primary continuous infusion of [3-³H]glucose, and then a blood sample was taken to determine plasma concentrations of insulin, glucose, and [3-³H]glucose, and calculation of basal rates of endogenous glucose appearance. The mice then received vehicle or a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.throughgastric tube. The animals were then given an infusion [3-³H]glucose containing insulin, which produces a modest net increase in plasma insulin concentrations. Blood glucose concentrations were measured and target glycemia was achieved by adjusting the glucose infusion rate. 2-deoxy-D-[1-¹⁴C] glucose and blood samples were taken. The mice were then sacrificed. Gastrocnemius muscle tissue and epididymal adipose tissue were collected and [³H]- and [¹⁴[C]-radioactivity in deproteinized plasma.

[00287] Body weight was assessed and brown adipose tissue (BAT) and gonadal white adipose tissue (WAT) were excised and weighed. Volume of oxygen ( _VO2 ) and volume of carbon dioxide production ( _VCO2 ) were measured and reported as mean _VO2 per hour normalized to body weight (mL/h/kg). Infrared beam interruption activity index and food intake were measured simultaneously.

Studies of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in male C57BL/6J mice

[00288] Mice were fed a Western HF-HSD diet or a normal chow diet (NCD) as a control. Animals were then treated with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for 4, 12, or 20 weeks and then sacrificed. Body weight and food intake were monitored weekly and total fat mass was analyzed. An intraperitoneal glucose tolerance test (IPGTT) was also performed and tail vein glucose levels were measured after glucose administration. Insulin resistance was calculated using a homeostatic model for insulin resistance. Mice were then sacrificed by collecting a blood sample via cardiac puncture. Plasma was obtained and tissues were collected along with the plasma for further biochemical and molecular analyses or for histological analysis.

Studies of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in methionine- and choline-deficient mice

[00289] Mice weighing 25 g were fed either a methionine-choline deficient diet (MCD to induce NASH) or a chow diet (as a control). Animal experiments and assessment of NAFLD and NASH were performed as described above for C57BL/6J mice fed a high-fat, high-sucrose diet.

Atherosclerosis studies in LDL-R knockout mice fed a high cholesterol diet

[00290] LDL-R knockout (KO) mice were sacrificed approximately 12 weeks after initiation of atherogenic feeding, and the hearts and aortas were perfused with PBS and then fixed. Atherosclerosis and biochemical parameters were measured using appropriate commercially available kits. For in vivo lipopolysaccharide (LPS) studies, mice were injected with LPS intraperitoneally and tail vein blood was collected. TNF levels were quantified using a mouse TNF ELISA assay. Blood cell counts were determined.

Studies of inherited mitochondrial diseases in Sco2 mice ^KO/KI

[00291] Compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof were dissolved in water and added to a standard powder diet at the appropriate concentration. The diet was changed every three days and given ad libitum for one month. Tissues were collected for histological analysis. Spectrophotometric activity of cI, cII, cIII, and cIV, as well as CS, was measured for quadriceps samples. NAD ⁺ was extracted from the tissues using acid and base extraction methods, respectively, and analyzed by mass spectrometry.

Studies of inherited mitochondrial disease in deletor mice

[00292] Male delator and wild-type mice were either fed chow diet (CD) or administered a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, with CD. The mice were monitored regularly for body weight, food intake, and exercise capacity, and their exercise capacity was measured. Oxygen consumption and carbon dioxide production, as well as spontaneous locomotor and feeding activity, were recorded. Tissue sections from the quadriceps, liver, and BAT were collected and dissected. Frozen quadriceps sections were analyzed for cyclooxygenase (COX) histochemical activity. and succinate dehydrogenase (SDH)in situ, cristae content in both BAT and muscle was determined using electron micrographs, and skeletal muscle samples were analyzed for citrate synthase activity.

Kidney disease research

[00293] Wild-type C57BL/6J mice were fed a standard commercial diet and divided into four groups: control; cisplatin; a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, alone. Mice were sacrificed and tissue samples and serum were collected. Creatinine and blood urea nitrogen (BUN) levels were measured, and proinflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified from serum or renal tissue homogenates. Mouse kidneys were collected and stained for analysis. Tubular damage was examined and assessed based on the percentage of cortical tubular necrosis. Neutrophil infiltration in stained tissue was quantified by counting the number of neutrophils per high-power field.

[00294] Alternatively, wild-type C57BL/6J mice were numbered and allowed to acclimate for a specified period and then randomized to different treatment groups based on their body weight. The different groups were maintained on a specific diet for a specified period of time. Body weight was measured and food intake was assessed. Blood was collected by retro-orbital puncture under light anesthesia and used to analyze basal blood urea nitrogen (BUN) levels.

[00295] Mice were anesthetized and placed on a surgical platform. Both kidneys were exposed by incisions and the renal pedicles were clamped using vascular clamps. The clamps were then removed and the surgical site was sutured. The sham-operated group underwent similar surgical procedures except that the clamping clamp was not used. Animals were monitored until recovery from anesthesia and they were returned to their home cage. Animals were observed daily for general clinical signs and symptoms and mortality.

[00296] On the day before termination, animals were individually placed in metabolic cages and urine was collected for assessment of urea, creatinine, sodium, and potassium. Blood was also collected by retroorbital puncture under light anesthesia and plasma was used for analysis of blood urea nitrogen (BUN) and serum creatinine levels. Animals were then euthanized and organs were collected. One kidney was fixed and the other was flash frozen and used for assessment of lipid peroxidation, GSH, MPO, and SOD levels.

Studies of ischemia/reperfusion-induced acute kidney injury

[00297] CD-1 (ICR) mice were treated with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, by gavage once daily. CD-1 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 randomized into two groups: mice receiving a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and mice receiving a vehicle control. Serum creatinine levels were measured and BUN measurements were recorded. Kidney tissue and tubular injury were then assessed.

Studies of cisplatin-induced acute kidney injury

[00298] C57BL6 mice were treated with compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, by gavage once daily. The animals were allowed to recover and sacrificed at 48, 72, and 96 hours after cisplatin injection.

[00299] Serum creatinine was measured as the primary endpoint. Tubular injury was scored on a 0-4 scale based on the percentage of tubules with necrosis, dilation, or cell swelling: 0, less than 5%; 1, 5-25%; 2, 25-50%; 3, 50-75%; and 4, greater than 75%. All high-power fields (x400) in the cortex and outer medulla were assessed by a blinded pathologist.

Effect on sepsis-induced acute kidney injury

[00300] C57BL6 mice (12-15 weeks old) were treated with compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, by intraperitoneal injection following sepsis induced by cecal ligation and puncture.

[00301] At the time of sacrifice, blood and kidney tissue were collected for measurement of primary and secondary endpoints. Primary endpoint (at 48 hours): serum creatinine. Secondary endpoints (at 48 hours) include: macrophage phenotype marker (IF staining), plasma NGAL, plasma and kidney inflammatory markers (IL-6, IL-18, TNF), and kidney injury markers (KIM-1, NGAL, TIMP2, and IGFBP7). Additional endpoints include; cell death (IF: annexin V and propidium iodide; caspase 3/7), autophagy, biogenesis (PGC-1, mitochondrial DNA), OXPHOS (complex I, III, IV activity), Sirt1 and Sirt3 expression, AMPK (total, P-AMPK, P-ACC and HIF-1.

[00302] Histological analysis was performed using H&E and PAS staining using standard protocols. Images were collected and analyzed using a light microscope (IX71, Olympus, Tokyo, Japan) with DP analysis software (DP70-BSW, Tokyo, Japan). Tubular injury in PAS-stained kidney sections was scored based on the percentage of tubular cortical necrosis: 0=normal, 1=1-10, 2=11-25, 3=26-45, 4=46-75, and 5=76-100%. Tubular injury score was used to evaluate protection against kidney injury.

Determination of the effect on FoxO1 phosphorylation levels

[00303] 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 each protein present was detected using a specific antibody.

Inhibitory action

[00304] The present invention also relates to a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, as defined herein, 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 a related embodiment, the method further comprises the presence of the compound in an amount effective to provide a concentration sufficient to selectively inhibit ACMSD in the cell.

[00305] Thus, preferably in an ACMSD inhibition assay ( i.e., in an ACMSD assay described herein, such as in Biological Example 1, or in ACMSD assays known in the literature), preferred compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, are compounds capable of reducing or preferentially inhibiting ACMSD and increasing NAD ⁺ levels and/or activating SIRT and SIRT downstream targets such as PGC-1, FoxO1, and/or SOD. Preferably, said inhibition is determined as the IC ₅₀ of said compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, according to said ACMSD inhibition assay. Preferred compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, have an IC ₅₀ at or below 1 μM, more preferably less than 300 nM, such as less than 100 nM, such as less than 50 nM, for inhibition of ACMSD.

Illustrative implementation options

[00306] Some embodiments of the present description are the following embodiments of I:

[00307] Implementation variant I-1. The compound represented by Formula (I):

(I)

or a pharmaceutically acceptable salt or tautomer thereof,

Where:

X is H, S, SR ² , NR ² , NR ² R ^2' , O, OH, OR ^h , F, Br or Cl;

W represents N or C;

(i) if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

(ii) if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

Y ¹ represents O, NR ⁴ or S(O) _q ;

each Y ² independently represents O, NH or S;

R ¹ is absent or is C ₆ -C ₁₀ arylene or heteroarylene, said heteroarylene comprising one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene or heteroarylene is optionally substituted with one or two R ^e ;

R ² is H or C ₁ -C ₄ alkyl;

R ^2' is H, C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; or

R ² and R ^2' together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O and S;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is H or C ₁ -C ₄ alkyl;

each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl;

each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl;

R ⁷ is H, A, B or C;

A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol, -(CH ₂ ) _r P(O)(OH)OR ^x , -(CH ₂ ) _r S(O) ₂ OH, -(CH ₂ ) _r C(O)NHCN or -(CH ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol optionally substituted with C ₁ -C ₆ alkyl,

B represents -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NR ^g R ^g' , -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ ^Rx , -(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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x ,

C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups;

R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x or -CO ₂ R ^x ;

R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;

each R ^e at each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN;

R ^f is absent, is H or methyl;

R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ ;

R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH;

R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

R ⁱ is (i) -(CH ₂ ) _s OC(O)C ₁ -C ₆ alkyl, wherein said alkyl is substituted with one or more NH ₂ ; (ii) (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH; or (iii) C ₁ -C ₆ alkyl substituted with one or more substituents each independently selected from OH and 4-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N or S;

R ^j is absent, represents H, C ₁ -C ₆ alkyl, or -CN;

each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl;

each R ^y and R ^z independently represents H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each m, p, q, r, and t is independently equal to 0, 1, or 2;

n is 0, 1, 2 or 3;

s is 1 or 2;

o is equal to 0, 1, 2, 3 or 4; And

represents a single bond or a double bond; and

provided that

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; then R ⁷ is not -COOH;

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; and R ⁷ is tetrazole; then R ^c is not H;

if X is O; R^frepresents H; W represents C; R^jrepresents -CN; L represents -S-C(R⁵)₂or -SCH₂CH₂-; R¹absent; then R⁷does not represent COOH or tetrazole;

if X is O, R ^f is H; W is N; R ^j is absent; R ^d is methyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH ₂ - or -OCH ₂ -; and R ¹ is phenylene; then R ⁷ is not -COOH, -CH ₂ COOH, or ; And

if X is O, R ^f is H, W is N, R ^j is absent, L is -NHCH ₂ -, -CH ₂ NH-, or -NH-C(O)-, and R ¹ is phenylene, then R ^d is not phenyl.

[00308] Implementation variant I-2. The compound according to embodiment I-1, characterized in that X is O, OH, OR^h, F, Br or Cl.

[00309] Embodiment I-3. The compound of embodiment I-1, wherein X is H, S, SR ² , NR ² , or NR ² R ^2' .

[00310] Embodiment I-4. A connection according to any of embodiments I-1 - I-3, characterized in that R ^f is absent.

[00311] Embodiment I-5. A compound according to any one of embodiments I-1 through I-3, wherein R ^f is H or methyl.

[00312] Embodiment I-6. A connection according to any one of embodiments I-1 - I-5, characterized in that W is N.

[00313] Embodiment I-7. The connection of embodiment I-6, characterized in that R ^j is absent.

[00314] Embodiment I-8. The connection of any one of embodiments I-1 - I-5, characterized in that W is C.

[00315] Embodiment I-9. The compound of embodiment I-8 wherein R ^j is H, C ₁ -C ₆ alkyl, or -CN.

[00316] Embodiment I-10. The compound of embodiment I-8 or I-9, wherein R ^j is -CN.

[00317] Embodiment I-11. A compound according to any one of embodiments I-1 through I-10, wherein R ^c is C ₁ -C ₆ alkyl, -CN, or halogen.

[00318] Embodiment I-12. A compound according to any one of embodiments I-1 through I-11, wherein R ^c is -CN or halogen.

[00319] Embodiment I-13. A compound according to any one of embodiments I-1 through I-12, wherein R ^c is -CN.

[00320] Embodiment I-14. A compound according to any one of embodiments I-1 through I-13, wherein R ^d is methyl.

[00321] Embodiment I-15. A compound of any one of embodiments I-1 through I-13 wherein R ^d is an optionally substituted 5-10 membered aryl.

[00322] Embodiment I-16. A compound of any one of embodiments I-1 through I-13 wherein R ^d is an optionally substituted 5- or 6-membered heteroaryl.

[00323] Embodiment I-17. A compound of any one of embodiments I-1 through I-13 wherein R ^d is optionally substituted 5- or 6-membered cycloalkyl.

[00324] Embodiment I-18. A compound of any one of embodiments I-1 through I-13 wherein R ^d is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.

[00325] 19. A connection according to any of the embodiments I-1 - I-13, characterized in that R^drepresents methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl or optionally substituted phenyl.

[00326] Embodiment I-20. A compound according to any one of embodiments I-1 through I-13, wherein R ^d is methyl.

[00327] Embodiment I-21. The compound of any one of embodiments I-1 through I-13, wherein R ^d is -CF ₃ .

[00328] Embodiment I-22. The compound of any one of embodiments I-1 through I-13, wherein R ^d is CR ^f F ₂ .

[00329] Embodiment I-23. A compound of any one of embodiments I-1 through I-13 wherein R ^d is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _r -5- or 6-membered cycloalkyl.

[00330] Embodiment I-24. A compound according to any one of embodiments I-1 through I-13, wherein R ^d is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl.

[00331] Embodiment I-25. The compound of any one of embodiments I-1 through I-24, wherein L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p -.

[00332] Embodiment I-26. The compound of embodiment I-25, wherein Y ¹ is S.

[00333] Embodiment I-27. The compound of any one of embodiments I-1 through I-24, 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-.

[00334] Embodiment I-28. A compound according to any one of embodiments I-1 through I-27, wherein R ¹ is C ₆ -C ₁₀ arylene.

[00335] Embodiment I-29. A compound according to any one of embodiments I-1 through I-27, wherein R ¹ is heteroarylene.

[00336] Embodiment I-30. A compound according to any of embodiments I-1 - I-27, characterized in that R ¹ is absent.

[00337] Embodiment I-31. A compound according to any one of embodiments I-1 - I-30, characterized in that R ⁷ is A.

[00338] Embodiment I-32. A compound of embodiment I-31 wherein A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole, wherein said -(CH ₂ ) _r tetrazole is optionally substituted with C ₁ -C ₆ alkyl.

[00339] Embodiment I-33. A compound according to any one of embodiments I-1 - I-30, characterized in that R ⁷ is B.

[00340] Embodiment I-34. The compound of embodiment I-31 wherein B is -(CH ₂ ) _r C(O)NR ^g R ^g' or -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' .

[00341] Embodiment I-35. The compound of any one of embodiments I-1 through I-30, wherein R ⁷ is C.

[00342] Embodiment I-36. The compound of embodiment I-31 wherein C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, or -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, wherein said aryl is substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, and OH.

[00343] Embodiment I-37. A compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof selected from the group consisting of:

Connection No. Structure I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30 I-31 I-32 I-33 I-34 I-35 And I-36

[00344] Embodiment I-38. A compound, pharmaceutically acceptable salt, or tautomer thereof selected from the group consisting of:

And

[00345] Embodiment I-39. A pharmaceutical composition comprising a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[00346] Embodiment I-40. The pharmaceutical composition of embodiment I-39 comprising one or more additional therapeutic agents.

[00347] Embodiment I-41. A method of treating, preventing, or reducing the risk of a disease or disorder inhibited by β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof.

[00348] Embodiment I-42. A method of treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing said disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof.

[00349] Implementation variant I-43. The method according to any one of embodiments I-41 - I-42, characterized in that said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency.

[00350] Embodiment I-44. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00351] Embodiment I-45. The method of embodiment I-44, wherein said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease.

[00352] Embodiment I-46. The method of embodiment I-45, wherein the general metabolic disorder is obesity or type II diabetes.

[00353] Embodiment I-47. A method for accelerating oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of one or more compounds of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00354] Embodiment I-48. A compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[00355] Embodiment I-49. A compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00356] Embodiment I-50. A compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00357] Embodiment I-51. A compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for use in accelerating oxidative metabolism.

[00358] Embodiment I-52. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with β-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00359] Embodiment I-53. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00360] Embodiment I-54. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00361] Embodiment I-55. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, to accelerate oxidative metabolism.

[00362] Embodiment I-56. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00363] Embodiment I-57. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00364] Embodiment I-58. Use of a compound of any one of embodiments I-1 through I-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.

[00365] Embodiment I-59. Use of a compound of any one of embodiments I-1 through I-38, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for accelerating oxidative metabolism.

[00366] Embodiment I-60. A method of treating, preventing, or reducing the risk of a disease or disorder inhibited by β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[00367] Embodiment I-61. A method of treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of a pharmaceutical composition of embodiment I-39.

[00368] Implementation variant I-62. The method according to any one of embodiments I-60 - I-61, characterized in that said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with excessive growth of microflora or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration of the transplant, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency.

[00369] Embodiment I-63. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[00370] Embodiment I-64. The method of embodiment I-63, wherein said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease.

[00371] Embodiment I-65. The method of claim 64, wherein the general metabolic disorder is obesity or type II diabetes.

[00372] Embodiment I-66. A method of treating acceleration of oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment I-39.

[00373] Embodiment I-67. The pharmaceutical composition of embodiment I-39 for use as a medicine.

[00374] I-68 implementation variant. A pharmaceutical composition according to embodiment I-39 for use in treating, preventing or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD)⁺).

[00375] Embodiment I-69. The pharmaceutical composition of embodiment I-39 for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00376] Embodiment I-70. The pharmaceutical composition of embodiment I-39 for use in accelerating oxidative metabolism.

[00377] Embodiment I-71. Use of a pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disease or disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00378] Embodiment I-72. Use of a pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00379] Embodiment I-73. Use of a pharmaceutical composition of embodiment I-39 for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00380] Embodiment I-74. Use of the pharmaceutical composition of embodiment I-39 to accelerate oxidative metabolism.

[00381] Embodiment I-75. Use of a pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00382] Embodiment I-76. Use of a pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00383] Embodiment I-77. Use of a pharmaceutical composition of embodiment I-39 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00384] Embodiment I-78. Use of the pharmaceutical composition of embodiment I-39 in the manufacture of a medicinal product for accelerating oxidative metabolism.

[00385] Embodiment II-1. A compound represented by formula (II):

(II)

or a pharmaceutically acceptable salt or tautomer thereof, wherein:

X is H, S, SR ² , NR ² , NR ² R ^2' , O, OH, OR ^h , F, Br or Cl;

W represents N or C;

(i) if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

(ii) if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

Y ¹ represents O, NR ⁴ or S(O) _q ;

each Y ² independently represents O, NH or S;

R ¹ is absent or represents C ₆ -C ₁₀ arylene, heteroarylene or C ₃ -C ₈ cycloalkylene, wherein said heteroarylene contains one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene, heteroarylene and C ₃ -C ₈ cycloalkylene are optionally substituted with one or two R ^e ;

R ² is H or C ₁ -C ₄ alkyl;

R ^2' is H, C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; or

R ² and R ^2' together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O and S;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is H or C ₁ -C ₄ alkyl;

each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl;

each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl;

R ⁷ is H, A, B or C;

A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol, -(C(R ⁶ ) ₂ ) _r P(O)(OH)OR ^x , -(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r C(O)NHCN or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein -(C(R ⁶ ) ₂ ) _r tetrazole, -(C(R ⁶ ) ₂ ) _r oxadiazolone, -(C(R ⁶ ) ₂ ) _r tetrazolone, -(C(R ⁶ ) ₂ ) _r thiadiazolol, -(C(R ⁶ ) ₂ ) _r isoxazol-3-ol are optionally substituted with C ₁ -C ₆ alkyl,

B represents -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ R ^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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x ,

C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups;

R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x or -CO ₂ R ^x ;

R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;

each R ^e at each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN;

R ^f is absent, is H or methyl;

R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ ;

R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH;

R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

R ⁱ is (i) -(CH ₂ ) _s OC(O)C ₁ -C ₆ alkyl, wherein said alkyl is substituted with one or more NH ₂ ; (ii) (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH; or (iii) C ₁ -C ₆ alkyl substituted with one or more substituents each independently selected from OH and 4-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N or S;

R ^j is absent, represents H, C ₁ -C ₆ alkyl, or -CN;

each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl;

each R ^y and R ^z independently represents H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each m, p, q, r, and t is independently equal to 0, 1, or 2;

n is 0, 1, 2 or 3;

s is 1 or 2;

o is equal to 0, 1, 2, 3 or 4; And

represents a single bond or a double bond; and

provided that

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; then R ⁷ is not -COOH;

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; and R ⁷ is tetrazole; then R ^c is not H;

if X is O; R^frepresents H; W represents C; R^jrepresents -CN; L represents -S-C(R⁵)₂or -SCH₂CH₂-; R¹absent; then R⁷does not represent COOH or tetrazole;

if X is O, R ^f is H; W is N; R ^j is absent; R ^d is methyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH ₂ - or -OCH ₂ -; and R ¹ is phenylene; then R ⁷ is not -COOH, -CH ₂ COOH, or ; And

if X is O, R ^f is H, W is N, R ^j is absent, L is -NHCH ₂ -, -CH ₂ NH-, or -NH-C(O)-, and R ¹ is phenylene, then R ^d is not phenyl.

[00386] Embodiment II-2. A compound represented by Formula (I):

(I)

or a pharmaceutically acceptable salt or tautomer thereof,

Where:

X is H, S, SR ² , NR ² , NR ² R ^2' , O, OH, OR ^h , F, Br or Cl;

W represents N or C;

(i) if 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 pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

(ii) if 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)(CH ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)O(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m C=(O)NR ³ (C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m NR ³ C=(O)(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m phenyl(C(R ⁵ ) ₂ ) _p -, -(C(R ⁵ ) ₂ ) _m pyridinyl(C(R ⁵ ) ₂ ) _p - or -(C(R ⁵ ) ₂ ) _m thiophenyl(C(R ⁵ ) ₂ ) _p -;

Y ¹ represents O, NR ⁴ or S(O) _q ;

each Y ² independently represents O, NH or S;

R ¹ is absent or is C ₆ -C ₁₀ arylene or heteroarylene, said heteroarylene comprising one or two 5-7 membered rings and 1-4 heteroatoms selected from N, O and S, and wherein said C ₆ -C ₁₀ arylene or heteroarylene is optionally substituted with one or two R ^e ;

R ² is H or C ₁ -C ₄ alkyl;

R ^2' is H, C ₁ -C ₄ alkyl or C ₃ -C ₇ cycloalkyl; or

R ² and R ^2' together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring containing 1-3 additional heteroatoms selected from N, O and S;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is H or C ₁ -C ₄ alkyl;

each R ⁵ at each occurrence is independently H or C ₁ -C ₄ alkyl;

each R ⁶ at each occurrence is independently H or C ₁ -C ₄ alkyl;

R ⁷ is H, A, B or C;

A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -Y ² (C(R ⁶ ) ₂ ) _r CO ₂ R ^x , -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol, -(CH ₂ ) _r P(O)(OH)OR ^x , -(CH ₂ ) _r S(O) ₂ OH, -(CH ₂ ) _r C(O)NHCN or -(CH ₂ ) _r C(O)NHS(O) ₂ alkyl, wherein -(CH ₂ ) _r tetrazole, -(CH ₂ ) _r oxadiazolone, -(CH ₂ ) _r tetrazolone, -(CH ₂ ) _r thiadiazolol, -(CH ₂ ) _r isoxazol-3-ol optionally substituted with C ₁ -C ₆ alkyl,

B represents -(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OC ₁ -C ₄ alkyl, -Y ² (C(R ⁶ ) ₂ ) _r C(O)NR ^g R ^g' , -Y ² (C(R ⁶ ) ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NR ^g R ^g' , -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' , -(CH ₂ ) _r C(O)NHS(O) ₂ NR ^g R ^g' , -(C(R ⁶ ) ₂ ) _r CO ₂ R ⁱ , -(C(R ⁶ ) ₂ ) _r NH ₂ CO ₂ ^Rx , -(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) ₂ OH, -O(C(R ⁶ ) ₂ ) _r S(O) ₂ OH, -(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x or -O(C(R ⁶ ) ₂ ) _r P(O) ₂ OR ^x ,

C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, halogen, -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r SC ₆ -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=CHCO ₂ R ^x or -(C(R ⁶ ) ₂ ) _r C(O)NHS(O) ₂ C ₁ -C ₄ alkyl, wherein said aryl and heteroaryl are substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen and OH, and wherein said heterocycloalkyl is substituted with one to two =O or =S groups;

R ^c is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -CN, -OR ^x or -CO ₂ R ^x ;

R ^d is methyl, CF ₃ , CR ^f F ₂ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _t -5- or 6-membered cycloalkyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;

each R ^e at each occurrence is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, C ₁ -C ₆ haloalkyl, -NHR ^z , -OH, or -CN;

R ^f is absent, is H or methyl;

R ^g is H, C ₁ -C ₆ alkyl, OH, -S(O) ₂ (C ₁ -C ₆ alkyl), or S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ ;

R ^g' is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, a 4-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O and S, C ₆ -C ₁₀ aryl or a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen and -OH, and wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, halogen and -OH;

R ^h is H, C ₁ -C ₄ alkyl, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, O, and S, wherein said alkyl is optionally substituted with one or more substituents each independently selected from NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, and C(O)NH ₂ ; and wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

R ⁱ is (i) -(CH ₂ ) _s OC(O)C ₁ -C ₆ alkyl, wherein said alkyl is substituted with one or more NH ₂ ; (ii) (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH; or (iii) C ₁ -C ₆ alkyl substituted with one or more substituents each independently selected from OH and 4-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N or S;

R ^j is absent, represents H, C ₁ -C ₆ alkyl, or -CN;

each R ^x at each occurrence is independently H, C ₁ -C ₆ alkyl, or C ₆ -C ₁₀ aryl;

each R ^y and R ^z independently represents H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each m, p, q, r, and t is independently equal to 0, 1, or 2;

n is 0, 1, 2 or 3;

s is 1 or 2;

o is equal to 0, 1, 2, 3 or 4; And

represents a single bond or a double bond; and

provided that

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; then R ⁷ is not -COOH;

if X is O; R ^f is H; W is C; R ^j is -CN; L is -SCH ₂ -; R ¹ is phenylene or pyridine; and R ⁷ is tetrazole; then R ^c is not H;

if X is O; R^frepresents H; W represents C; R^jrepresents -CN; L represents -S-C(R⁵)₂or -SCH₂CH₂-; R¹absent; then R⁷does not represent COOH or tetrazole;

if X is O, R ^f is H; W is N; R ^j is absent; R ^d is methyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is -SCH ₂ - or -OCH ₂ -; and R ¹ is phenylene; then R ⁷ is not -COOH, -CH ₂ COOH, or ; And

if X is O, R ^f is H, W is N, R ^j is absent, L is -NHCH ₂ -, -CH ₂ NH-, or -NH-C(O)-, and R ¹ is phenylene, then R ^d is not phenyl.

[00387] Embodiment II-3. The compound of embodiment II-1 or II-2, wherein X is O, OH, OR ^h , F, Br, or Cl.

[00388] Embodiment II-4. The compound of embodiment II-1 or II-2, wherein X is H, S, SR ² , NR ² , or NR ² R ^2' .

[00389] Embodiment II-5. A compound according to any one of embodiments II-1 - II-4, characterized in that R ^f is absent.

[00390] Embodiment II-6. A compound according to any one of embodiments II-1 through II-4, wherein R ^f is H or methyl.

[00391] Embodiment II-7. A compound according to any one of embodiments II-1 through II-6, wherein W is N.

[00392] Embodiment II-8. The compound of embodiment II-7, wherein R ^j is absent.

[00393] Embodiment II-9. A compound according to any one of embodiments II-1 through II-6, wherein W is C.

[00394] Embodiment II-10. The compound of embodiment II-9 wherein R ^j is H, C ₁ -C ₆ alkyl, or -CN.

[00395] Embodiment II-11. The compound of embodiments II-9 or II-10, wherein R ^j is -CN.

[00396] Embodiment II-12. The compound of any one of embodiments II-1 through II-11, wherein R ^c is C ₁ -C ₆ alkyl, -CN, or halogen.

[00397] Embodiment II-13. A compound according to any one of embodiments II-1 through II-12, wherein R ^c is -CN or halogen.

[00398] Embodiment II-14. The compound of any one of embodiments II-1 through II-12, wherein R ^c is -CN.

[00399] Embodiment II-15. A compound according to any one of embodiments II-1 through II-14, wherein R ^d is methyl.

[00400] Embodiment II-16. A compound according to any one of embodiments II-1 through II-14, wherein R ^d is an optionally substituted 5-10 membered aryl.

[00401] Embodiment II-17. A compound of any one of Embodiments II-1 through II-14 wherein R ^d is an optionally substituted 5- or 6-membered heteroaryl.

[00402] Embodiment II-18. A compound according to any one of Embodiments II-1 through II-14, wherein R ^d is optionally substituted 5- or 6-membered cycloalkyl.

[00403] Embodiment II-19. A compound of any one of embodiments II-1 through II-14 wherein R ^d is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.

[00404] Embodiment II-20. A compound of any one of Embodiments II-1 through II-14 wherein R ^d is methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl, or optionally substituted phenyl.

[00405] Embodiment II-21. A compound according to any one of embodiments II-1 through II-14, wherein R ^d is methyl.

[00406] Embodiment II-22. The compound of any one of embodiments II-1 through II-14, wherein R ^d is -CF ₃ .

[00407] Embodiment II-23. The compound of any one of embodiments II-1 through II-14, wherein R ^d is CR ^f F ₂ .

[00408] Embodiment II-24. The compound of any one of embodiments II-1 through II-14 wherein R ^d is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, -(C(R ⁶ ) ₂ ) _r -5- or 6-membered heteroaryl, -(C(R ⁶ ) ₂ ) _r -5- or 6-membered cycloalkyl.

[00409] Embodiment II-25. The compound of any one of embodiments II-1 through II-14, wherein R ^d is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl.

[00410] Embodiment II-26. The compound of any one of embodiments II-1 through II-25, wherein L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p -.

[00411] Embodiment II-27. The compound of embodiment II-26, wherein Y ¹ is S.

[00412] Embodiment II-28. The compound of any one of embodiments II-1 through 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-.

[00413] Embodiment II-29. The compound of any one of embodiments II-1 through II-28, wherein R ¹ is C ₆ -C ₁₀ arylene.

[00414] Embodiment II-30. A compound according to any one of embodiments II-1 through II-28, wherein R ¹ is heteroarylene.

[00415] Embodiment II-31. A compound according to any one of embodiments II-1 through II-28, wherein R ¹ is absent.

[00416] Embodiment II-32. The compound of any one of embodiments II-1 through II-31, wherein R ⁷ is A.

[00417] Embodiment II-33. The compound of embodiment II-32 wherein A is -(C(R ⁶ ) ₂ ) _r CO ₂ R ^x or -(CH ₂ ) _r tetrazole, wherein said -(CH ₂ ) _r tetrazole is optionally substituted with C ₁ -C ₆ alkyl.

[00418] Embodiment II-34. The compound of any one of embodiments II-1 through II-31, wherein R ⁷ is B.

[00419] Embodiment II-35. The compound of embodiment II-32 wherein B is -(CH ₂ ) _r C(O)NR ^g R ^g' or -(CH ₂ ) _r S(O) ₂ NR ^g R ^g' .

[00420] Embodiment II-36. The compound of any one of embodiments II-1 through II-31, wherein R ⁷ is C.

[00421] Embodiment II-37. The compound of embodiment II-32 wherein C is -(CH ₂ ) _r CN, -(CH ₂ ) _s OH, or -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, wherein said aryl is substituted with one to three substituents each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, and OH.

[00422] Embodiment II-38. A compound, pharmaceutically acceptable salt, or tautomer thereof selected from the group consisting of:

Connection No. Structure I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30 I-31 I-32 I-33 I-34 I-35 And I-36

[00423] Embodiment II-39. A compound, pharmaceutically acceptable salt, or tautomer thereof selected from the group consisting of:

I-37 I-38 I-39 I-40 And I-41 I-42 I-43 I-44 I-45 I-46 I-47 I-48 I-49 I-50 And I-51

[00424] Embodiment II-40. A compound, pharmaceutically acceptable salt, or tautomer thereof selected from the group consisting of:

And

[00425] Embodiment II-41. A pharmaceutical composition comprising a compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[00426] Embodiment II-42. The pharmaceutical composition of embodiment II-41 comprising one or more additional therapeutic agents.

[00427] Embodiment II-43. A method of treating, preventing, or reducing the risk of a disease or disorder inhibited by β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof.

[00428] Embodiment II-44. A method of treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing said disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of one or more compounds of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof.

[00429] Implementation variant II-45. The method according to any one of embodiments II-43 to II-44, wherein said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency.

[00430] Embodiment II-46. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00431] Embodiment II-47. The method of embodiment II-46, wherein said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease.

[00432] Embodiment II-48. The method of embodiment II-47, wherein the general metabolic disorder is obesity or type II diabetes.

[00433] Embodiment II-49. A method for accelerating oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of one or more compounds of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, that provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ).

[00434] Embodiment II-50. A compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[00435] Embodiment II-51. A compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00436] Embodiment II-52. A compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00437] Embodiment II-53. A compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for use in accelerating oxidative metabolism.

[00438] Embodiment II-54. Use of a compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with β-amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00439] Embodiment II-55. Use of a compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00440] Embodiment II-56. Use of a compound of any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00441] Embodiment II-57. Use of a compound according to any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, to accelerate oxidative metabolism.

[00442] Embodiment II-58. Use of a compound of any one of embodiments II-1 through 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 disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00443] Embodiment II-59. Use of a compound of any one of embodiments II-1 through 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 disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00444] Embodiment II-60: Use of a compound of any one of embodiments II-1 through 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.

[00445] Embodiment II-61. Use of a compound according to any one of embodiments II-1 through II-40, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for accelerating oxidative metabolism.

[00446] Embodiment II-62. A method of treating, preventing, or reducing the risk of a disease or disorder inhibited by β-amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[00447] Embodiment II-63. A method of treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD ⁺ ) levels, comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with reduced NAD ⁺ levels, a therapeutically effective amount of a pharmaceutical composition of embodiment II-41.

[00448] Implementation variant II-64. The method according to any one of embodiments II-62 to II-63, wherein said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency.

[00449] Embodiment II-65. A method of treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[00450] Embodiment II-66. The method of embodiment II-65, wherein said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease.

[00451] Embodiment II-67. The method of embodiment II-66, wherein the general metabolic disorder is obesity or type II diabetes.

[00452] Embodiment II-68. A method of treating acceleration of oxidative metabolism comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of embodiment II-41.

[00453] Embodiment II-69. The pharmaceutical composition of embodiment II-41 for use as a medicine.

[00454] Embodiment II-70. The pharmaceutical composition of embodiment II-41 for use in treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00455] Embodiment II-71. The pharmaceutical composition of embodiment II-41 for use in treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00456] Embodiment II-72. The pharmaceutical composition of embodiment II-41 for use in accelerating oxidative metabolism.

[00457] Embodiment II-73. Use of a pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disease or disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00458] Embodiment II-74. Use of a pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00459] Embodiment II-75. Use of a pharmaceutical composition of embodiment II-41 for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00460] Embodiment II-76. Use of the pharmaceutical composition of embodiment II-41 to accelerate oxidative metabolism.

[00461] Embodiment II-77. Use of a pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with amino-carboxymuconate-semialdehyde decarboxylase dysfunction (ACMSD).

[00462] Embodiment II-78. Use of a pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ).

[00463] Embodiment II-79. Use of a pharmaceutical composition of embodiment II-41 in the manufacture of a medicament for treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction.

[00464] Embodiment II-80. Use of the pharmaceutical composition of embodiment II-41 in the manufacture of a medicinal product for accelerating oxidative metabolism.

Examples

[00465] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure will become apparent from the following various examples. The examples provided illustrate various components and methods suitable for practicing the present disclosure. In general, the present disclosure extends to any novel one or any novel combination of features disclosed in the present disclosure (including the appended claims and drawings). The examples provided are not limiting of the disclosure as claimed. Thus, features, integers, characteristics, compounds, or chemical moieties described in connection with a particular aspect, embodiment, or example of the present disclosure should be understood as applicable to any other aspect, embodiment, or example described herein unless incompatible therewith. Based on the provided description, those skilled in the art can determine and use other components and methods suitable for practicing the present disclosure. In addition, unless otherwise stated, any feature described herein may be replaced by an alternative feature serving the same or similar purpose.

[00466] The present invention is further described by way of example only and with reference to the following examples:

EXAMPLES

GETTING CONNECTIONS

General methods and materials

[00467] All chemicals were purchased from Sigma-Aldrich, Alfa Aesar. ¹ H NMR spectra were recorded at 200 and 400 MHz, and ¹³ C NMR spectra were recorded at 100.6 and 50.3 MHz using the deuterated solvents listed below. TLC was performed on aluminum-backed silica plates (silica gel 60 F254). All reactions were performed under nitrogen atmosphere using distilled solvents. All compounds tested were >95% pure by HPLC analysis. HPLC grade water was obtained on a Milli-Ro/Milli-Q tandem system. HPLC analytical measurements were performed on a Shimadzu LC-20AProminence instrument equipped with a CBM-20A communication bus module, two LC-20AD dual-piston pumps, an SPD-M20A photodiode array detector, and a Rheodyne 7725i injector with a 20 µL stainless steel loop.

[00468] Abbreviations used in the following examples and elsewhere in this description:

Ac ₂ O acetic anhydride

AcOH acetic acid

AIBN Azobisisobutyronitrile

atm. atmosphere

w wide

DIPEA N, N -diisopropylethylamine

DCM dichloromethane

DME dimethoxyethane

DMF N,N -dimethylformamide

DMSO dimethyl sulfoxide

BPO dibenzoyl peroxide

EDC N -(3-Dimethylaminopropyl)- N' -ethylcarbodiimide hydrochloride

ESI electrospray ionization

EtOAc ethyl acetate

EtO ₂ diethyl ether

EtOH ethanol

EtO ^- Na ⁺ sodium ethoxide

Et ₃ NH ⁺ Cl ^- triethylamine hydrochloride

h. hour(s)

HPLC high performance liquid chromatography

LCMS liquid chromatography mass spectrometry

m multiplet

MeI methyl iodide

MeOH methanol

MHz megahertz

min. minutes

MS molecular sieves

MTBE 2-methoxy-2-methylpropane

Microwave. microwave

NBS N-bromosuccinamide

NMR nuclear magnetic resonance

PET petroleum ether

ppm parts per million

p-TSA para-toluenesulfonic acid

room temp. room temperature

TLC thin layer chromatography.

Example 1: Intermediate 1.4. 4-oxo-6-thiophen-2-yl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

[00469] To a stirred solution of compound 1.1 (0.96 g, 8.8 mmol), 1.2 (672 mg, 8.8 mmol) and 1.3 (1 g, 0.83 mL) in ethanol (55 mL) was added _K2CO3 (1.57 g, 11.44 mmol). Stirring was continued at reflux overnight. The resulting yellowish solid was collected _after cooling, dissolved in 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 was obtained as a yellowish solid (1 g, 4.25 mmol). Yield 49%. ¹ H NMR (200 MHz, DMSO -d ₆ ) δ 7.22 (m, 1H), 7.68 (m, 1H), 7.85 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H).

Example 2: Intermediate 2.2. Sodium 6-oxo-4-trifluoromethyl-1,6-dihydropyrimidine-2-thiolate

[00470] Sodium (0.35 g, 16.29 mmol) was dissolved in absolute EtOH (25 mL) under N ₂ atmosphere. 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 to room temperature, the resulting precipitate was collected by vacuum filtration and washed with cold EtOH (2×5 mL) to give (1.34 g, 6.14 mmol) of intermediate 2.2 . Yield 38%. ESIMS (-) m/z: 194.8 [MH].

Example 3: Intermediate 3.3. 2-Mercapto-6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonitrile

[00471] To a stirred solution of KOH (0.58 g, 10.41 mmol) in absolute EtOH (20 mL) were added ethyl 3-oxo-3-phenylpropionate 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 h. Then, the mixture was cooled at room temperature and concentrated under reduced pressure. The crude mixture was poured into H ₂ O (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 vacuum filtration and washed with H ₂ O (2×5 mL). The solid was then triturated with AcMe to give intermediate 3.3 (0.49 g, 2.14 mmol) as a yellowish solid. Yield 21%. ESI-MS (-) m/z: 227.3 [MH] ^-

Example 4: Intermediate 4.2. 4-Benzyl-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile

[00472] 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 K ₂ CO ₃ (2.2 g, 21.6 mmol). Stirring was continued at reflux for 16 h. The mixture was cooled to room temperature. The white solid was collected and dissolved in water. The pH was adjusted to 3 by adding 3 N HCl. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine and dried over anhydrous Na ₂ SO ₄ . The title intermediate 4.2 (800 mg, 3.28 mmol) was obtained as a light yellow solid. Yield: 20%. ¹ H NMR (200 MHz, DMSO- d ₆ ) δ 3.93 (s, 2H), 7.26-7.41 (m, 5H), 13.15 (br s, 1H).

Example 5: Intermediate 5.2 2-Mercapto-6-oxo-4-thiophen-2-yl-1,6-dihydropyridine-3-carbonitrile

[00473] To a stirred solution of KOH (0.28 g, 5.04 mmol) in absolute EtOH (10 mL) were added ethyl 3-oxo-3-thiophen-2-yl propionate 5.1 (0.77 mL, 5.04 mmol) and 2-cyanothioacetamide 3.2 (0.50 g, 5.04 mmol), and the resulting mixture was stirred under reflux for 8 h. The mixture was then cooled at room temperature and the formed precipitate was collected by vacuum filtration and washed with EtOH (2×5 mL) to give intermediate 5.2 (0.17 g, 0.72) as a yellowish solid. Yield 12%. ESIMS (-) m/z: 233.3 [MH] ^- .

Example 6: Intermediate 6.4 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydropyridine-3,5-dicarbonitrile

Stage 1: Ethyl 2-cyano-3-thiophene-2-yl acrylic acid (6.1)

[00474] To a solution of thiophene-2-carboxaldehyde 1.3 (1 g, 8.9 mmol), ethyl cyanoacetate 1.1 (0.94 mL, 8.9 mmol) in EtOH (20 mL) was added piperidine (3 drops). Stirring was continued at room temperature for 16 h. The solvent was removed in vacuo. The crude product was dissolved in water, extracted with EtOAc (3 x 50 mL). The organic phase was collected, washed with brine and dried over anhydrous Na ₂ SO ₄ . The title intermediate 6.1 (1.3 g, 6.27 mmol) was obtained as a white solid. Yield 70%.

Stage 2: 6-Mercapto-2-oxo-4-thiophen-2-yl-1,2-dihydropyridine-3,5-dicarbonitrile (6.2)

[00475] Piperidine (4 drops) was added to a solution of intermediate 6.1 (1.2 g, 5.79 mmol) in EtOH (15 mL). Stirring was continued at reflux for 16 h. After cooling, a red precipitate formed. The precipitate was collected, washed with cold EtOH and dried under vacuum. The title intermediate 6.2 (640 mg, 2.46 mmol) was obtained as a red powder. Yield 42%. ¹ H NMR (200 MHz, DMSO- d ₆ ) δ 7.24-7.27 (m, 1H), 7.53-7.55 (m, 1H), 7.94-7.95 (m, 1H), 13.0 (br s, 1H).

Example 7: Intermediate 7.1 Potassium 3-Cyano-6-oxo-4-trifluoromethyl-1,6-dihydropyridine-2-thiolate

[00476] To a stirred solution of KOH (0.91 g, 16.29 mmol) in absolute EtOH (32 mL) were 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 h. The mixture was then cooled at room temperature and left to stand overnight. The resulting copious precipitate was collected by vacuum filtration and washed with EtOH (2×5 mL) to give intermediate 7.1 (2.01 g, 7.78 mmol) as a white solid. Yield 48%. ESIMS (-) m/z: 218.9 [MH] ^-

Example 8: Intermediate 8.3. Ethyl (3-bromomethylphenyl)acetate

Stage 1: Ethyl m-tolylacetic acid (8.2)

[00477] To a solution of 8.1 (15 g, 99.88 mmol) in EtOH (absolute) (400 mL) was added HCl (conc.) (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) and dried over Na ₂ SO ₄ , and evaporated under reduced pressure. The title compound 8.2 was obtained as a colorless oil (17 g, 95.39 mmol). Yield 96%. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.28 (t, J = 7.1 Hz, 3H), 2.37 (s, 2H), 3.6 (s, 2H), 4.18 (q, J = 7.11 Hz, 2H), 7.20-7.35 (m, 4H). GC/MS m/z 178.1 (M+).

Stage 2: Ethyl ester of (3-bromomethylphenyl)acetic acid (8.3)

[00478] 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 at reflux for 4 h. The volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc (300 mL) and saturated aqueous 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) eluting with PET/Et ₂ O 2% to 4% to give the product. The title compound 8.3 (10 g, 38.89 mmol) was obtained as a yellowish oily substance. Yield 66%. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.27 (t, J = 7.1 Hz, 3H), 3.62 (s, 2H), 4.17 (k, J = 7.13 Hz, 2H), 4.50 (s, 2H), 7.09-7.13 (m, 3H), 7.21-7.28 (m, 1H).

Example 9: Intermediate 9.3. 3-Bromomethylbenzamide

Stage 1: 3-Methylbenzamide (9.2)

[00479] A solution of compound 9.1 (1.54 mL, 12.8 mmol) and _K2CO3 (707 mg, 5.12 mmol) in _H2O (5 mL) was heated under microwave irradiation at ₁₃₀ C, 200 psi, 200 W for 20 min. After cooling, the resulting white precipitate was collected and dried under reduced pressure to give the title compound 9.2 as white crystals (870 mg, 6.4 mmol). Yield 50%. GC-MS (m/z) 135.1 (M+).

Stage 2: 3-Bromomethylbenzamide (9.3)

[00480] 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 CH ₃ CN (20 mL). Stirring was continued at reflux for 4 h. The volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO ₃ (300 mL). The organic phase was collected and dried over Na ₂ SO ₄ . The title compound 9.3 (250 mg, 1.16 mmol) was obtained as a yellowish solid. Yield 53%.

Example 10: Intermediate 10.4 3'-Bromomethyl-3,5-difluoro-4-methoxybiphenyl

Stage 1: 3,5-Difluoro-4-methoxy-3'-methylbiphenyl (10.3)

[00481] To a solution of compound 10.1 (0.18 mL, 1.33 mmol) in DME (15 mL) was added tetrakispalladium (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 K ₂ CO ₃ (745 mg, 3.56 mmol) were added successively. Stirring was continued at reflux for 4 h. 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. 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 (400 MHz, CDCl ₃ ) δ 2.43 (s, 3H), 4.04 (s, 3H), 7.14 (d, J = 9.3, 2H), 7.32-7.33 (m, 4H).

Stage 2: 3'-Bromomethyl-3,5-difluoro-4-methoxybiphenyl (10.4)

[00482] To a solution of intermediate 10.3 (260 mg, 1.1 mmol) in CH ₃ CN (15 mL) were added BPO (4 mg, 0.0055 mmol) and NBS (210 mg, 1.22 mmol). Stirring was continued at reflux overnight. The solvent was removed under reduced pressure. The reaction mixture was partitioned between NaHCO _{3 (sat.)} and DCM. The organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with PET/Et ₂ O to give the title compound 10.4 (250 mg, 0.77 mmol) as a yellow oil. Yield 72%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.06 (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).

Example 11: Intermediate 11.2. (3-Bromomethylphenyl)acetic acid

[00483] To a suspension of compound 11.1 (750 mg, 5 mmol) in CCl ₄ (15 mL) were added AIBN (41 mg, 0.25 mmol) and NBS (933.7 mg, 5.24 mmol). Stirring was continued at reflux overnight. The solvent was removed under reduced pressure. The reaction mixture was dissolved in water, extracted with EtOAc (3 x 20 mL), washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with CH ₂ Cl ₂ /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+).

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

Stage 1: [3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)phenyl]acetic acid (12.1)

[00484] 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). The title intermediate 12.1 was obtained (200 mg, 0.52 mmol) as a pure yellowish solid after purification by flash chromatography eluting _{with CH2Cl2} /MeOH (10% for the product) and triturating with _EtO2 /acetone. Yield 25%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 3.49 (s, 2H), 4.53 (s, 2H), 7.16 (d, J =6.8 Hz, 1H), 7.26 (t, J =7.2 Hz, 1H), 7.36 (m, 3H), 8.05 (d, J =4.4 Hz, 1H), 8.27 (s, 1H), 12.13 (s, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.3, 40.9, 88.5, 116.8, 127.6, 128.9, 129.1, 129.8, 130.4, 131.9, 135.2, 135.8, 137.0, 139.9, 159.1, 161.6, 165.7, 172.9. HPLC 95.8%.

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

[00485] A mixture of intermediate 12.1 (300 mg, 0.78 mmol) and _POCl3 (6 ml) was heated at 80°C for 4 h. The crude reaction mixture was then poured onto ice. The resulting yellow precipitate was collected and dried under reduced pressure to give the title intermediate 12.2 (250 mg, 0.62 mmol) as a yellowish solid. Yield 79%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 3.53 (s, 2H), 4.50 (s, 2H), 7.16 (d, J =7.5 Hz, 1H), 7.27 (t, J =7.4 Hz, 1H), 7.36-7.39 (m, 3H), 8.13 (d, J =4.9 Hz, 1H), 8.3 (d, J =3.9 Hz, 1H), 12.25 (shs, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 35.1, 40.9, 97.7, 115.5, 127.6, 128.8, 129, 130.2, 130.4, 133.3, 135.7, 136, 137, 138.6, 160.3, 163.2, 172.9, 174.

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

Stage 1: 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzoic acid (13.2)

[00486] To a stirred suspension of intermediate 1.4 (250 mg, 1.06 mmol) and _K2CO3 (440 mg, 3.18 mmol) _{in CH3CN} (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 (350 mL). Trituration with hot acetone gave the title intermediate 13.2 (45 mg, 0.12 mmol) as a yellowish solid. Yield 12%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.62 (s, 2H), 7.33 (t, J =4.3 Hz, 1H), 7.44 (t, J =7.6 Hz, 1H), 7.72 (d, J =7.5 Hz, 1H), 7.82 (d, J =7.5 Hz, 1H), 8.05 (m, 2H), 8.26 (d, J =3.8 Hz, 1H), 12.99 (s, 1H); ¹³ C NMR (100 MHz, DMSO) δ 33.9, 88.7, 116.5, 128.8, 129.3, 129.9, 130.2, 131.5, 132.1, 133.7, 135.4, 137.9, 139.7, 159.0, 161.2, 165.3, 167.4. HPLC: 97.2%

Stage 2: 3-(4-Chloro-5-cyano-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)benzoic acid (13.3)

[00487] A mixture of intermediate 13.2 (300 mg, 0.81 mmol) and _POCl3 (6 mL) was heated at 80 °C for 4 h. The reaction mixture was then poured onto ice. The resulting yellow precipitate was collected and purified by flash chromatography eluting with DCM/MeOH (3% for product) to give intermediate 13.3 (120 mg, 0.3 mmol) as a yellowish solid. Yield 79%. ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.8, 88.7, 116.5, 128.8, 129.3, 129.9, 130.2, 131.4, 132.1, 133.7, 135.5, 137.9, 139.6, 159, 161.1, 165.2, 167.3.

Example 14: Intermediate 14.2. 3-Bromomethylbenzonitrile

[00488] To a solution of compound 14.1 (2 mL, 17.07 mmol) in CCl ₄ was added a mixture of NBS (2.9 g, 17.1 mmol) and BPO (16 mg, 0.06 mmol). Stirring was continued at reflux for 16 h and then the reaction mixture was allowed to warm to room temperature. The resulting solid was collected, washed with CCl ₄ and dried under reduced pressure. The title compound 14.2 was isolated as a white solid (2.84 g, 14.5 mmol). Yield 85%. GC/MS-) 196.9 (M+).

Example 15: Intermediate 15.1 2-(3-Bromomethylphenyl)ethanol

[00489] To a solution of intermediate 11.2 (500 mg, 2.17 mmol) in THF (10 mL) at 0 °C was added dropwise BH ₃ -THF (1 M in THF, 2.8 mL). The mixture was stirred at 0 °C for 1 h and then at room temperature for 12 h. The mixture was diluted with THF/H ₂ O (1:1 v:v, 15 mL) and washed with saturated aqueous K ₂ CO ₃ . The phases were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . Purification of the crude product by flash chromatography (eluted with DCM/MeOH) afforded the title intermediate 15.1 (400 mg, 1.85 mmol) as a white solid. Yield 85%. GC/MS (m/z) 214 (M+).

Example 16: Intermediate connection 16.2. 2 (3-Bromomethylphenyl)acetonitrile

[00490] 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 at reflux for 4 h. Volatiles were removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The organic phase was collected and dried over Na ₂ SO ₄ . The title compound 16.2 (250 mg, 1.18 mmol) was obtained as a yellowish solid after purification by flash chromatography (eluted with PET/EtOAc). Yield 50%.

Example 17: Intermediate 17.3. 5-(3-Bromomethylphenyl)-2-methyl-2 H -tetrazole

Stage 1: 5-m-tolyl-2H-tetrazole (17.1)

[00491] A mixture of compound 14.1 (1.02 mL, 8.54 mmol), NaN ₃ (832 mg, 12.8 mmol) and Et ₃ N∙HCl (1.76 g, 12.8 mmol) in toluene (20 mL) was heated under reflux for 4 h. The solvent was then removed under reduced pressure. The crude mixture was poured into water and the resulting aqueous solution was acidified to pH 1 with 3 N HCl and extracted with EtOAc (3×20 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ 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 (200 MHz, DMSO- d ₆ ) δ 2.39 (s, 3H), 7.39 (m, 1H), 7.48 (t, J = 7.58 Hz, 1H), 7.80 (s, 1H), 7.85 (m, 1H); GC/MS (m/z) 160.1 (M+).

Stage 2: 2-Methyl-5-m-tolyl-2H-tetrazole (17.2)

[00492] 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 H ₂ O. The organic layer was separated, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. Purification of the crude product gave the title intermediate 17.2 (500 mg, 2.87 mmol) as a white solid. Yield 46%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37 (s, 3H), 7.26-7.39 (m, 1H), 7.35-7.39 (m, 1H), 7.91-7.96 (m, 2H).

Stage 3: 5-(3-Bromomethylphenyl)-2-methyl-2H-tetrazole (17.3)

[00493] To a suspension of compound 17.2 (200 mg, 1.15 mmol) in CH ₃ CN (15 mL) were added BPO (21 mg, 0.057 mmol) and NBS (163.5 mg, 0.92 mmol). Stirring was continued at 92C overnight. The solvent was removed under reduced pressure. The reaction mixture was dissolved in water, extracted with EtOAc (320 mL), washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with CH ₂ Cl ₂ /MeOH (7% for product) to give the title compound 17.3 (261 mg, 1.03 mmol) as a white solid. Yield 90%. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.41 (s, 3H), 4.56 (s, 2H), 7.46-7.52 (m, 1H), 8.07-8.09 (m, 1H), 8.19 (s, 1H).

Example 18: Intermediate 18.1 5-(3-Bromomethylphenyl)-1H-tetrazole

[00494] To a suspension of compound 17.1 (300 mg, 1.87 mmol) in CH ₃ CN (15 mL) were added AIBN (31 mg, 0.18 mmol) and NBS (333 mg, 1.87 mmol). Stirring was continued at reflux overnight. The solvent was removed under reduced pressure. The reaction mixture was dissolved in water, extracted with EtOAc (320 mL), washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with CH ₂ Cl ₂ /MeOH (7% for product) to give the title compound 18.1 (150 mg, 0.62 mmol) as a light yellow solid. Yield 34%.

Example 19: Intermediate 19.5. 3-Bromomethylbenzenesulfonamide

Stage 1: 3-Chlorosulfonylbenzoic acid (19.2)

[00495] A mixture of compound 19.1 (1 g, 8.13 mmol) and chlorosulfonic acid (4 mL) was stirred at 125C for 2 h. The mixture was poured dropwise into ice water. The resulting solid was collected, solubilized in EtOAc and washed with water (320 mL). The organic layer was dried _{over Na2SO4} and evaporated under reduced pressure. The title intermediate 19.2 (1.19 g, 5.39 mmol) was obtained as a white solid. Yield 65%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.45 (t, J = 7.69 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 8.1 (s, 1H), 13.9 (br s, 1H).

Stage 2: 3-Sulfamoylbenzoic acid (19.3)

[00496] Intermediate 19.2 (1.10 g, 5.39 mmol) was added portionwise to a cold solution of 25% NH ₄ OH (10 ml). Stirring was continued at room temperature for 2 h and the resulting mixture was concentrated. The crude product was suspended in water (4 ml) and then 37% HCl solution was added dropwise to the mixture. The resulting precipitate was collected and dried under reduced pressure to give the title intermediate 19.3 (943 mg, 4.6 mmol) as a white solid. Yield 87%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.50 (br s, 2H), 7.71 (t, J = 7.78 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.38 (s, 1H), 13.4 (br s, 1H).

Stage 3: 3-Hydroxymethylbenzenesulfonamide (19.4)

[00497] To a stirred solution of intermediate 19.3 (940 mg, 4.67 mmol) was added _BH3 -THF complex (14 mL, 14.01 mmol) cooled to 0 °C dropwise and stirring was continued for 4 h at room temperature. The reaction mixture was then cooled to 0 °C and quenched by dropwise addition of MeOH. After 15 min, 3 N HCl (37 mL) was added to the mixture and the volatiles were removed under reduced pressure. The aqueous phase was extracted with EtOAc (320 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%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 4.51 (s, 2H), 7.34 (s, 2H), 7.5 (d, J= 5 Hz, 2H), 7.68 (t, J= 5.2 Hz, 1H), 7.8 (s, 1H).

Stage 4: 3-Bromomethylbenzenesulfonamide (19.5)

[00498] 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. Then water was carefully added to the mixture and the phases were separated. The aqueous phase was extracted with DCM (220 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%. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.53 (s, 2H), 7.54 (t, J =10.7 Hz, 1H), 7.69 (d, J =7.6 Hz, 1H), 7.88 (d, J =7.8 Hz, 1H), 7.97 (s, 1H).

Example 20: Intermediate 20.2 4-Benzyl-2-mercapto-6-oxo-1,6-dihydropyridine-3-carbonitrile

[00499] 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 85C overnight. The reaction mixture was poured into water, the pH was lowered to 5 by adding AcOH, then washed with EtOAc (320 mL). Then the pH was adjusted to 3 by adding 3 N HCl solution. The aqueous phase was extracted with EtOAc (330 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 (400 MHz, DMSO- d ₆ ) δ 3.63 (s, 2H), 5.81 (s, 1H), 7.17-7.36 (m, 5H), 13.1 (br s, 1H).

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

[00500] To a stirred suspension of intermediate 1.4 (2.13 g, 9.1 mmol) and K ₂ CO ₃ (1.88 g, 13.6 mmol) in CH ₃ CN (80 mL) was added intermediate 8.3 (2.45 g, 9.52 mmol) and stirring was continued at gentle reflux for 16 h. Then the solvent was removed under reduced pressure. The crude product was dissolved in water and the resulting aqueous solution was neutralized with 3 N HCl. The resulting pale yellow solid was collected, washed with ice water and dried under reduced pressure. The title compound I-1 (3.1 g, 7.46 mmol) was obtained as a gray solid after trituration with Et ₂ O. Yield 82%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 1.15 (d, J =7.03 Hz, 3H), 3.62 (s, 2H), 4.03 (k, J =7.16 Hz, 2H), 4.55 (s, 2H), 7.17 (d, J =7.1 Hz, 1H), 7.28 (t, J =7.7 Hz, 1H), 7.38 (m, 3H), 8.1 (d, J =4.7 Hz, 1H), 8.29 (d, J =3.35 Hz, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 14.4, 34.2, 60.7, 88.6, 116.6, 127.8, 129.1, 129.1, 129.9, 130.3, 132.1, 135.2, 135.5, 137.1, 139.7, 159.1, 161.1, 165.3, 171.4. HPLC > 97.9%.

Example 22: 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzamide (Compound I-2)

[00501] To a stirred suspension of intermediate 1.4 (182 mg, 0.78 mmol) and intermediate 9.3 (200 mg, 0.65 mmol) in _CH3CN (20 mL) was added _K2CO3 (119 mg, 0.86 mmol) and stirring was continued at gentle reflux for 16 _h . 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 3 N HCl and extracted with EtOAc (320 mL). The combined organic phases were washed with brine and dried over _Na2SO4 to give the title compound I-2 ₍ 120 mg, 0.24 mmol) as a yellowish solid after trituration with hot _Et2O . Yield 42%. ¹ H NMR _{(400 MHz, DMSO-d6} ) δ 4.61 (s, 2H), 7.3 (m, 1H), 7.41 (m, 2H), 7.63 (d, J =7.12 Hz, 1H), 7.76 (d, J =7.3 Hz, 1H), 7.97 (s, 2H), 8.01 (d, J =4.47 Hz, 1H), 8.3 (d, J =2.8 Hz, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.5, 88.1, 117.1, 127.3, 129.1, 129.3, 130.4, 132.5, 132.5, 135.5, 135.9, 137.7, 140.2, 159.4, 161.6, 165.7, 168.4. HPLC > 94.2%.

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

Step 1: 2-({[3-(3,5-difluoro-4-hydroxyphenyl)phenyl]methyl}sulfanyl)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile ( 22.1 )

[00502] 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 (350 mL). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ to give intermediate 22.1 (180 mg, 0.038 mmol) as a pale yellow powder after flash chromatography eluting with CH ₂ Cl ₂ /MeOH (4% for the product). Yield 55%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 3.93 (s, 3H), 4.60 (s, 2H), 7.34-7.43 (m, 4H), 7.5 (d, J =4.3 Hz, 1H), 7.60 (d, J =7.5 Hz, 1H), 7.84 (s, 1H), 8.0 (d, J =4.9 Hz, 1H), 8.29 (d, J =4.9 Hz, 1H), 13.9 (shs, 1H).

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

[00503] To a stirred suspension of intermediate 22.1 (170 mg, 0.36 mmol) in DCM (25 mL) was added 1 M _BBr3 in DCM (0.72 mL, 0.72 mmol) and stirring was continued at reflux for 16 h. The reaction mixture was quenched with MeOH and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography eluting with DCM/MeOH (5% for product). The title compound I-3 (90 mg, 0.2 mmol) was obtained as a white solid after trituration with hot _Et2O . Yield 42%. ¹ H NMR (400 MHz, DMSO) δ 4.59 (s, 3H), 7.31 (d, J= 9.1 Hz, 2H), 7.36 (m, 1H), 7.39 (d, J =7.6 Hz, 1H), 7.45 (d, J =7.7 Hz, 1H), 7.56 (d, J= 7.5 Hz, 1H), 7.81 (s, 1H), 8.07 (d, J =5 Hz, 1H), 8.3 (d, J =3.8 Hz, 1H), 10.34 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 88.7, 110.3 ( ² J _CF = 15.1 Hz), 110.3 ( ² J _CF = 15.5 Hz), 125.8, 127.4, 128.5, 129.7, 130, 130.5, 132.1, 133.5 ( ³ J _CF = 16 Hz), 133.7 ( ³ J _CF = 16 Hz), 135.3, 138.1, 138.4, 139.7, 152.9 ( ¹ J _CF = 239.9 Hz), 153.01 ( ¹ J _{CF =} 240.1 MHz), 159.0, 161.3, 165.5. HPLC: 98.4%.

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

[00504] To a stirred solution of the intermediate compound12.2(80 mg, 0.19 mmol) and MeOH (0.04 ml, 0.95 mmol) in DMF (3 ml) were added K₂CO₃(60 mg, 0.43 mmol) and continued stirring at room temperature for 16 h. The reaction mixture was poured into water and the resulting aqueous mixture was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na₂SO₄. Purification of the crude product by flash chromatography (eluted with DCM/MeOH, 1.5% for product) afforded the title compound.I-4(45 mg, 0.11 mmol) as a white solid. Yield 58% ;¹H NMR (400 MHz, DMSO-d ₆ ) δ 3.56 (s, 3H), 3.66 (s, 2H), 4.54 (s, 2H), 7.17 (d,J=7.2 Hz, 1H), 7.27 (t,J=7.6 Hz, 1H), 7.33-7.38 (m, 3H), 8.07 (d, J=4.8 Hz, 1H), 8.28 (d,J=3.6 Hz, 1H).¹³C NMR (100 MHz, DMSO-d ₆ ) δ 34.2, 40.3, 52.1, 88.5, 116.6, 127.8, 129, 129.1, 129.8, 130.3, 132, 135.1, 135.3, 137.1, 139.8, 159.1, 161.4, 165.5, 171.8. HPLC > 97.1%.

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

[00505] 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 H ₂ O (310 mL), brine (10 mL), dried over Na ₂ SO ₄ 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. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.63 (s, 2H), 4.45 (s, 2H), 7.21 (m, 1H), 7.31 (m, 2H), 7.39 (m, 2H), 7.70 (br s, 1H), 8.45 (br s, 1H). ¹³ C-NMR (CDCl ₃ , 100 MHz) s: 29.3, 40.7, 100.1, 116.0, 127.9, 128.7, 128.9, 129.4, 130.1, 133.1, 133.6, 134.6, 136.6, 138.7, 155.8, 159.7, 174.3, 177.1. HPLC > 95%.

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

[00506] 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 (320 mL). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The title compound I-6 (80 mg, 0.2 mmol) was obtained as a white solid after trituration with Et ₂ O. Yield 39%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 0.73 (m, 4H), 2.95 (m, 1H), 3.53 (s, 2H), 4.45 (s, 2H), 7.13 (d, J =7.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.33-7.35 (m, 2H), 7.93 (d, J =4.9 Hz, 1H), 8.18 (d, J =3.2 Hz, 1H), 8.21 (s, 1H), 12.3 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 6.6, 6.6, 25, 34.3, 40.8, 79.7, 116.7, 127.3¸128.5, 128.6, 129.2, 130.1, 130.7, 133.2, 135.4, 138.3, 140.1, 158.7, 162.8, 172.8, 172.8. HPLC > 99.3%.

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

[00507] [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 ₃ in THF (18 mL, 7.466 mmol) and the resulting translucent solution was stirred at room temperature for 72 h. Then, the mixture was poured into AcOEt (15 mL), washed with 3 M HCl (5 mL), saturated aqueous NaHCO ₃ (10 mL), saturated brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography ( _CH2Cl2 /MeOH/AcOH, 99:1:0.1 to 90:10:0.1 ₎ to afford the title compound I-7 (86 mg, 0.22 mmol) as a white solid. Yield 94%; MS/MS ESI(+): 382.9. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 3.53 (s, 2H), 4.39 (s, 2H), 7.13 (d, J =7.3 Hz, 1H), 7.24 (t, J =7.1 Hz, 1H), 7.29 (m, 1H), 7.35 (m, 2H), 7.8 (shs, 1H), 7.94 (d, J= 4.3 Hz, 1H), 8.20 (m, 1H), 12.32 (shs, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.3, 40.9, 78.9, 116.9, 127.6, 128.6, 128.7, 129.3, 130.4, 130.8, 133.4, 135.5, 138.3, 140.4, 159.1, 163.7, 173. HPLC > 97.9%.

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

[00508] _Et3N (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%, _H2 pressure: 8 bar, temperature: 40 °C, transfer solvent: THF, flow rate: 1.0 mL/min). The resulting reaction mixture (ca. 5 mL) was diluted with EtOAc (15 mL), washed with 3 M HCl (5 mL) and brine (10 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (column: RP-18, eluted with _H2O /MeOH from 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 , 400 MHz) 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 (exact s, 1H), 9.03 (s, 1H).

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

[00509] To a stirred solution of intermediate 12.2 (100 mg, 0.25 mmol) in DMF (3 mL) was added 33% MeNH ₂ (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 3 M HCl solution and then extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ to give the title compound I-9 (80 mg, 0.2 mmol) as a white solid. Yield 80%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 2.93 (d, J = 4.5 Hz, 3H), 3.53 (s, 2H), 2.92 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.27-7.29 (m, 1H), 7.33 (m, 2H), 7.94 (d, J =5.1 Hz, 1H), 8.1 (k, J =4.5 Hz, 1H), 8.18 (d, J =3.8 Hz, 1H), 12.33 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 28.6, 34.5, 40.9, 79.6, 116.9, 127.4, 128.6, 128.7, 129.3, 130.2, 130.7, 133.3, 135.5, 138.3, 140.3, 158.5, 161.9, 172.9, 173.1. HPLC > 98.1%.

Example 30: 3-(5-Cyano-4-methylamino-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)benzoic acid (Compound I-10)

[00510] To a stirred solution of intermediate 13.3 (90 mg, 0.23 mmol) in DMF (3 mL) was added 33% MeNH ₂ (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 3 M HCl and then extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with DCM/MeOH (4% for product) to give the title compound I-10 (45 mg, 0.12 mmol) as a white solid. Yield 51%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 2.94 (d, J =4.4 Hz, 3H), 4.49 (s, 2H), 7.28 (t, J =4.4 Hz, 1H), 7.44 (t, J =7.7 Hz, 1H), 7.70 (d, J =7.5 Hz, 1H), 7.81 (d, J =7.7 Hz, 1H), 7.92 (d, J =5, Hz, 1H), 8.04 (k, J =4.5 Hz, 1H), 8.06 (s, 1H)), 8.18 (d, J =3.8 Hz, 1H), 12.92 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 28.6, 34.2, 79.8, 116.8, 128.3, 129.1, 129.2, 130, 130.7, 131.3, 133.3, 133.5, 139.3, 140.2, 158.5, 161.9, 167.4, 172.9. HPLC > 95.1%.

Example 31: 2-(3-Cyanobenzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-11)

[00511] To a stirred solution of intermediate 1.4 (200 mg, 0.85 mmol) and K ₂ CO ₃ (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 3 M HCl solution and then extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography eluting with DCM/MeOH to afford the title compound I-11 (50 mg, 0.17 mmol) as a white solid. Yield 17%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.60 (s, 2H), 7.35 (d, J = 4.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.96 (s, 1H), 8.1 (d, J = 5.02 Hz, 1H), 8.27 (d, J = 3.9 Hz, 1H), 13.80 (br s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.2, 88.8, 111.8, 116.5, 118.9, 130, 130.2, 131.6, 132.1, 132.8, 134.1, 135.4, 139.3, 139.6, 159, 161.2, 165.1. HPLC > 99.1%.

Example 32: 2-[3-(2-Hydroxyethyl)benzylsulfanyl]-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-12)

[00512] 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 then removed under reduced pressure. The resulting mixture was poured into water, acidified to pH 6 by adding 3 M HCl solution and then extracted with EtOAc (320 mL). The combined organic phase was 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 (400 MHz, DMSO- d ₆ ) δ 2.47 (t, J = 8.35 Hz, 2H), 2.67 (t, J = 7.01 Hz, 2H), 4.48 (s, 2H), 4.51 (br s, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.32-7.36 (m, 2H), 8.06 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 3.9 Hz, 1H), 13.80 (br s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.3, 62.3, 62.3, 88.3, 116.9, 126.8, 128.5, 128.8, 129.8, 129.9, 131.8, 135.1, 136.9, 139.9, 140.3, 159, 162, 165.9. HPLC > 96.1%.

Example 33: 2-(3-Cyanomethylbenzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-13)

[00513] 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 3 M HCl solution and then extracted with EtOAc (320 ml). The combined organic phase was 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 product) to afford the title compound I-13 (300 mg, 0.82 mmol) as a yellow solid. Yield 96%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.01 (s, 2H), 4.52 (s, 2H), 7.24 (d, J = 7.49 Hz, 1H), 7.31-7.36 (m, 2H), 7.43-7.45 (m, 2H), 8.0 (d, J = 5 Hz, 1H), 8.23 (d, J = 3.8 Hz, 1H), 13.80 (br s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 22.6, 33.9, 87.9, 117.5, 119.5, 127.5, 128.5, 128.9, 129.6, 129.6, 131.3, 131.9, 134.5, 138.6, 140.3, 159.1, 164.1, 166.7. HPLC > 97.7%.

Example 34: 2-[3-(2-Methyl-2H-tetrazol-5-yl)-benzylsulfanyl]-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-14)

[00514] 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. Then the solvent was removed under reduced pressure. The resulting solid was collected and dried under reduced pressure to give the title compound I-14 (200 mg, 0.49 mmol) as a yellowish solid. Yield 58%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.40 (s, 3H), 4.66 (s, 2H), 7.35 (m, 1H), 7.51 (t, J =7.5 Hz, 1H), 7.66 (d, J =6.9 Hz, 1H), 7.94 (d, J =7.2 Hz, 1H), 8.08 (d, J =4.1 Hz, 1H), 8.21 (s, 1H), 8.28 (s, 1H), 13.80 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.9, 40.5, 88.7, 116.5, 125.7, 127.2, 127.5, 129.9, 130, 131.3, 132.1, 135.4, 138.6, 139.7, 159.1, 161.1, 164.2, 165.2. HPLC > 99.3%.

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

[00515] 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. Then the solvent was removed under reduced pressure. The crude product was dissolved in water and the resulting aqueous mixture was extracted with EtOAc (320 mL). The combined organic phase was 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%. ^1H NMR (400 MHz, CDCl ₃ ) δ 3.60 (s, 2H), 3.79 (m, 4H), 3.93 (m, 4H), 4.41 (s, 2H), 7.17-7.20 (m, 2H), 7.27-7.36 (m, 2H), 7.37 (d, J =8.23 Hz, 2H), 7.61 (d, J =5.1 Hz, 1H), 8.32 (d, J =3.5 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 35.1, 40.6, 47.7, 47.7, 66.5, 66.5, 80.6, 118.4, 127.7, 128.3, 128.6, 128.8, 129.7, 131.7, 132.4, 133.5, 137.6, 139.9, 161.6, 162.9, 172.6, 176.3. HPLC > 98.1%.

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

Stage 1 . 4-[2-(3-Carboxymethylbenzenesulfanyl)-5-cyano-6-thiophen-2-yl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (36.1).

[00516] To a stirred suspension of intermediate 12.2 (250 mg, 0.62 mmol) and K ₂ CO ₃ (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, the aqueous mixture was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . 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 yellowish solid. Yield 18%.

Stage 2 . [3-(5-Cyano-4-piperazin-1-yl-6-thiophen-2-yl-pyrimidin-2-ylsulfanylmethyl)phenyl]acetic acid (I-16).

[00517] 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 (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The title compound I-16 (20 mg, 0.044 mmol) was obtained as a white solid after trituration with hot Et ₂ O. Yield 37%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 2.83 (m, 4H), 3.51 (s, 2H), 3.81 (m, 4H), 4.39 (s, 3H), 7.13 (d, J =7.03 Hz, 1H), 7.24-7.33 (m, 4H), 7.95 (d, J =4.4 Hz, 1H), 8.20 (d, J =2.8 Hz, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.6, 41.2, 45.5, 45.5, 48.4, 48.4, 118.7, 127.2, 128.6, 128.7, 129.2, 130.1, 131.8, 133.7, 135.8, 138.1, 140.1, 161.5, 162.4, 172, 173.1. HPLC > 90.9%.

Example 37. Ethyl ester of [3-(5-cyano-1-methyl-4-oxo-6-thiophen-2-yl-1,4-dihydropyrimidin-2-ylsulfanylmethyl)phenyl]acetic acid (compound I-17).

[00518] To a stirred suspension of compound I-1 (300 mg, 0.73 mmol) and K ₂ CO ₃ (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 (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ to give the title compound I-17 (298 mg, 0.7 mmol) as a yellowish solid. Yield 96%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 0.14 (t, J =7.12 Hz, 3H), 3.41 (s, 3H), 3.62 (s, 2H), 4.03 (k, J =7.1 Hz, 2H), 4.64 (s, 2H), 7.19 (d, J =7.6 Hz, 1H), 7.27-7.31 (m, 1H), 7.35 (t, J =4.1 Hz, 1H), 7.40 (m, 2H), 8.08 (d, J =4.9 Hz, 1H), 8.28 (d, J =3.8 Hz, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 14.4, 31.1, 36.1, 40.5, 60.6, 87.5, 116.5, 127.9, 129.1, 129.2, 130, 130.4, 132.1, 135.3, 135.4, 136.2, 139.5, 157.1, 160.1, 166.4, 171.3. HPLC > 95.1%.

Example 38. 3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzenesulfonamide (compound I-18)

[00519] 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. Then the solvent was removed under reduced pressure. The crude mixture was dissolved in water and then extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The title compound I-18 (50 mg, 0.12 mmol) was obtained as a yellowish solid after trituration with hot Et ₂ O. Yield 28%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.65 (s, 2H), 7.34 (t, J =4.6 Hz, 1H), 7.40 (s, 2H), 7.52 (t, J =7.6 Hz, 1H), 7.72 (t, J =6.1 Hz, 2H), 7.94 (s, 1H), 8.06 (d, J =4.8 Hz, 1H), 8.27 (d, J =3.6 Hz, 1H), 13.8 (s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.7, 88.6, 116.6, 125.2, 126.1, 129.7, 129.9, 132, 132.5, 135.4, 138.4, 139.7, 144.8, 159.1, 161.4, 165.3. HPLC > 95.1%.

Example 39: [3-(3-Cyano-6-oxo-4-phenyl-1,6-dihydropyridin-2-ylsulfanylmethyl)phenyl]acetic acid (Compound I-19)

[00520] 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 brownish powder. Yield 37%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 3.55 (s, 2H), 4.5 (s, 2H), 6.51 (s, 1H), 7.16 (d, J =7.4 Hz, 1H), 7.27 (t, J =7.7 Hz, 1H), 7.37 (m, 2H), 7.51-7.53 (m, 3H), 7.55-7.56 (m, 2H), 12.17 (shs, 2H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.5, 40.6, 95.9, 108, 116.2, 127.6, 128.3, 128.3, 128.5, 128.5, 128.9, 128.9, 130, 130.3, 135.4, 135.9, 137.5, 155.9, 162.1, 164.9, 172.7; HPLC: 96.88%.

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

[00521] 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 with AcOH. The precipitate was collected, washed with cold water and dried under vacuum. Compound I-20 (90 mg, 0.22 mmol) was obtained as a brownish powder. Yield 42%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 3.55 (s, 2H), 4.51 (s, 2H), 6.62 (s, 1H), 7.15 (d, J =7.4 Hz, 1H), 7.24-7.28 (m, 2H), 7.35 (d, J =6.4 Hz, 2H), 7.75 (d, J =3.5 Hz, 1H), 7.85 (d, J =4.9 Hz, 1H), 12.1 (ws, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.6, 40.6, 93.8, 104.5, 116.5, 127.6, 128.6, 128.6, 128.7, 128.7, 129.5, 130.3, 130.3, 135.4, 136.6, 137.4, 147.4, 165.1, 172.7; HPLC: 96.5%.

Example 41: [3-(3,5-Dicyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyridin-2-ylsulfanylmethyl)phenyl]acetic acid (compound I-21)

[00522] 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 with AcOH. The precipitate was collected, washed with cold water and dried under vacuum. Compound I-21 (110 mg, 0.27 mmol) was obtained as a brownish powder. Yield 35%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 3.56 (s, 2H), 4.48 (s, 2H), 7.63 (d, J =7.6 Hz, 1H), 7.24-7.28 (m, 2H), 7.38-7.40 (m, 2H), 7.54 (dd, J =1.1 Hz, J=3.6 Hz, 1H), 7.93 (dd, J =1.1 Hz, J =5 Hz, 1H), 8.12 (shs, 1H), 12.29 (shs, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.3, 40.6, 85.8, 93.1, 115.5, 127.8, 128, 128, 128.6, 130.5, 130.9, 131.4, 131.4, 132.9, 135.3, 137.4, 150.8, 159.8, 166.9, 172.8; HPLC: 97.5%.

Example 42: 2-oxo-6-[3-(1H-tetrazol-5-yl)-benzylsulfanyl]-4-thiophen-2-yl-1,2-dihydropyridine-3,5-dicarbonitrile (compound I-22)

[00523] 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 with AcOH. The precipitate was collected, washed with cold water and dried under vacuum. Compound I-22 (90 mg, 0.27 mmol) was obtained as a yellowish powder. Yield 38%. ^1H NMR (400 MHz, DMSO _-d6 ) δ 4.6 (s, 2H), 7.26 (dd, J =5.0 Hz, J =3.6 Hz, 1H), 7.54-7.56 (m, 2H), 7.76 (d, J =7.7 Hz, 1H), 7.90-7.94 (m, 2H), 8.1 (s, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.2, 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%

Example 43: [3-(4-Benzyl-3-cyano-6-oxo-1,6-dihydropyridin-2-ylsulfanylmethyl)phenyl]acetic acid (compound I-23)

[00524] 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 with AcOH. The precipitate was collected, washed with cold water and dried under vacuum. Compound I-23 (100 mg, 0.25 mmol) was obtained as a yellowish powder. Yield 40%. ^1H NMR (400 MHz, 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%.

Example 44: (5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanyl)acetic acid (Compound I-24)

[00525] 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. Then another 0.3 equivalents of DIPEA and chloroacetic acid were added to complete the reaction. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 with 3 N HCl. The precipitate was collected and purified by reverse phase flash chromatography eluting with _H2O /MeOH from 10 to 80%. Compound I-24 (210 mg, 0.71 mmol) was obtained as a yellowish powder. Yield 83%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.0 (s, 2H), 7.33 (t, J=4.7 Hz, 1H), 8.1 (d, J=4.9 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 12.8 (br s, 1H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 33.4, 88.5, 116.5, 129.8, 132.3, 135.6, 139.5, 159, 161.1, 165.2, 169.3; HPLC: 99.6%.

Example 45: 6-oxo-2-(1H-tetrazol-5-ylmethylsulfanyl)-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-25)

[00526] To a stirred solution of the intermediate compound1.4(200 mg, 0.85 mmol) and DIPEA (0.18 ml, 1.02 mmol) in acetone/DMSO (20:2 ml) were added the intermediate 5-chloromethyl-1H-tetrazole (101 mg, 0.85 mmol). Stirring was continued overnight at room temperature. Then another 0.3 equivalents of DIPEA and 5-chloromethyl-1H-tetrazole were added to complete the reaction. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 by adding 3 N HCl. The precipitate was collected and purified by reverse phase flash chromatography eluting with a mixture of H₂O/MeOH from 10 to 80%. Compound I-25(120 mg, 0.37 mmol) was obtained as a yellowish powder. Yield 44%.¹H NMR (400 MHz, DMSO-d ₆) δ 4.82 (s, 2H), 7.31 (t,J=4.2 Hz, 1H), 8.0 (d,J=4.9 Hz, 1H), 8.22 (d,J=3.8 Hz, 1H);¹³C NMR (100 MHz, DMSO-d ₆) 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%.

Example 46: 2-(1H-Tetrazol-5-ylmethylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (compound I-26)

[00527] 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 with 3 N HCl. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was 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 H NMR (400 MHz, DMSO -d ₆ ) δ 4.69 (s, 2H), 6.67 (s, 1H), 15.1 (br s, 1H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 23.1, 107.7, 120.6 (q, J _CF = 2.7 Hz), 152, 154.3, 163.9, 164.8; HPLC: 97.9%

Example 47: (6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-2-ylsulfanyl)acetic acid (compound I-27)

[00528] 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 with 3 N HCl. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude reaction mixture was purified by reverse phase flash chromatography eluting with H ₂ O/MeOH 5 to 65% to give the product. Compound I-27 (125 mg, 0.49 mmol) was obtained as a white powder. Yield 58%. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 3.96 (s, 2H), 6.63 (s, 1H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 33.1, 108, 120.6 (q, JCF=2.7 Hz), 163.1, 165.4, 169.5; HPLC: 95.9%.

Example 48: [3-(6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)phenyl]acetic acid (compound I-28)

[00529] 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 with 3 N HCl. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude reaction mixture was purified by reverse phase flash chromatography eluting with H ₂ O/MeOH from 5 to 80% to give the product. Compound I-28 (100 mg, 0.29 mmol) was obtained as a white powder. Yield 45%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.54 (s, 2H), 4.52 (s, 2H), 6.87 (s, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.33-7.35 (m, 2H), 12.18 (br s, 1H); HPLC: 98.1%.

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

[00530] 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 with 3 N HCl. The white solid was collected and described as the title compound. Compound I-29 (160 mg, 0.45 mmol) was obtained as a white powder. Yield 70%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.50 (s, 2H), 6.63 (s, 1H), 7.54 (t, J =7.7 Hz, 1H), 7.64 (d, J =7.5 Hz, 1H), 7.9 (d, J =7.6 Hz, 1H), 8.13 (s, 1H), 13.3 (shs, 1H); HPLC: 95.2%.

Example 50: (4-Benzyl-5-cyano-6-oxo-1,6-dihydropyrimidin-2-ylsulfanyl)acetic acid (Compound I-30)

[00531] To a stirred solution of intermediate 4.2 (110 mg, 0.45 mmol) and DIPEA (0.086 mL, 0.5 mmol) in acetone (10 mL) was added chloroacetic acid (43 mg, 0.45 mmol). Stirring was continued overnight at reflux. The mixture was cooled to room temperature and diluted with crushed ice and water. The pH was adjusted to 3 with 3 N HCl. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The crude reaction mixture was purified by reverse phase flash chromatography eluting with H ₂ O/MeOH from 5 to 80% to give the product. Compound I-30 (95 mg, 0.32 mmol) was obtained as a white powder. Yield 69%. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 3.92 (s, 2H), 4.0 (s, 2H), 7.24-7.28 (m, 1H), 7.31-7.32 (4H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.4, 42.6, 95.0, 115.4, 127.4, 129, 129, 129.3, 129.3, 136.4, 160.7, 166.3, 169.4, 169.4; HPLC: 98.9%.

Example 51: 3-(6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzoic acid (compound I-31)

[00532] To a stirred solution of the intermediate compound2.1(200 mg, 0.92 mmol) and DIPEA (0.19 ml, 1.1 mmol) in DMSO (5 ml) were added 3-(2-chloromethyl)benzoic acid13.1(170 mg, 1 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 with 3 N HCl. The white precipitate was collected and dried under vacuum. The crude product was purified by reverse phase chromatography eluting with H2O/MeOH from 4 to 80%. CompoundI-31(120 mg, 0.36 mmol) was obtained as a white powder. Yield 40%. ¹H NMR (400 MHz, DMSO-d ₆) δ 2.5 (s, 2H), 4.45 (s, 2H), 6.61 (s, 1H), 7.42 (t,J=7.6 Hz, 1H), 7.48 (d,J=7.4 Hz, 1H), 7.81 (d,J=7.58 Hz, 1H), 8.02 (s, 1H), 13.12 (shs, 1H); ¹³C NMR (100 MHz, DMSO-d ₆) δ 33.8, 107.7, 120.6 (k,J _CF =2.7 Hz), 128.6, 128.9, 130.4, 131.3, 134, 138.3, 150, 163, 165, 167.4; HPLC: 98.8%.

Example 52: 3-(6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzoic acid (compound I-32)

[00533] To a stirred solution of intermediate 4.2 (200 mg, 0.92 mmol) and DIPEA (0.16 mL, 0.9 mmol) in acetone (10 mL) was added 5-chloromethyl-1H-tetrazole (97 mg, 0.82 mmol). Stirring was continued overnight at reflux. The mixture was diluted with crushed ice and water. The pH was adjusted to 3 with 3 N HCl. The mixture was extracted with EtOAc (330 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . Compound I-32 (58 mg, 0.18 mmol) was obtained as a white powder after purification by reversed-phase flash chromatography eluting with _H2O /MeOH from 5 to 80%. Yield 20%. ^1H NMR (400 MHz, DMSO -d6 ) δ 3.90 ₍ s, 2H), 4.74 (s, 2H), 7.13-7.21 (m, 5H); HPLC: 98.9%.

Example 53: [3-(4-Benzyl-5-cyano-6-oxo-1,6-dihydropyrimidin-2-ylsulfanylmethyl)phenyl]acetic acid (Compound I-33)

[00534] To a stirred solution of intermediate 4.2 (150 mg, 0.2 mmol) and DIPEA (0.12 ml, 0.68 mmol) in acetone (10 ml) was added intermediate 11.2 (146 mg, 0.68 mmol). Stirring was continued overnight at reflux. The mixture was cooled to room temperature and diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected and dried under vacuum. The title compound I-33 (80 mg, 0.2 mmol) was obtained as a white solid. Yield: 33%. ^1H NMR (400 MHz, DMSO -d6 ) δ 3.5 (s, 2H), 4.0 (s, 2H), 4.37 (s, 2H), 7.12-7.32 (m, 9H) _; ¹³ C NMR (100 MHz, DMSO - _d6 ) δ 34.2, 42.6, 54.1, 95.2, 116, 127.5, 127.8, 128.9, 129, 129.1, 129.1, 129.6, 129.6, 130.4, 135.7, 136.8, 137.5, 161, 166.7, 172.6, 173.1; HPLC: 90.2%

Example 54: 4-Benzyl-6-oxo-2-[3-(1H-tetrazol-5-yl)-benzylsulfanyl]-1,6-dihydropyrimidine-5 carbonitrile (compound I-34)

[00535] To a stirred solution of intermediate 4.2 (150 mg, 0.62 mmol) and DIPEA (0.12 ml, 0.68 mmol) in acetone (10 ml) was added intermediate 18.1 (162 mg, 0.68 mmol). Stirring was continued overnight at reflux. The mixture was cooled to room temperature and diluted with crushed ice and water. The pH was adjusted to 5 by adding AcOH. The precipitate was collected and dried under vacuum. The crude product was suspended in water, acidified to pH 3 by adding 3 N HCl solution and extracted with EtOAc (320 ml). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The title compound I-34 (125 mg, 0.31 mmol) was obtained as a light yellow solid. Yield: 50%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.0 (s, 2H), 4.51 (s, 2H), 7.17-7.28 (m, 5H), 7.41-7.47 (2H), 7.90 (d, J=6.82 Hz, 1H), 8.06 (s, 2H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.7, 42.5, 95.5, 115.5, 124.7, 126.2, 127.3, 128.8, 128.9, 128.9, 129.4, 129.4, 129.9, 132.1, 136.5, 139, 158, 160.6, 166.2, 172.7; HPLC: 93%.

Example 55: 3-(4-Benzyl-5-cyano-6-oxo-1,6-dihydropyrimidin-2-ylsulfanylmethyl)benzoic acid (compound I-35)

[00536] To a stirred solution of intermediate 4.2 (150 mg, 0.62 mmol) and DIPEA (0.14 mL, 0.82 mmol) in acetone (10 mL) was added 3-(2-chloromethyl)benzoic acid 13.1 (116 mg, 0.68 mmol). Stirring was continued overnight at room temperature. The mixture was cooled to room temperature and diluted with crushed ice and water. The pH was adjusted to 3 by adding 3 N HCl. The precipitate was collected and dried under vacuum. The title compound I-35 (160 mg, 0.42 mmol) was obtained as a light yellow solid. Yield: 68%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.0 (s, 2H), 4.46 (s, 2H), 7.25-7.36 (m, 5H), 7.44 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 8.0 (s, 1H), 13.1 (shs, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.7, 42.5, 95.5, 115.5, 127.4, 128.6, 129, 129, 129.1, 129.4, 129.4, 130.3, 131.2, 133.8, 136.5, 138.1, 160.5, 166.2, 167.4, 172.7; HPLC: 98%, HPLC: 98%.

Example 56: [3-(3-cyano-6-oxo-4-trifluoromethyl-1,6-dihydropyridin-2-ylsulfanylmethyl)phenyl]acetic acid (compound I-36)

[00537] To a stirred solution of intermediate 7.1 (164 mg, 0.63 mmol) and DIPEA (0.12 mL, 0.71 mmol) in DMSO (5 mL) was added intermediate 11.2 (150 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 with 3 N HCl, then extracted with EtOAc (320 mL). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ . The crude product was purified by reverse phase chromatography eluting with H ₂ O/MeOH from 8% to 40% to give the product. The title compound I-36 (85 mg, 0.23 mmol) was obtained as a white powder. Yield: 37%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.55 (s, 2H), 4.53 (s, 2H), 6.87 (s, 1H), 7.16 (m, 1H), 7.26 (m, 1H), 7.35 (m, 2H), 12.2 (br s, 1H). ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 34.1, 40.8, 91.5, 105.3, 113.8, 121.5 (q, JCF=2.7 Hz), 127.8, 128.8, 129, 130.6, 135.7, 137.1, 142 (q, JCF=0.3 Hz), 164.6, 165.6, 173; HPLC: 97.8%.

Example 57: [3-(5-Cyano-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidin-2-ylsulfanyl)propionic acid (compound I-37)

[00538] To a stirred solution of the intermediate compound1.4(200 mg, 0.84 mmol) and DIPEA (0.16 ml, 0.93 mmol) in acetone (10 ml) were added 3-bromopropionic acid (57.1) (142 mg, 0.93 mmol). Stirring was continued overnight at room temperature. The mixture was then diluted with crushed ice and water, and the pH was adjusted to 3 with 3 N HCl. The resulting precipitate was collected and dried under vacuum. The title compoundI-37(180 mg, 0.58 mmol) was obtained as a light yellow solid. Yield: 69%.¹H NMR (400 MHz, DMSO-d ₆) δ 2.75-2.80 (m, 2H), 3.34-3.39 (m, 2H), 7.32-7.36 (m, 1H), 8.0-8.24 (m, 1H), 8.24-8.27 (m, 1H), 12.18 (brs, 1H), 13.72 (brs, 1H); ¹³C NMR (100 MHz, DMSO-d ₆) δ 26.2, 33.8, 40.7, 88.4, 1116.6, 130.1, 131.9, 135.4, 139.9, 158.9, 161.1, 165.6, 173.1; HPLC: 96.6%.

Example 58: 3-(6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-2-ylsulfanyl)propionic acid (compound I-38)

[00539] To a stirred solution of intermediate 2.2 (150 mg, 0.69 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMSO (5 mL) was added 3-bromopropionic acid (57.1) (115 mg, 0.75 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with crushed ice and water and the pH was adjusted to 3 with 3 N HCl. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na₂SO₄. The connection specified in the headerI-38(65 mg, 0.24 mmol) was obtained as a white powder. Yield: 35%.¹H NMR (400 MHz, DMSO-d ₆) δ 2.69 (t, J=6.68 Hz, 2H), 3.27 (t, J=6.7 Hz, 2H), 6.61 (s, 1H), 12.9 (shs, 2H); HPLC: 98.8%.

Example 59: 2-(3,5-Difluoro-4-hydroxybenzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-39)

Step 1: 2-(3,5-Difluoro-4-methoxybenzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (59.2)

[00540] To a solution of intermediate 1.4 (150 mg, 0.64 mmol) in DMSO (5 mL) were added DIPEA (0.12 mL, 0.7 mmol) and intermediate 59.1 (135 mg, 0.7 mmol). Stirring was continued at room temperature for 16 h. The crude mixture was poured into water and acidified to pH 3 by adding 3 N HCl solution. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . Intermediate 59.2 (168 mg, 0.42 mmol) was obtained as an orange powder. Yield: 67%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 3.87 (s, 2H), 4.5 (s, 3H), 7.28 (d, J =9.1 Hz, 2H), 7.36 (t, J =4.6 Hz, 1H), 8.1 (d, J =4.9 Hz, 1H), 8.28 (d, J= 3.8 Hz, 1H).

Step 2: 2-(3,5-Difluoro-4-hydroxybenzylsulfanyl)-6-oxo-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (I-39)

[00541] To a stirred suspension of intermediate 59.2 (160 mg, 0.41 mmol) in DCM (10 mL) was added 1 M _BBr3 in DCM (0.5 mL, 0.45 mmol) cooled to 0 °C. Stirring was continued at room temperature for 16 h. The reaction was quenched by addition of MeOH and the solvents were removed in vacuo. The crude product was purified by flash chromatography eluting with DCM/MeOH from 0 to 6% to give the product. The title compound I-39 (68 mg, 0.18 mmol) was obtained as a white powder after trituration with _Et2O . Yield: 44%. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 4.47 (s, 2H), 7.17 (d, J =8.3 Hz, 2H), 7.36 (t, J =4.6 Hz, 1H), 8.28 (d, J =3.9 Hz, 1H), 10.25 (s, 1H), 13.9 (shs, 1H); ¹³ C NMR (100 MHz, DMSO - d ₆ ) δ 33.3, 88.7, 112.7 (d, JCF ₌ 28.6 Hz), 112.9 (d, _JCF =28.6 Hz), 116.5, 127.8 (t, JCF =32.8 Hz), 130, 132.1, 133.4 (t, JCF = 63.7 Hz) _, 135.4, 139.7, 151.0 ( _{d, JCF} = 28.9 Hz) _, 153.4 (d, JCF =28.6 Hz), 158.9, 161.2, 165.2; HPLC: 95.7 _% .

Example 60: 2-(3,5-Difluoro-4-hydroxybenzylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (compound I-40)

Stage 1: 2-(3,5-Difluoro-4-methoxybenzylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (60.1)

[00542] Using the procedure described in Example 59 (step 1) and starting from intermediate 2.2 (200 mg, 0.91 mmol), 59.1 (211.8 mg, 1.1 mmol) and DIPEA (0.19 mL, 1.1 mmol) in DMSO (5 mL), the title intermediate 60.1 (200 mg, 0.56 mmol) was obtained as a white powder. Yield 62%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.88 (s, 2H), 4.33 (s, 3H), 6.63 (s, 1H), 7.21 (d, J = 9.2 Hz, 2H).

Stage 2: 2-(3,5-Difluoro-4-hydroxybenzylsulfanyl)-6-trifluoromethyl-3H-pyrimidin-4-one (I-40)

[00543] To a stirred suspension of intermediate 60.1 (190 mg, 0.54 mmol) in DCM (10 mL) was added 1 M _BBr3 in DCM (0.6 mL, 0.59 mmol) cooled to 0 °C. Stirring was continued at room temperature for 16 h. The reaction was quenched with MeOH. The solvents were removed in vacuo. The crude product was purified by flash chromatography eluting with DCM/MeOH from 0 to 6% to give the product. The title compound I-40 (61 mg, 0.18 mmol) was obtained as a white powder after trituration with _Et2O . Yield: 33%. ¹ H NMR (400 MHz, DMSO- d ₆ ) 4.29 (s, 2H), 6.63 (s, 1H), 7.11 (d, J = _7.82 Hz, 2H), 10.19 (s, 1H), 13.15 (br s, 1H); ¹³ C NMR (100 MHz, DMSO -d ₆ ) δ 33.3, 113.1 (d, JCF ₌ 28.2 Hz), _113.2 (d, JCF ₌ 28.4 Hz), 119.6, 122.3, 128.2, 133.3 (t, JCF ₌ 64.1 Hz) _, 150.9 (d, JCF = 28.3 Hz), 153.3 (d, JCF = 28.4 Hz) _; HPLC: 98.3%.

Example 61: 4-Benzyl-2-(3,5-difluoro-4-hydroxybenzylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (compound I-41)

Stage 1: 4-Benzyl-2-(3,5-difluoro-4-methoxy-benzylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (61.1)

[00544] Using the method described in Example 59 (step 1) and starting from intermediate 4.2 (200 mg, 0.82 mmol), 59.1 (189.9 mg, 0.98 mmol) and DIPEA (0.17 mL, 0.98 mmol) in DMSO (5 mL), the title intermediate 60.1 (200 mg, 0.5 mmol) was obtained as a white powder. Yield 61%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.87 (s, 2H), 4.02 (s, 2H), 4.35 (s, 2H), 7.0 (d, J=8.9 Hz, 2H), 7.3 (m, 5H).

Stage 2: 4-Benzyl-2-(3,5-difluoro-4-hydroxybenzylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (compound I-41)

[00545] To a stirred suspension of intermediate 61.1 (190 mg, 0.54 mmol) in DCM (10 mL) was added 1 M _BBr3 in DCM (0.5 mL, 0.52 mmol) cooled to 0 °C. Stirring was continued at room temperature for 16 h. The reaction was quenched with MeOH. The solvents were removed in vacuo. The crude product was purified by flash chromatography eluting with DCM/MeOH from 0 to 6% to give the product. The title compound I-41 (40 mg, 0.1 mmol) was obtained as a white powder after trituration with Et ₂ O. Yield: 22%. ¹ H NMR (400 MHz, DMSO _-d6 ) 4.02 (s, 2H), 4.3 (s, 2H), 6.93 (d, J=7.6 Hz, 2H), 7.27 (m, 4H), 7.9 (brs, 1H), 10.2 (s, 1H), 13.92 (brs, 1H); HPLC 96.7%.

Example 62: 6-oxo-2-{[4-(1H-tetrazol-5-yl)cyclohexylmethyl]amino}-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (compound I-42)

Step 1 : (4-Carbamoylcyclohexylmethyl)carbamic acid tert-Butyl ester 62.2)

[00546] To a solution of the starting intermediate 62.1 (1.3 g, 5.1 mmol) in CH ₃ CN (20 mL) were added pyridine (0.45 mL, 5.55 mmol), Boc ₂ O (1.67 g, 7.65 mmol) and ammonium bicarbonate (605 mg, 7.65 mmol). Stirring was continued at room temperature for 16 h. The crude mixture was poured into water. The aqueous phase was extracted with EtOAc (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The title compound 62.2 (1 g, 3.9 mmol) was obtained as a white powder. Yield: 76%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.8 (k, J =2.6 Hz, 2H), 1.45 (s, 9H), 1.63 (s, 2H), 1.86 (d, J =13.3 Hz, 2H), 1.97 (d, J =13.4 Hz, 2H), 2.11 (t, J =3.4 Hz, 1H), 2.99 (m, 2H), 4.5 (s, 1H), 5.38 (m, 2H).

Step 2 : (4-Cyanocyclohexylmethyl)carbamic acid tert-Butyl ester (62.3)

[00547] To a solution of the starting intermediate 62.2 (200 mg, 0.78 mmol) in DCM (10 mL) was added (0.3 mL, 1.95 mmol). The mixture was cooled to 0 °C and TFA anhydride (0.14 mL, 0.98 mmol) was added dropwise. Stirring was continued at room temperature for 16 h. The reaction mixture was poured into water, extracted with DCM (320 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ to give the title compound 62.3 (150 mg, 0.62 mmol) as a yellow oily substance. Yield 84%. ^1H NMR (400 MHz, CDCl ₃ ) δ 0.98-1 (m, 2H), 1.46 (s, 9H), 1.52 (m, 2H), 1.57-1.61 (m, 1H), 1.75-1.77 (m, 1H), 1.83-1.87 (m, 2H), 2.12-2.16 (m, 2H), 2.35-2.42 (m, 1H), 2.98 (t, J =6.4 Hz, 2H), 3.58 (d, J =6.8 Hz, 1H), 4.61 (shs, 1H).

Step 3 : [4-(1H-tetrazol-5-yl)cyclohexylmethyl]carbamic acid tert-butyl ester (62.4)

[00548] To a solution of the starting intermediate 62.3 (200 mg, 0.84 mmol) in DMF (3 mL) were added sodium azide (164 mg, 2.52 mmol) and NH4Cl (135 mg, 2.52 mmol). Stirring was continued at 140 °C for 25 h. The crude mixture was poured into water, acidified to pH 3 by adding 3 M HCl solution. The aqueous phase was extracted with EtOAc (3x 20 mL). The combined organic phase was washed with brine and dried over Na ₂ SO ₄ . The title compound 62.4 (160 mg, 0.56 mmol) was obtained as a white powder. Yield: 67%. ¹ H NMR (200 MHz, DMSO _-d6 ) δ 1.01 (t, J =6.8 Hz, 2H), 1.36-1.52 (m, 11H), 1.76 (d, J =11.7 Hz, 2H), 2.01 (d, J =11.0 Hz, 2H), 2.72-2.96 (m, 3H), 6.59-6.87 (m, 1H), 14.1 (shs, 1H).

Step 4 : C-[4-(1H-Tetrazol-5-yl)cyclohexyl]methylamine (62.5)

[00549] To a solution of intermediate 62.4 (450 mg, 1.60 mmol) in dioxane (5 ml) was added 4 M HCl in dioxane (13.2 ml). Stirring was continued at room temperature for 16 h. The solvent was removed in vacuo to give the title intermediate 62.5 (378 mg, 1.73 mmol) as a white powder as the hydrochloride salt. Yield 95%. ¹ H NMR (200 MHz, DMSO _-d6 ) δ 1.0-1.14 (m, 2H), 1.46-1.52 (m, 3H), 1.84 (d, J=13.1 Hz, 2H), 2.01 (d, J=13.4 Hz, 2H), 2.64-2.70 (m, 2H), 2.93 (m, 1H), 8.05 (shs, 3H).

Step 5 : 6-oxo-2-{[4-(1H-tetrazol-5-yl)cyclohexylmethyl]amino}-4-thiophen-2-yl-1,6-dihydropyrimidine-5-carbonitrile (Compound I-42)

[00550] To a stirred solution of intermediate 62.6 (250 mg, 0.88 mmol) in DMSO (5 mL) were added DIPEA (0.3 mL, 1.76 mmol) and intermediate 62.5 (211 mg, 0.97 mmol). Stirring was continued at 80 °C for 4 h. The crude mixture was poured into water, acidified to pH 3 and extracted with EtOAc (320 mL). The crude product was purified by flash chromatography eluting with DCM/MeOH (6% for the product). The title compound I-42 (24 mg, 0.06 mmol) was obtained as a yellowish solid. Yield 7%. ESIMS (-) m/z: 381.4 (MH). HPLC: 88%

Example 63: Preparation of intermediate 1b.3

Stage 1: Preparation of intermediate compound 1b.2

[00551] To a stirred solution of compound 1b.1 (500 mg, 2.13 mmol) in _H2O /EtOH (2 mL+4 mL) were added NaOH (85 mg, 2.13 mmol) and MeI (0.12 mL, 2.13 mmol). Stirring was continued at 60 °C for 30 min. The title compound 1b.2 was collected as a yellow powder after filtration of the reaction mixture (491 mg, 4.9 mmol). Yield 92%.

Stage 2: Preparation of intermediate compound 1b.3

[00552] To a stirred solution of the compound1b.2(200 mg, 0.8 mmol) in CHCl₃(6 mL) was added mCPBA (207 mg, 1.2 mmol). Stirring was continued at room temperature for 16 h. The yellow solid was collected and washed with DCM and Et₂O. The compound specified in the title1b.3received (190 mg, 0.67 mmol) as a pale yellow solid. Yield 84%.

Example 64: Preparation of intermediate 2b.2

Stage 1: Preparation of intermediate compound 2b.2

[00553] To a solution of the starting intermediate 2b.1 (200 mg, 0.83 mmol) in MeOH (3 mL) was added 30% ammonia in water (2 mL). Stirring was continued at room temperature for 24 h. The solvent was then removed in vacuo. The title intermediate 2b.2 (143 mg, 0.74 mmol) was obtained as a yellowish powder without further purification. Yield 90%.

Example 65: Preparation of intermediate 3b.6

Stage 1: Preparation of intermediate compound 3b.2

[00554] To a stirred and boiling solution of 3b.1 (1.00 g, 7.62 mmol) in MeCN (30 mL) was added dropwise a solution of NBS (1.42 g) and BPO 70% (13 mg, 0.04 mmol) in MeCN (10 mL). After 30 min, the mixture was slowly cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ (15 mL). The mixture was extracted with AcOEt (330 mL), washed with saturated brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The title intermediate 3b.2 (1.60 g) was used directly in the next step.

Stage 2: Preparation of intermediate compound 3b.3

[00555] A solution of intermediate 3b.2 (1.60 g, crude product from previous step) in MeOH (15 ml) was treated with 28% aqueous NH ₃ (15 ml) and the resulting mixture was stirred for 16 h. The volatiles were removed under reduced pressure and the crude mixture was poured into H ₂ O (30 ml) and washed with AcOEt (330 ml). The aqueous phase was concentrated under reduced pressure. The title intermediate 3b.3 (1.17 g) was used in the next step without purification.

Stage 3: Preparation of intermediate compound 3b.4

[00556] To a stirred suspension of intermediate 3b.3 (1.17 g, crude product from previous step) in _{CH2Cl2 (} 30 mL) were added _Boc2O (1.99 g, 9.14 mmol) and DIPEA (3.32 mL, 19.06 mmol), the mixture was allowed to react at room temperature for 2 h to give a translucent solution. _H2O (20 mL) was added, the two phases were separated and the organic phase was washed with 0.5 M aqueous citric acid solution (220 mL), _H2O (20 mL), brine (20 _mL ), dried over _Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (petroleum ether/AcOEt 9:1 to 7:3) to afford the title intermediate 3b.4 as a thick oil in 28% yield from 3.1 . ESI-MS (+) m/z: 247.2 (M+H).

Stage 4: Preparation of intermediate compound 3b.5

[00557] A mixture of intermediate 3b.4 (525 mg, 2.13 mmol), sodium azide (415 mg, 6.39 mmol) and triethylammonium chloride (880 mg, 6.39 mmol) in toluene (40 mL) was stirred and refluxed for 18 h. After cooling to room temperature, saturated aqueous NaHCO ₃ solution (15 mL) was added and the mixture was stirred vigorously for 10 min. The two phases were separated and the organic phase was extracted with H ₂ O (330). All aqueous phases were combined and acidified to pH = 3 by adding 0.5 M citric acid. The resulting acidic aqueous phase was extracted with CH ₂ Cl ₂ (350 mL), washed with saturated brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The title intermediate 3b.5 (214 mg, 0.74 mmol) was obtained as a white solid. Yield: 35%. ESI-MS (-) m/z: 288.2 (MH).

Stage 5: Preparation of intermediate compound 3b.6

[00558] Intermediate 3b.5 (205 mg, 0.71 mmol) was dissolved in MeOH (10 mL) and treated with 37% HCl (0.29 mL, 3.35 mmol) at 50 °C for 2 h. The volatiles were removed under reduced pressure to afford intermediate 3b.6 in near quantitative yield as the hydrochloride salt. ESI-MS (+) m/z: 190.3 (M+H); ESI-MS (-) m/z: 188.2 (MH).

Example 66: Preparation of intermediate 4b.4

Stage 1: Preparation of intermediate compound 4b.2

[00559] To a solution of intermediate 4b.1 (2 g, 11.86 mmol) in DCM (20 mL) were added TEA (1.99 mL, 14.2 mmol) and BOC ₂ O (2.717 g, 12.45 mmol). Stirring was continued at room temperature for 5 h. The crude mixture was poured into water and extracted with DCM. The organic phase was washed with brine and dried over Na ₂ SO ₄ . The title intermediate 4b.2 (2 g, 8.61 mmol) was obtained as a white solid. Yield 72%.

Stage 2: Preparation of intermediate compound 4b.3

[00560] To a solution of the starting intermediate 4b.2 (2 g, 7.26 mmol) in DMF (6 mL) were added NaN ₃ (839 mg, 12.91 mmol) and ammonium chloride (689 mg, 12.91 mmol). Stirring was continued at 140 °C for 6 h. The crude mixture was poured into water and brine, then extracted with EtOAc at pH = 3. The organic phase was dried over Na ₂ SO ₄ and evaporated in vacuo. The title intermediate 4b.3 (2.2 g, 8.0 mmol) was obtained as a white solid. Yield 93%.

Stage 3: Preparation of intermediate compound 4b.4

[00561] The starting intermediate 4b.3 (1.5 g, 5.48 mmol) was stirred overnight in 4 M HCl in dioxane (10 mL). The solvent was removed in vacuo. The title intermediate 4b.4 (1.14 g, 5.38 mmol) was obtained as a white solid. Yield 98%.

Example 67: Preparation of intermediate 5b.2

[00562] To a solution of intermediate 5b.1 (1 g, 6.1 mmol) in EtOH (10 mL) were added NH ₂ CN (0.7 mL, 9.1 mmol) and HNO ₃ (0.25 mL, 6.1 mmol). Stirring was continued at reflux for 16 h. The mixture was cooled to 0 °C and Et ₂ O was added. The white precipitate was collected. This gave the title intermediate 5b.2 (1 g, 3.7 mmol) as a white solid as the HNO ₃ salt. Yield 60%.

Example 68: Preparation of intermediate 6b.2

[00563] To a solution of intermediate 6b.1 (1 g, 6.1 mmol) in EtOH (10 mL) were added NH ₂ CN (0.7 mL, 9.1 mmol) and HNO ₃ (0.25 mL, 6.1 mmol). Stirring was continued at reflux for 16 h. The mixture was cooled to 0 °C and Et ₂ O was added. The white precipitate was collected. The title intermediate 6b.2 (1.2 g, 4.4 mmol) was obtained as a yellowish solid as a HNO ₃ salt. Yield 72%.

Example 69: Obtaining compound I-43

[00564] To a stirred suspension of intermediate 1b.3 (200 mg, 0.85 mmol) in DMSO (5 mL) were added DIPEA (0.29 mL, 1.7 mmol) and intermediate 2b.2 (164 mg, 0.94 mmol). Stirring was continued at 80 C for 4 h. The crude mixture was poured into water, acidified to pH 3 and extracted with EtOAc (320 mL). The crude reaction mixture was purified by flash chromatography eluting with DCM/MeOH (3% for product). The title compound I-43 (50 mg, 0.13 mmol) was obtained as a yellowish solid. Yield 15%. ^1H NMR (400 MHz, _DMSO d6 ) δ 4.69 (2H), 7.25 (m, 1H), 7.58 (m, 2H), 7.91 (m, 2H), 8.0 (s, 1H), 8.16 (m, 1H), 11.94 (brs, 1H); ¹³ C NMR (100 MHz, _DMSO d6 ) δ 44.2, 81.8, 117.8, 124.6, 126.1, 126.3, 129.3, 129.9, 130.7, 130.9, 130.9, 133.9, 140.5, 141.1, 154.4, 161.6, 162.1. HPLC 96.3%.

Example 70: Obtaining the I-44 connection

Stage 1: Synthesis of intermediate 8b.2

[00565] To a solution of intermediate 8b.1 (195 mg, 0.72 mmol) and intermediate 5b.2 (150 mg, 0.72 mmol) in DMF (2 mL) was added piperidine (0.14 mL, 1.45 mmol). The mixture was sealed in a Q-tube and heated at 120 °C for 16 h. The mixture was cooled to room temperature, poured into water, extracted with EtOAc and purified by flash chromatography eluting with DCM/MeOH (5% for product). The title intermediate 8b.2 (200 mg, 0.39 mmol) was obtained as a brownish powder. Yield 54%

Stage 2: Synthesis of compound I-54

[00566] To a solution of intermediate 8b.2 (150 mg, 0.41 mmol) in EtOH (10 mL) was added 1 M NaOH solution (1.2 mL). Stirring was continued at gentle reflux for 16 h. The precipitate was collected by filtration and dissolved in water. The pH was adjusted to 3 by adding 3 N HCl solution. The precipitate was collected and dried under vacuum to give the title compound I-44 (100 mg, 0.295 mmol) as a brown solid. Yield 72%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 7.31 (t, J = 4.22 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 7.48 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.99 (d, J =4.7 Hz, 1H), 8.25 (m, 2H), 10.1 (s, 1H), 11.9 (shs, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 83.5, 117.4, 122.4, 125.3, 125.7, 129.5, 129.6, 131.2, 131.8, 134.3, 137.9, 140.8, 152.5, 161.4, 161.9, 167.3. HPLC: 98.4%

Example 71: Obtaining the I-45 connection

Stage 1: Synthesis of intermediate 9b.1

[00567] To a solution of intermediate 8b.1 (990 mg, 0.72 mmol) and intermediate 6b.2 (1.18 g, 4.34 mmol) in DMF (10 mL) was added piperidine (0.86 mL, 8.68 mmol). The mixture was heated at 150 °C for 16 h. The mixture was cooled to room temperature, poured into water, and the pH was adjusted to 3 with HCl (3 N). The solid was collected and washed with acetone. The title intermediate 9b.1 (250 mg, 0.68 mmol) was obtained as a gray powder. Yield 14%

Stage 2: Synthesis of compound I-45

[00568] To a solution of intermediate 9b.1 (150 mg, 0.41 mmol) in EtOH (10 mL) was added 1 M NaOH (1.2 mL). Stirring was continued at gentle reflux for 16 h. The solvent was removed under vacuum. The solid was suspended in EtOH (5 mL), sonicated and filtered. The sodium salt was dissolved in ice-water and the pH was adjusted to 3 with 3 N HCl. The gummy precipitate was collected and dried under vacuum to give the title compound I-45 (90 mg, 0.21 mmol) as a brown solid. Yield 65%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 7.32 (d, J = 4.1 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 8.0 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 3.8 Hz, 1H), 10.23 (s, 1H), 11.9 (br s, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 83.9, 117.2, 120.5, 120.5, 126.2, 129.7, 130.7, 130.7, 131.3, 134.5, 140.7, 141.9, 152.5, 161.3, 167.2; HPLC: 95.56%.

Example 72: Obtaining the I-46 compound

[00569] To a solution of intermediate 1b.3 (100 mg, 0.36 mmol) in DMSO (3 mL) was added 1,4-trans-aminocyclohexane (51 mg, 0.36 mmol). Stirring was continued at 80 °C for 16 h. The mixture was poured into water and the pH was adjusted to 3 with HCl (3 N). The gummy precipitate was collected and dried under vacuum. The crude product was purified by flash chromatography eluting with 15% DCM/MeOH and acetone due to the low solubility of the compound. The title compound I-46 (40 mg, 0.12 mmol) was obtained as a yellowish powder. Yield 32%. ¹ H NMR (200 MHz, DMSO d ₆ ) δ 1.34 (m, 4H), 1.92 (m, 4H), 2.20 (brs, 1H), 3.73 (brs, 1H), 7.27 (t, J = 4.2 Hz, 1H), 7.61 (s, 1H), 7.91 (d, J =4.9 Hz, 1H), 8.15 (m, 1H), 12.0 (shs, 1H). ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 27.8, 27.8, 31.1, 31.1, 41.7, 41.7, 50.2, 81.05, 118.0, 129.4, 130.7, 133.9, 141.3, 153.9, 161.6, 176.8; HPLC: 96.3%.

Example 73: Obtaining the I-47 connection

[00570] To a solution of intermediate 1b.3 (150 mg, 0.53 mmol) in DMSO (5 mL) was added 1,4-cis-aminocyclohexane (76 mg, 0.53 mmol). Stirring was continued at 80 °C for 16 h. Ice was added to the mixture while stirring. The white solid was collected and then purified by flash chromatography eluting with DCM/MeOH. The title compound I-47 (70 mg, 0.2 mmol) was obtained as a white solid. Yield 38%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 1.71 (m, 8H), 2.4 (br s, 1H), 4.05 (s, 1H), 7.28 (t, J = 4.2 Hz, 1H), 7.3 (m, 1H), 7.93 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 3.23 Hz, 1H), 10.9 (br s, 1H), 12.1 (br s, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 24.6, 28.8, 47.6, 48.9, 55.3, 55.3, 81.2, 117.8, 129.4, 130.8, 133.9, 141.2, 153.6, 161.6, 161.7, 176.5; HPLC: 98.51%.

Example 74: Obtaining the I-48 connection

Stage 1: Synthesis of intermediate 12b.2

[00571] To a solution of the starting intermediate 1b.3 (400 mg, 1.42 mmol) in DMSO (5 mL) were added DIPEA (0.36 mL, 2.13 mmol) and intermediate 12b.1 (344 mg, 1.7 mmol). Stirring was continued at 80 °C for 16 h. The crude mixture was poured into water. The pH of the solution was adjusted to 3 by adding HCl (3 N). The aqueous phase was extracted with EtOAc. The mixture was purified by flash chromatography eluting with DCM/MeOH. The title intermediate 12b.2 (200 mg, 0.54 mmol) was obtained as a yellowish powder. Yield 38%.

Stage 2: Synthesis of compound I-48

[00572] To a solution of intermediate 12b.2 (200 mg, 0.52 mmol) in MeOH (15 mL) was added 1 M NaOH (3 mL). Stirring was continued at gentle reflux for 16 h. The solvent was removed under vacuum. The sodium salt was dissolved in ice-water, the pH was adjusted to 3 by adding 3 N HCl. The gel precipitate was collected and dried under vacuum to give the title compound I-48 (150 mg, 0.42 mmol) as a yellowish solid after trituration with Et ₂ O. Yield 82%. ESIMS (+) m/z: 353.3 (M+H).

Example 75: Obtaining an I-49 connection

[00573] To a stirred solution of intermediate 1b.3 (150 mg, 0.53 mmol) in DMF (10 mL) was added intermediate 3b.6 (120 mg, 0.53 mmol) and DIPEA (0.46 mL, 2.65 mmol) and the mixture was reacted at 105 °C for 6 h. After cooling to room temperature, the mixture was poured into H ₂ O (25 mL) and washed with Et ₂ O (220 mL). The aqueous solution was added 3.0 M HCl until pH = 1 and the mixture was extracted with CH ₂ Cl ₂ /MeOH 9:1 (v/v, 330 mL). The combined organic phases were concentrated under reduced pressure and the crude product was purified by reverse phase flash chromatography (H ₂ O/MeCN from 8:2 to 1:9). The collected compound with impurities (15 mg) was triturated with cold acetone to obtain 10 mg of pure compound I-49 (yield: 5%). ESI-MS (-) m/z: 389.4 (MH). ¹ H NMR (400 MHz, DMSO d ₆ ) δ 4.25 (s, 2H), 4.55 (d, J = 4.74 Hz, 2H), 7.17 (s, 1H), 7.26 (m, 4H), 7.91 (d, J = 4.8 Hz, 1H), 7.94 (br s, 1H), 8.16 (d, J = 3.3 Hz, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 29.4, 44.3, 81.5, 117.9, 126.5, 127.9, 128.2, 129.1, 129.3, 130.8, 133.9, 136.8, 139.4, 141.1, 154.6, 155.8, 161.6, 162.4; HPLC: 99.5%.

Example 76: Obtaining the I-50 connection

Stage 1: Synthesis of intermediate 14b.2

[00574] To a solution of intermediate 1b.3 (200 mg, 0.71 mmol) in DMSO (5 mL) were added DIPEA (0.18 mL, 1.07 mmol) and intermediate 14b.1 (164 mg, 0.85 mmol). Stirring was continued at 80 °C for 16 h. The mixture was poured into water and extracted with EtOAc (320 mL). The mixture was purified by flash chromatography eluting with 1.5% DCM/MeOH to give the product. The title intermediate 14b.2 (173 mg, 0.43 mmol) was obtained as a yellow solid. Yield 62%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 1.13 (t, J = 7.1 Hz, 3H), 3.63 (s, 2H), 4.02 (k, J = 7.0 Hz, 2H), 4.56 (d, J = 5.8 Hz, 2H), 7.16 (m, 1H), 7.27 (m, 4H), 7.93 (m, 1H), 7.94 (d, J =4.0 Hz, 1H), 8.17 (d, J =3.8 Hz, 1H), 11.91 (shs, 1H).

Stage 2: Synthesis of compound I-50

[00575] To a solution of intermediate 14b.2 (165 mg, 0.42 mmol) in EtOH (6 mL) was added 1 M NaOH solution (1.3 mL). Stirring was continued at gentle reflux for 16 h. The mixture was cooled to room temperature and the precipitate was collected. The sodium salt was dissolved in ice water, the pH was adjusted to 1 by adding 3 N HCl solution. The precipitate was collected and dried under vacuum to give the title compound I-50 (75 mg, 0.21 mmol) as a white solid. Yield 49%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 3.55 (s, 2H), 4.57 (d, J = 5.8 Hz, 2H), 7.16 (m, 1H), 7.27 (m, 4H), 7.84 (m, 1H), 7.92 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 3.7 Hz, 1H), 11.73 (br s, 1H), 12.49 (br s, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 41.0, 44.3, 81.6, 117.8, 126.3, 128.7, 129.1, 129.1, 129.3, 130.9, 134.0, 135.5, 138.8, 141.1, 154.3, 161.7, 161.9, 173.0; HPLC: 95.2%.

Example 77: Obtaining Compound I-51

[00576] To a solution of intermediate 4b.2 (211.6 mg, 1 mmol) in DMSO (5 mL) was added DIPEA and stirring was continued at room temperature for 10 min. Then a solution of compound 1b.3 in DMSO was added. Stirring was continued at 90 °C for 16 h. The crude product was collected, dried and purified by flash chromatography eluting with 6% DCM/MeOH to give the product. The title compound I-51 was obtained (25 mg, 0.06 mmol) as a yellow solid after trituration with EtOAc. Yield 7%. ¹ H NMR (400 MHz, DMSO d ₆ ) δ 4.68 (d, J = 5.7 Hz, 2H), 7.27 (t, J = 4.1 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.9 (d, J = 4.9 Hz, 1H), 8.0 (d, J = 7.7 Hz, 2H), 8.18 (d, J = 3.6 Hz, 1H), 12.1 (br s, 1H); ¹³ C NMR (100 MHz, DMSO d ₆ ) δ 44.2, 53.9, 81.7, 117.8, 123.6, 127.4, 127.4, 128.7, 129.3, 130.9, 134.0, 141.0, 142.2, 154.5, 155.7, 161.6, 162.1; HPLC: 96.6%.

BIOLOGICAL ACTIVITY

Biological Example 1: Determination of ACMSD1 Inhibition

[00577] The activity of compounds 1-36 as ACMSD1 inhibitors was determined by measuring the conversion of 3OH-anthranilic acid to the product (i.e., ACMS) in an in vitro spectrophotometric assay.

[00578] A pre-assay mixture consisting of 3-hydroxyanthranilic acid (3OH-HA), 3-hydroxyanthranilic acid, 3,4-dioxygenase (HAO), and dialyzed crude extract from E. coli BL21 (DE3) cells expressing the recombinant enzyme was incubated at 25°C while monitoring the increase in absorbance at 360 nm due to the formation of ACMS from 3OH-HA. After the reaction was complete, an aliquot of ACMSD1 solution (prepared and purified from Pichia pastoris yeast overexpressing the recombinant enzyme) was added for ~2 min and the decrease in absorbance at 360 nm was monitored at 15 s intervals. The effect of ACMS concentration on enzyme activity was studied by varying the concentration of 3OH-HA from 2 to 20 μM. Kinetic parameters were calculated from the initial velocity values using the Lineweaver-Burk plot.

[00579] The rate of decrease in absorbance due to ACMSD1 was calculated by subtracting the absorbance value of the control reaction mixture without ACMSD from the absorbance value described above. One unit of ACMSD activity is the amount of enzyme that converts 1 mmol ACMS per minute at 25 C. The absence or reduction of ACMSD1 activity (e.g., using ACMSD inhibitors) results in slow spontaneous degradation of ACMS (i.e., cyclization to form quinolinic acid).

[00580] Enzyme activity was determined at a concentration of 10 μM HAA in the presence of the compounds from Table 1 below. The compounds were tested at a concentration of approximately 5 μM and 10 μM and the IC ₅₀ was calculated for compounds showing inhibitory activity greater than 50%. The results are presented in Table 1. In Table 1, A represents <0.1 μM; B represents 0.1 to 1 μM; C represents 1 to 10 μM; and D represents >10 μM.

TABLE 1:

Connection No. Structure Activity,
IC ₅₀ hACMSD I-1 C I-2 B I-3 A I-4 C I-5 B I-6 C I-7 B I-8 B I-9 B I-10 C I-11 C I-12 C I-13 C I-14 C I-15 C I-16 D I-17 D I-18 B I-19 A I-20 A I-21 A I-22 A I-23 C I-24 C I-25 A I-26 A I-27 B I-28 B I-29 A I-30 B I-31 C I-32 A I-33 A I-34 A I-35 B I-36 B I-37 C I-38 n/a I-39 C I-40 n/a I-41 C I-42 n/a I-43 A I-44 n/a I-45 n/a I-46 D I-47 n/a I-48 C I-49 A I-50 C I-51 B

Biological Example 2: Determination of ACMSD-1 modulation in HEK293T cells

[00581] HEK293T cells (ATCC) were seeded in six-well plates and transfected using Fugene HD to transiently express ACMSD. Twenty-four hours after transfection, the cells were stimulated for 48-72 hours with various concentrations of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and then lysed to measure ACMSD activity by measuring the conversion of 3OH-anthranilic acid to the product (i.e., β-amino-carboxymuconate-semialdehyde, ACMS) in an in vitro spectrophotometric assay. Total protein content of the cell lysates was determined by the Bradford assay. This value was used to determine the specific enzyme activity normalized across all samples (mU/mL or δE/δt/mg total protein).

[00582] It is known that the ACMSD-1 enzyme is expressed in the liver, kidney and brain; therefore, the available cell lines for these cell types were tested to determine the expression levels of ACMSD. The inventors investigated whether ACMSD-1 is expressed in transformed cell lines from liver and kidney, such as HepG2, HEK293T, Hep3B, etc. ACMSD was transfected to express the enzyme in various cell conditions, such as COS-7, HEK293T and HepG2. It was found that HEK293T cells were the best system with the highest protein production, which allows for reliable measurement of ACMSD1 enzyme activity. This is likely due to the more efficient transfection observed in HEK293T.

[00583] After determining the optimal stimulation time and transfection protocol, the cells were stimulated with various concentrations of the compound of formula (I) or a pharmaceutically acceptable salt thereof (from about 50 nM to about 5 μM).

Biological example 3: Determination of NAD content ⁺ in primary human hepatocytes treated with a compound according to the present description

[00584] The concentration or content of NAD ⁺ was determined in primary human hepatocytes treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof. The vehicle (NT) was used as a control sample.

[00585] At least three experiments were performed by treating primary hepatocytes with different concentrations of the compound of formula (I) or a pharmaceutically acceptable salt thereof (0.5 μM and 5 μM) 48 hours after seeding. The compounds were replaced every 24 hours and then the cells were directly harvested and lysed with ACN/ _H2O (5:1 ratio). LCMS/MS was used to detect and measure the concentration/content of NAD ⁺ .

Biological example 4: Determination of NAD content ⁺ in primary human hepatocytes treated with a compound according to the present description

[00586] The concentration or content of NAD ⁺ was determined in primary human hepatocytes treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as a known ACMSD inhibitor, MEHP. MEHP was used as a control sample.

[00587] At least three experiments were performed by treating primary hepatocytes with different concentrations of the compound of formula (I) or a pharmaceutically acceptable salt thereof (0.5 μM, 5 μM, and 50 μM) 48 hours after seeding. The compounds were replaced every 24 hours and then the cells were directly harvested and lysed with ACN/ _H2O (5:1 ratio). LCMS/MS was used to determine and measure the concentration/content of NAD ⁺ .

Biological Example 5: Modulation of SOD2 Activity in AML-12 Cells and Primary Mouse Hepatocytes

[00588] Modulation of SOD-2 activity was measured in AML-12 cells and in primary mouse hepatocytes treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[00589] The mouse hepatocyte cell line AML-12 (murine liver alpha cells 12) was purchased from ATCC and grown at 37C in a humidified atmosphere of 5% _CO2 /95% air in Dulbecco's modified Eagle's medium/F-12 (DMEM/F-12) supplemented with 0.005 mg/mL insulin, 0.005 mg/mL transferrin, 5 ng/mL selenium, 40 ng/mL dexamethasone, and 1% gentamicin. ACMSD inhibitors were first reconstituted from powder in DMSO to a stock concentration of 1 mM. The resulting stock solution was further diluted with water to a concentration of 100 μM, which was used to treat the cells.

[00590] Primary hepatocytes were obtained from 8-12 week old C57BL/6J mice by collagenase perfusion. The livers of mice were perfused with Hanks' balanced salt solution (HBSS, KCl, 5.4 mM; _KH2PO4 , _0.45 mM; NaCl, 138 mM; _NaHCO3 , 4.2 mM; _Na2HPO4 , _0.34 mM; glucose, 5.5 mM; HEPES, 1 M; EGTA, 50 mM; _CaCl2 , 50 mM; pH 7.4). The livers were then flushed at 5 ml/min through the portal vein. After flushing, the livers were perfused with collagenase solution (0.025%). Cell viability was assessed by the trypan blue assay. Isolated primary hepatocytes were plated in DMEM (Gibco) containing 10% FCS, 10 units/ml penicillin and HEPES for buffering. Cells were maintained in culture at 37°C in a humidified atmosphere of 5% _CO2 /95% air. After 6-8 hours of cell attachment, the medium was replaced with medium containing various concentrations of ACMSD inhibitor (i.e., compound of formula (I) or a pharmaceutically acceptable salt thereof) or appropriate concentrations of DMSO (as a control). Primary hepatocytes were harvested after approximately 24 hours unless otherwise indicated.

[00591] Primary hepatocytes or AML-12 cells were then lysed in 20 mM HEPES buffer (Gibco), pH 7.2, containing 1 mM EGTA (Sigma), 210 mM mannitol (Sigma), and 70 mM sucrose (AMRESCO). Total protein concentration was determined by the Bradford assay (BioRad). SOD-2 activity was determined at various time points after treatment with the ACMSD inhibitor using a SOD assay kit (Cayman Chemical) according to the manufacturer's instructions. Specifically, to determine SOD2 activity, 2 mM potassium cyanide was added to the assay solution, which inhibits both Cu/Zn-SOD and extracellular SOD, resulting in the detection of only Mn-SOD (SOD-2) activity. Absorbance was measured on a Victor X4 multichannel plate reader (Perkin-Elmer) at 450 nm. Results were expressed as U/ml/mg protein according to the standard curve and the measured protein concentration.

[00592] Oxidative stress resistance was investigated by measuring SOD2 activity.

Biological Example 6: Determination of NAD Content ⁺ in primary mouse hepatocytes

[00593] NAD ⁺ levels were determined in primary human hepatocytes treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[00594] NAD ⁺ was extracted by acid extraction. Samples were collected and homogenized in 70% glacial perchloric acid ( _{HClO4 )} . After pelleting insoluble protein fragments by adding potassium carbonate ( _K2CO3 ), samples were separated by high performance liquid chromatography (HPLC) and analyzed by mass spectrometry. Proteins in the pellets were quantified by Bradford assay and used for normalization.

[00595] Treatment of primary hepatocytes with the ACMSD inhibitor of formula (I) or a pharmaceutically acceptable salt thereof at concentrations of 5 nM, 10 nM, and 50 nM for 24 hours was studied to determine whether there was a significant and dose-dependent increase in intracellular NAD ⁺ levels.

Biological Example 7: RT-qPCR Analysis of SIRT1-Regulated Genes in AML-12 Cells, Hepa-1.6 Cells, and Primary Mouse Hepatocytes Treated with the Compound According to the Description

[00596] The expression of ACMSD genes and genes known to be regulated by SIRT1 (an enzyme that is strictly dependent on NAD ⁺ ), such as Pgc1a , Sod1, Sod2 (MnSOD), was analyzed in AML-12 cells, Hepa-1.6 cells, and primary mouse hepatocytes treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[00597] Cells (AML-12, Hepa-1.6, HEK-293, primary human and mouse hepatocytes) were treated with various concentrations of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Total RNA was extracted from the cells using TRIzol (Invitrogen) according to the manufacturer's instructions. RNA was treated with DNase and 2 μg of RNA was used for reverse transcription (RT). 50X diluted cDNA was used for quantitative reverse transcription-PCR (RT-qPCR) reactions. RT-qPCR reactions were performed on a Light-Cycler System (Roche Applied Science) and qPCR Supermix (QIAGEN) with the indicated primers. The average of at least three technical replicates was used for each biological data point.

[00598] It is known that dose-dependent increases in mRNA expression levels of genes are regulated by SIRT1 (an enzyme that is strictly dependent on NAD ⁺ ), such as Pgc1a , Sod2 (MnSOD), but not Sod1 (Cu-Zn SOD). Primary mouse hepatocytes were treated for 24 hours with a compound of formula (I) or a pharmaceutically acceptable salt thereof (range from 5 nM to 500 nM) and changes in the expression levels and mRNA levels of Pgc1a and Sod2 (MnSOD) were observed. The changes in mRNA expression are consistent with activation of SIRT1, followed by induction of NAD ⁺ levels due to inhibition of ACMSD1 activity.

Biological Example 8: Modulation of Caspase 3/7 Activity in MDCK Cells

[00599] An in vitro study was conducted in MDCK cells to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on acute kidney injury.

[00600] MDCK cells (MDCK (NBL-2) ATCC CCL-34™) were grown in ATCC Basic Medium, Eagle's Complete Minimum Essential Medium, Catalog #30-2003, with fetal bovine serum (FBS) to a final concentration of 10%. 10,000 cells were plated in 96 wells and 24 hours after the cells were plated, the medium was changed to fresh medium supplemented with 1% FBS. Cisplatin (50 μM for 16 hours) was then used to initiate cellular injury. Various concentrations (from about 1 μM to about 125 μM) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (in 1% DMSO) were added in combination with cisplatin or 1 hour before the addition of cisplatin.

[00601] Caspase 3/7 activity (Promega) was determined by standard methods by reading the fluorescent signal on a Victor V plate reader (PerkinElmer). Each experiment/experimental condition was performed in triplicate.

[00602] Caspase activity was analyzed as a percentage effect normalized to pure cisplatin (100%) and to vehicle-treated cells used as a reference with 0% caspase activity. Data were analyzed using GraphPad software. One-way analysis of variance (Dunnett's multiple comparison test) was used for statistical analyses.

[00603] MDCK cells were treated with various concentrations of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Biological example 9: Cytotoxicity and hERG screening

[00604] Cytotoxicity: 20,000 HePG2 and AML-12 cells were seeded in a 96-well plate (Viewplate, PerkinElmer). The dose response of the compound of formula (I) or a pharmaceutically acceptable salt thereof was determined using an HP D300 digital pipette over a concentration range of 10 nM to 300 μM with a constant DMSO content of 1% in the medium. Cells were stimulated for 4 hours at 37°C; the supernatant was used to release LDH (Cytotox-one, Promega) as a measure of necrosis, lysing the cells to measure ATP levels to determine cell viability (Celltiter-glo, Promega) according to the manufacturer's instructions.

[00605] The Predictor hERG Assay Kit (Invitrogen), containing membrane preparations from Chinese hamster ovary cells stably transfected with the hERG calcium channel and a high-affinity red fluorescent ligand of the hERG channel (labeled compound), was used to determine the binding affinity of the hERG channel of compounds of formula (I) or pharmaceutically acceptable salts thereof. Compounds that bind to the hERG channel protein (competing compounds) were identified by their ability to displace the labeled compound, resulting in a decrease in fluorescent polarization. The final concentration of DMSO in each well was maintained at 1%. The assays were performed according to the manufacturer's protocol (Invitrogen).

Biological Example 10: Antidiabetic Effect in C57BL/6J and KK-Ay Mice

[00606] A glucose tolerance test was performed in male C57BL/6J and KK-Ay mice to determine the effect of compounds of formula (I) or their pharmaceutically acceptable salts on glucose and insulin levels.

[00607] Male C57BL/6J and KK-Ay mice aged 6-7 weeks were purchased from, for example, Charles River Laboratories (France) and CLEA (Japan), respectively. Starting from the age of 8 weeks, the mice were fed a standard diet (CD-Harlan 2018), a high-fat diet (HFD-Harlan 06414). The compound of formula (I) or a pharmaceutically acceptable salt thereof was mixed with the HFD in an amount of 180 mg.kg ^-1 diet. Based on daily food intake, this provides a daily dose of approximately 15 mg.kg ^-1 body weight. The mice were fasted for 4 hours before collecting blood and tissue for RNA extraction, lipid measurements and histology. Oxygen consumption was measured on an Oxymax device (Columbus Instruments). Histological and transmission electron microscopy analyses were performed.

[00608] An oral glucose tolerance test was performed on animals fasted overnight. Glucose was administered by gavage at a dose of 2 g/kg. An intraperitoneal insulin tolerance test was performed on animals fasted for 4 hours. Insulin was administered by injection at a dose of 0.75 U/kg body weight. Glucose was quantitatively measured using a Maxi Kit 4 glucometer (Bayer Diagnostic) or a Glucose RTU (bioMerieux Inc.), and plasma insulin concentrations were measured using an enzyme-linked immunosorbent assay (Cristal Chem Inc.). Statistical differences were determined using analysis of variance or Student's t-test.

Biological example 11: Antidiabetic and obesity effects in LepR mutant db/db mice

[00609] A study was conducted on the antidiabetic effect of compounds of formula (I) or their pharmaceutically acceptable salts in mice with genetic obesity Leprdb /J (db/db).

[00610] Animals were bred and maintained under temperature and humidity controlled conditions according to FELASA protocols. Mice were fed a high fat diet (HFD) (Harlan 06414) from three weeks of age. Most pharmacological studies were initiated in eight-week-old diabetic db/db mice or wild-type (wt) controls.

Subchronic intervention

[00611] db/db mice were administered a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily between 5 and 6 p.m., before the onset of the dark phase (6 p.m.), for 14 days. Blood samples were collected 4 hours after the mice were no longer able to access food, before the first dose, and 18 ± 2 hours after the last dose. Glucose concentrations in each blood sample were determined.

Acute glucose exposure

[00612] Baseline blood samples were collected randomly from free-feeding db/db mice between 6 and 8 a.m., following the onset of the light phase (6 a.m.), then compounds of formula (I) or pharmaceutically acceptable salts thereof were administered, food was restricted, and a second blood sample was collected 4 hours after administration. Mice were then subjected to an oral glucose tolerance test (OGTT1: 1 g glucose/kg body weight) and blood glucose concentrations were determined at 0.5, 1, 2, 3, and 4 hours after each glucose load.

Euglycemic hyperinsulinemic clamp test

[00613] An indwelling jugular vein catheter was inserted into db/db mice under ketamine/xylazine anesthesia. Food access was withheld after six to seven days (after 6 a.m.). Conscious mice were placed in an oversized rat restrainer and warmed with heating pads. The catheter ends were then connected to syringes in CMA402 pumps (Axel Semrau, Sprockhövel, Germany). After 110 minutes of primary continuous infusion of [3- ³ H]glucose (1.85 kBq/min), a blood sample was collected to determine plasma insulin, glucose, and [3- ³ H]glucose concentrations and to calculate the baseline rate of endogenous glucose production. Mice were then gavaged with vehicle or a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[00614] Then, an infusion of [3- ³ H]glucose (3.7 kBq/min) containing insulin (36 pmol/kg*min ^-1 ; HumulinR, Lilly, USA) was started via a glucose clamp, creating a moderate net increase in plasma insulin concentrations. Blood glucose concentrations were measured every 10 minutes and the desired glycemic level was achieved by adjusting the 20% glucose infusion rate (GIR). At 120 minutes, 2-deoxy-D-[1- ¹⁴ C]glucose (370 kBq) was administered intravenously. Blood samples were collected at 30, 60, 90, 100, 110, 120, 122, 125, 130, and 140 minutes. Mice were then euthanized (i.e., by intravenous ketamine/xylazine overdose). Gastrocnemius muscles and epididymal adipose tissue were collected, immediately flash frozen in liquid nitrogen and stored at -80°C. 2-[ ^14C ]deoxyglucose-6-phosphate was extracted from the tissue and the rate of glucose uptake (Rg) was calculated.

[00615] Plasma [ ³ H] and [ ¹⁴ C] radioactivity was determined in protein-free plasma after [ ³ H ₂ O evaporation]. Glucose fluxes at baseline and during 60-90 and 90-120 min in the glucose squeeze were estimated as follows: whole body glucose disappearance rate (Rd) = [3- ³ H]GIR (disintegrations per minute)/plasma [3- ³ H]glucose specific activity (disintegrations per minute*mol); baseline endo-Ra = [3- ³ H]GIR (disintegrations per minute)/plasma [3- ³ H]glucose specific activity (disintegrations per minute*mol); endo-Ra in the glucose squeeze = GIR˗Rd. Ultima-Gold scintillation cocktail, radioisotopes and Tri-Carb2910TR were purchased from Perkin Elmer (Germany).

Blood, plasma, urine analysis

[00616] Blood samples were collected from the lateral tail veins. Blood glucose was measured with a glucometer (Contour, Bayer Vital, Germany), urine and plasma glucose were measured with a colorimetric glucose assay Glucose LabAssay (Wako, Germany), as well as with HbA1c with A1cNow+ (Bayer Vital) or Clover analyzer (Inopia, South Korea).

Analysis of disease onset and survival

[00617] Disease onset was defined as the last day of individual peak body weight before gradual weight loss. Disease stages were defined as follows: early disease was defined as the duration of time between peak body weight and 10% loss of peak body weight. Late disease was defined as the duration of time between 10% loss of peak body weight and the end stage of disease. The end stage of disease was defined as the day when the animal could no longer stand up within 30 seconds after being placed on its side for three consecutive trials. Animals were euthanized at the end stage of disease.

Measuring body composition

[00618] Body weight was measured weekly for at least 13 weeks. Brown adipose tissue (BAT) and gonadal white adipose tissue (WAT) were excised at the indicated ages. Total lean mass, % WAT, and BMD were determined using DEXA (PIXImus DEXA; GE).

Indirect calorimetry, food intake and activity

[00619] The animals were first weighed and allowed to habituate to the experimental cage. The volume of oxygen (VO ₂ ) and the volume of carbon dioxide produced (VCO ₂ ) were measured every 20 minutes using the Comprehensive Laboratory Animal Monitoring System (CLAMS) (Columbus Instruments) and recorded as an average VO ₂ per hour normalized to body weight (mL/h/kg). The CLAMS instrument simultaneously measured the activity level by counting the number of interruptions of the infrared beam, as well as food intake. More specifically, food intake was measured by subtracting the mass of the powdered food pellets at the end of the experiment from the initial mass at the beginning of the experiment. To complement the described experiment and to control for new conditions that may affect feeding behavior, we also conducted a more "manual" experiment in which food pellets of a given mass were placed in a clean cage in which the mice lived at the same time every day. The next day, the mass of the remaining pellets was recorded and subtracted from the initial mass. The described experiment was carried out for 14 consecutive days. The body mass of each mouse was also recorded daily. The results obtained for each genotype are similar to those obtained using CLAMS.

Statistical analysis.

[00620] Taking a statistically significant value of 1- greater than 0.9, the inventors initially evaluated the appropriate number of groups from the pilot studies. One-way or two-way analysis of variance (Bonferroni tests of obtained results) or t-tests were performed.

Biological example 12: Effect on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in mice

[00621] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in male C57BL/6J rats fed a high-fat, high-sucrose diet.

[00622] Male C57BL/6J mice (The Jackson Laboratory, Bar Harbor, Maine, USA) were maintained on a 14 h light/10 h dark cycle at 21-23°C and were provided with free access to water throughout the experiment. From 6 weeks of age, mice were fed a ‘Western’ HF-HSD diet containing 44.6% kcal from fat (of which 61% saturated fatty acids) and 40.6% kcal from carbohydrates (mainly sucrose, 340 g/kg diet) (TD.08811, diet containing 45% kcal from fat, Harlan Laboratories Inc., Madison, WI, USA) or a normal diet (NCD) as a control (V1534-000 Ssniff R/M-H, Ssniff Spezialdiäten GmbH, Soest, Germany). The animals were then administered a compound of formula (I) or a pharmaceutically acceptable salt thereof or a control agent for 4, 12 or 20 weeks (n=8 per group for each time point) and then euthanized.

[00623] Body weight and food intake were monitored once weekly on the same day. After sedation with sodium pentobarbital (ip injection, 50 mg/kg body weight), total fat mass was analyzed by dual-energy X-ray absorptiometry (DEXA) (PIXImus densitometer, Lunar Corp., Madison, WI, USA). An intraperitoneal glucose tolerance test (IPGTT) was performed in mice deprived of food for 6 hours. Tail vein glucose levels were measured with a Bayer Contour glucometer immediately before (0 min time point) and at 15, 30, 60, 90, and 150 minutes after glucose administration (1 g glucose/kg body weight). Insulin resistance was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR) index: (fasting insulin (ng/mL) fasting glucose (mg/dL))/405.

Put to sleep

[00624] After 6 h of fasting, mice were anesthetized with sodium pentobarbital (ip injection, 50 mg/kg body weight) and euthanized by draining blood by cardiac puncture. Plasma was obtained by centrifugation of blood (6000 rpm for 5 min at 4°C), which was collected in heparinized syringes. Tissues were either flash frozen in liquid nitrogen or stored at -80°C along with plasma for further biochemical and molecular analyses, or preserved for histological analysis.

Histological analysis

[00625] Liver specimens were routinely fixed in buffered formalin (4%) and embedded in paraffin. Serial 4-mm sections were stained with H&E and picrosirius red to assess fibrosis. Frozen liver sections were stained with Oil Red O to assess lipid accumulation. All liver biopsy specimens were analyzed by a liver pathologist blinded to nutritional status or surgery. Steatosis, activity, and fibrosis were semiquantitatively assessed according to the NASH Clinical Trials Center Network criteria. Steatosis grade (percentage of hepatocytes containing lipid droplets) was graded as 0 (<5%), 1 (5-33%), 2 (>33-66%), and 3 (>66%). Hepatocyte ballooning was graded as 0 (none), 1 (few), or 2 (many cells/definite ballooning). Lobular inflammation foci were graded as 0 (none), 1 (<2 foci/200 field), 2 (2-4 foci/200 field), and 3 (>4 foci/200 field). Fibrosis was graded as fibrosis stage F0 (no fibrosis), stage F1a (mild, zone 3, perisinusoidal fibrosis), stage F1b (moderate, zone 3, perisinusoidal fibrosis), stage F1c (portal/periportal fibrosis), stage F2 (perisinusoidal and portal/periportal fibrosis), stage F3 (bridging fibrosis), and stage F4 (cirrhosis). The diagnosis of NASH is based on accepted histologic criteria. Disease severity was assessed using NAS (NAFLD activity score) as an unweighted sum of steatosis, hepatocyte ballooning, and lobular inflammation scores. Percent fibrosis was quantified by morphometry from digitized Sirius red-stained sections using the Aperio system after adjusting the fibrosis detection threshold under visual guidance. Results are expressed as collagen proportional area.

Biological Example 13: Effect on Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in Methionine and Choline Deficient Mice

[00626] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in male wild-type mice fed a diet deficient in methionine and choline.

[00627] Wild-type mice were used, maintained on a 12-hour light/dark cycle, with free access to food and water. At least 5 animals were analyzed at each time point. All experiments were repeated at least three times. To examine the effects of diet, 8-12-week-old male mice weighing 25 g were provided access to methionine-choline deficient (MCD) chow (to initiate NASH) or normal chow (as a control). Animal experiments and assessment of NAFLD and NASH were performed as described above in Example 55 for mice fed a high-fat, high-sucrose diet.

Biological Example 14: Effect on Atherosclerosis in LDL-R Knockout Mice Fed a High-Cholesterol Diet

[00628] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on atherosclerosis in LDL-R knockout mice fed a high cholesterol diet.

[00629] LDL-R knockout (KO) mice were backcrossed for ten generations with the C57BL/6J strain to produce congenic C57BL/6J animals. Control animals used in all experiments were littermates. Animals were administered a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a control agent. Mice were euthanized 12 weeks after initiation of the atherogenic diet (TD94059; Harlan), after which the heart and aorta were perfused with PBS and then fixed (Shandon Formal Fixx, Thermo Scientific). Atherosclerosis was assessed by staining the aortic root with Oil Red O and quantified using MetaMorph software. Biochemical parameters were measured using appropriate kits in COBAS C111 (Roche). For in vivo lipopolysaccharide (LPS) studies, mice were injected intraperitoneally with 100 mg LPS and bled from the tail vein. TNF levels were quantified using the TNF Ready-SET-Go! enzyme-linked immunosorbent assay (eBioscience). Blood cell counts were determined using the Advia2120 (Siemens Healthcare Diagnostics).

[00630] Student's t-test was used to calculate statistical significance. In case of multivariate testing (i.e. comparison of more than two groups), analysis of variance was performed before the test. A value of P<0.05 was considered statistically significant. Results were expressed as mean ± SEM.

Biological Example 15: Effect on Congenital Mitochondrial Disease in Sco2 Mice ^KO/KI

[00631] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on congenital mitochondrial disease in Sco2 ^KO/KI mice.

[00632] Anti-COI, anti-COX5a, anti-Ndufa9, anti-SDH-HA, and anti-Core 2 were purchased from Invitrogen; anti-GAPDH was purchased from Millipore; anti-FoxO1 and anti-acetylated-FoxO1 were purchased from Cell Signaling and Santa Cruz, respectively. Anti-mouse secondary antibodies were purchased from Amersham. Chemical reagents were purchased from Sigma. Oligonucleotides were purchased from PRIMM, Italy.

[00633] Compounds of formula (I) or their pharmaceutically acceptable salts were dissolved in water and added to standard powdered feed (Mucedola, Italy) at the appropriate concentration of 50 mg/kg/day. Granules containing compounds of formula (I) or their pharmaceutically acceptable salts, or carriers, were reconstituted manually and stored frozen at -20°C until use. The feed was changed every three days, and only the required amount was thawed each time, and free access to feed was provided for one month. Sco2 ^KO/KI mice were maintained in a room with controlled temperature and humidity, with a 12-hour light/dark cycle and free access to water and feed. Animals were euthanized by cervical dislocation.

Morphological analysis

[00634] For histochemical analysis, tissues were frozen in isopentane pre-cooled with liquid nitrogen. Serial 8 mm thick sections were stained for COX and SDH.

Biochemical analysis of MRC complexes

[00635] Quadriceps samples were stored in liquid nitrogen and homogenized in 10 mM phosphate buffer (pH 7.4) and the spectrophotometric activity of cI, cII, cIII, and cIV, as well as CS, was measured as described. Note that all blocks with cII activity are multiplied by 10 for clarity.

Definition of NAD ⁺

[00636] NAD ⁺ was extracted by acid and base extraction, respectively. Tissue NAD ⁺ was analyzed by mass spectrometry as described previously.

Biological example 16: Effect on congenital mitochondrial disease in deletor mice

[00637] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on congenital mitochondrial disease in deletor mice.

[00638] The deleter mouse model is generated on a congenic C57BL/6 background and has been characterized previously (Tyynismaa et al., 2005); WT mice are littermates of the same congenic strain of C57BL/6J mice. Male deleter or WT mice were fed normal chow (CD) or a compound of formula (I) or a pharmaceutically acceptable salt thereof mixed with CD at the appropriate concentration. Chow pellets were prepared manually by mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with powdered chow as described in Example 58 for Sco2 ^KO/KI mice and stored at -20°C. Mice were housed in a standard animal facility with a 12-hour light/dark cycle. They had free access to chow and water. The pre-treatment group consisted of 12 deletor and 12 WT mice, and the post-treatment group consisted of 24 deletor and 24 WT mice, which were administered the compound of formula (I) or a pharmaceutically acceptable salt thereof, or CD diet. During the intervention, the mice's weight, food intake, and exercise capacity were monitored routinely. Exercise capacity was measured twice using a treadmill exercise test (Exer-6M Treadmill, Columbus Instruments) at the beginning and end of the feeding period. The exercise test protocol consisted of an initial running speed of 7 m/s, which was increased every 2 minutes by 2 m/s and continued until the animal could no longer run or fell off the belt several times at the stimulus site.

[00639] Oxygen consumption and carbon dioxide production, as well as spontaneous movement and feeding behavior, were recorded using a comprehensive laboratory animal monitoring system (CLAMS; Columbus Instruments, Ohio, USA). Mice were housed individually in a CLAMS chamber for 3 days; no recordings were made on the first day and night, which constituted the equilibration period, followed by 24-hour recordings at thermoneutrality (+30°C). O ₂ consumption and CO ₂ production data were used to calculate respiratory gas exchange rates and analyzed separately for light (inactive) and dark (active) periods of the day.

Morphological analysis

[00640] Tissue sections were prepared from quadriceps, liver, and brown adipose tissue (BAT). Specimens were embedded in OCT mounting medium (Tissue-Tek) and snap frozen in 2-methylbutane in liquid nitrogen. Frozen sections (12 μm) from quadriceps were simultaneously analyzed for in situ histochemical activity of COX and succinate dehydrogenase (SDH). Activities were counted on COX-negative and COX-negative plus SDH-positive quadriceps sections, as well as on normal fibers. Approximately 2000 fibers were counted from each mouse sample. The intensity of histochemical COX activity from quadriceps for oxidative and non-oxidative fibers was measured using Image J software. Frozen sections (8 μm) from liver and BAT were stained with Oil Red O. For plastic embedding, quadriceps, liver and BAT samples were fixed in 2.5% glutaraldehyde, treated with 1% osmium tetroxide, dehydrated in ethanol and embedded in epoxy resin. Semi-thin (1 μm) sections were stained with methyl blue (0.5% w/v) and boric acid (1% w/v). Regions of interest for ultrastructural analysis were selected by inspection of sections under a light microscope. For transmission electron microscopy, ultrathin (60-90 nm) sections were cut on grids and stained with uranyl acetate and lead citrate, and visually examined with a transmission electron microscope. Crista content in BAT and muscle was determined from electron micrographs using a 1 μm "intramitochondrial dipstick" positioned perpendicular to the crista. Skeletal muscle samples were also analyzed for citrate synthetase activity.

Biological Example 17: Effect on Kidney Disease

[00641] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on kidney disease in C57BL/6J WT mice. (Wei, Q., et al., “ Mouse model of ischemic acute kidney injury: technical notes and tricks ” American Journal of Physiology-Renal Physiology, 303(11), F1487-F1494)

[00642] C57BL/6J WT mice were purchased from Charles-River. All mice were provided access to standard commercial chow and maintained at an ambient temperature of 20-22°C with a relative humidity of 50 ± 5% with a 12/12 hour light/dark cycle in a pathogen-free facility. Experimental mice were 8 weeks old and were divided into four groups: (1) control (n=5); (2) cisplatin (20 mg/kg; Sigma Chemical, St. Louis, MO; n=5); (3) a compound of formula (I) or a pharmaceutically acceptable salt thereof and cisplatin (n=5); and (4) a compound of formula (I) or a pharmaceutically acceptable salt thereof alone (40 mg/kg; n=5). The dose and time of administration of cisplatin for initiating nephrotoxicity were selected according to a published method. The compound of formula (I) or a pharmaceutically acceptable salt thereof was administered orally once daily for 4 days. Cisplatin was administered as a single injection 12 hours after the first administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Mice were euthanized 72 hours after the single injection of cisplatin.

Analysis of renal function markers and proinflammatory cytokines

[00643] For renal function analysis, serum was isolated and stored at -80°C until use. Serum creatinine and BUN levels were measured using an assay kit according to the manufacturer's instructions (BioVision, Milpitas, CA). In addition, proinflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified in serum or renal tissue homogenates using an enzyme-linked immunosorbent assay (Quantikine kit; R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. For cytokine measurement, renal tissue was homogenized in phosphate-buffered saline containing 0.05% Tween-20. Aliquots containing 300 mg of total protein were used. A metabolic cage was used to collect urine for urinary cytokine analysis. The sample size for each group was five.

Alternative research on the impact on kidney disease

[00644] Alternatively, C57BL/6J WT mice were numbered and allowed to acclimate for 5-7 days before the experiment. (Wei, Q., et al. “ Mouse model of ischemic acute kidney injury: technical notes and tricks ”, American Journal of Physiology-Renal Physiology, 303(11), F1487-F1494). Mice were randomly assigned to different treatment groups based on their body weight. The different groups were maintained on Harlan 2916 chow. Mice were then maintained on the respective diets for 10 days until bilateral ischemic kidney injury. Body weight was measured once at randomization and once on day 7. Food intake was measured once on day 7. Blood was collected by retroorbital puncture under light isoflurane anesthesia and used for baseline blood urea nitrogen (BUN) analysis on day 9.

[00645] Mice were anesthetized with ketamine (80 mg/kg, i.p.) and/or xylazine (10 mg/kg, i.p.) and placed on the surgical platform in the supine position. Both kidneys were exposed through lateral incisions and the renal pedicles were occluded with vascular clamps for 25 minutes. The clamps were then removed and the surgical site was sutured. After wound closure, 1 ml of saline was injected intraperitoneally to prevent dehydration. The sham-operated group underwent similar surgeries except that the occlusion clamp was not used. Animals were observed until recovery from anesthesia and returned to their home cage. Animals were monitored daily for general clinical signs, symptoms, and mortality.

[00646] On the penultimate day, animals were individually placed in metabolic cages for 12 hours and urine was collected for determination of urea, creatinine, sodium and potassium.

[00647] On days 12, 14, and 16, blood was collected by retroorbital puncture under light isoflurane anesthesia, and plasma was used for analysis of blood urea nitrogen (BUN) and serum creatinine levels. The animals were then euthanized by _CO2 inhalation and the organs were collected. One kidney was fixed in 10% neutral buffered formalin, and the other was snap frozen in liquid nitrogen, stored at -80°C, and used for assessment of lipid peroxidation, GSH, KIM1, MPO, NGAL, and SOD levels.

Histological analysis and neutrophil count

[00648] Mouse kidneys were fixed in 4% formaldehyde and embedded in paraffin wax. 5-mm-thick sections were deparaffinized in xylene and rehydrated with graded concentrations of ethanol. H&E and PAS staining were performed according to standard protocols. Images were recorded and analyzed using a light microscope (IX71, Olympus, Tokyo, Japan) with DP analyzer software (DP70-BSW, Tokyo, Japan). Tubular injury in PAS-stained kidney sections was examined under a light microscope and 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%. Slides were scored in a blinded manner and expressed as mean ± SD of 10 representative fields per group. The severity of tubular necrosis, defined as loss of the proximal brush border of the tubule and formation of urinary casts, was used to classify specimens. The sample size for each group was 10. Neutrophil infiltration was quantified on PAS-stained tissue by a renal pathologist who counted neutrophils per field at high power (x400). At least 10 fields on the outer border of the outer medulla were counted for each slide.

[00649] All values are presented as mean ± SD. One-way analysis of variance was used to calculate statistical significance of results in all analyses, and P values < 0.05 were considered statistically significant.

Biological example 18: Effect on acute kidney injury induced by ischemia/reperfusion

[00650] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on ischemia/reperfusion (I/R)-induced acute kidney injury in CD-1 (ICR) mice.

[00651] CD-1 (ICR) mice were purchased from Charles River Laboratory (Wilmington, MA). Mice were maintained in a temperature- and humidity-controlled environment with a 12:12 h light-dark cycle and had free access to standard rodent chow (TekLad, Madison, WI) and drinking water.

[00652] Mice were incised in the midline of their dorsum and both renal pedicles were clamped for 45 minutes with microaneurysm clamps (00396-01; Fine Science Tools, Foster City, CA). After clamp removal, the kidneys were examined for restoration of blood flow. Animals were allowed to recover and euthanized 48 hours after reperfusion. Mice were administered 100 mg/kg of the compound of formula (I) or a pharmaceutically acceptable salt thereof by gavage once daily. CD-1 mice were divided into four groups: (1) sham-injured young mice (n=4) (6-7 weeks of age); (2) I/R-injured young mice (n=8); (3) sham-injured adult mice (n=4) (20-24 years of age); and (4) I/R-injured adult mice (n=11). Another 27 adult mice (20-24 weeks old) were randomly divided into two groups: 13 mice received the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the remaining 14 mice received the vehicle as a control.

[00653] Serum creatinine was measured using the QuantiChrom Creatinine Assay Kit (DICT-500, BioAssay Systems, Hayward, CA). BUN was measured using Infinity Stable Liquid Urea (Nitrogen) Reagent (TR12421; ThermoTrace, Victoria, Australia).

Renal tissue assessment

[00654] Kidneys were fixed in 4% paraformaldehyde, embedded in paraffin, and stained with hematoxylin and eosin (4 mm thickness). Tubular injury was scored on a scale of 0 to 4 based on the percentage of tubules with necrosis, dilation, or swelling of cells: 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 scored by a blinded pathologist.

[00655] All values are expressed as mean ± SD. Statistical analysis was performed using GraphPad Prism 4.00 (San Diego, CA) with unpaired Student's t-test for two data sets and analysis of variance with Bonferroni correction for multiple groups. A P value < 0.05 was considered significant.

Biological example 19: Effect on cisplatin-induced acute kidney injury

[00656] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof on cisplatin-induced acute kidney injury in C57BL6 mice.

[00657] C57BL6 mice were purchased from Charles River Laboratory (Wilmington, MA). Mice were maintained in a temperature- and humidity-controlled environment with a 12:12 h light-dark cycle and had free access to standard rodent chow (TekLad, Madison, WI) and drinking water.

[00658] Mice were incised in the midline of their dorsum and both renal pedicles were clamped for 45 minutes with microaneurysm clamps (00396-01; Fine Science Tools, Foster City, CA). Cisplatin was injected intraperitoneally at 20 mg/kg body weight. Animals were allowed to recover and euthanized at 48, 72, and 96 hours after the cisplatin injection. Mice were administered 100 mg/kg of the compound of formula (I) or a pharmaceutically acceptable salt thereof by gavage once daily. C57BL6 mice were divided into four groups: (1) sham-injured young mice (n=4) (6-7 weeks of age); (2) cisplatin-injured young mice (n=8); (3) sham-injured adult mice (n=4) (20-24 years of age); and (4) adult mice with cisplatin-induced injury (n=11). Another 27 adult mice (20-24 weeks old) were randomly divided into two groups: 13 mice received the compound of formula (I) or its pharmaceutically acceptable salt, and the remaining 14 mice received the vehicle as a control.

[00659] Serum creatinine was measured using the QuantiChrom Creatinine Assay Kit (DICT-500, BioAssay Systems, Hayward, CA). BUN was measured using Infinity Stable Liquid Urea (Nitrogen) Reagent (TR12421; ThermoTrace, Victoria, Australia).

Renal tissue assessment

[00660] Kidneys were fixed in 4% paraformaldehyde, embedded in paraffin, and stained with hematoxylin and eosin (4 mm thickness). Tubular injury was scored on a scale of 0 to 4 based on the percentage of tubules with necrosis, dilation, or cell 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 scored by a blinded pathologist.

[00661] All values are expressed as mean ± SD. Statistical analysis was performed using GraphPad Prism 4.00 (San Diego, CA) with unpaired Student's t-test for two data sets and analysis of variance with Bonferroni correction for multiple groups. A P value < 0.05 was considered significant.

Biological example 20: Effect on acute kidney injury caused by sepsis

[00662] A study was conducted to determine the effect of compounds of formula (I) or pharmaceutically acceptable salts thereof against acute kidney injury induced by sepsis in C57BL6 mice (12-15 weeks old).

[00663] C57BL6 mice were purchased from Charles River Laboratory (Wilmington, MA). Mice were maintained in a temperature- and humidity-controlled environment with a 12:12 h light-dark cycle and had free access to standard rodent chow (TekLad, Madison, WI) and drinking water. Sepsis was induced by cecal ligation and puncture (CLP). The CLP procedure is described below: the lower abdomen was shaved, cleaned with 70% ethanol, and a 1 cm laparotomy was performed, identifying and exposing the cecum. The cecum was measured from the ileocecal valve to the tip, ligated at ~50%, punctured once (through) with a 21-gauge needle, and returned to the peritoneal cavity after expression to express fecal matter. The abdominal wall was then closed with flaps using 4-0 Silk running sutures. Control animals underwent the same laparotomy, cecal identification, and externalization but without ligation or puncture. Animals were then injected subcutaneously with 1 mL of saline and buprenorphine at the scruff of the neck and placed on thermal blankets under observation. Animals were treated with ampicillin sulbactam (250 mg/kg every 12 hours IP for 3 days) and analgesics (0.05 mg/kg buprenorphine for 3 days).

[00664] The compound of formula (I) or a pharmaceutically acceptable salt thereof was administered at two different time points: A. At the time of CLP (early phase); and B. 24 hours after CLP via IP injection.

[00665] Blood and kidney tissue were collected at the time of euthanasia to measure the primary and secondary endpoints.

[00666] Primary endpoint (48 hours): serum creatinine. Secondary endpoints (48 hours) include: Macrophage phenotype marker (IF dye), plasma NGAL, plasma and kidney inflammatory markers (IL-6, IL-18, TNF), and kidney injury markers (KIM-1, NGAL, TIMP2, and IGFBP7). Secondary endpoints include: cell death (IF: annexin V and propidium iodide; caspase 3/7), autophagy, biogenesis (PGC-1, mitochondrial DNA), OXPHOS (complex I, III, IV activity), Sirt1 and Sirt3 expression, AMPK (total, P-AMPK), P-ACC, and HIF-1.

Histological analysis

[00667] Mouse kidneys were fixed in 4% formaldehyde and embedded in paraffin wax. 5-mm-thick sections were deparaffinized in xylene and rehydrated with graded concentrations of ethanol. H&E and PAS staining were performed according to standard protocols. Images were recorded and analyzed using a light microscope (IX71, Olympus, Tokyo, Japan) with DP analyzer software (DP70-BSW, Tokyo, Japan). Tubular injury in PAS-stained kidney sections was examined under a light microscope and 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%. Slides were scored in a blinded manner and results are expressed as mean ± SD of 10 representative fields per group. The severity of tubular necrosis, reflecting the loss of the proximal brush border of the tubule and the formation of urinary casts, was used to classify the samples. The sample size for each group was n = 6 per group in groups 2, 4-9; and n = 3 for group 1, for a total of 45. Tubular injury score was used to assess protection against renal injury.

Biological example 21: Effect on FoxO1 phosphorylation level

[00668] AML-12 cells were treated with various concentrations of the compound of formula (I) or a pharmaceutically acceptable salt thereof for 24 hours. The cells were then lysed in lysis buffer (50 mM Tris, 150 mM KCl, 1 mM EDTA, 1% NP40) containing protease and phosphatase inhibitors and analyzed by DNS-PAGE/Western blotting. Blocking and antibody incubation were performed in 5% milk. Each protein present was detected with its specific antibody. Tubulin antibody was purchased from Sigma Inc, FoxO1 and phospho-FoxO1 (Ser256) antibodies were purchased from Cell Signaling. Antibody detection reactions were performed by enhanced chemiluminescence (Advansta, CA, USA) using X-ray films.

[00669] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the singular forms "a" and "an" include the plural forms unless the context clearly dictates otherwise. Although the same or equivalent methods and materials as those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated herein by reference. References cited herein do not constitute prior art to the claimed disclosure. In case of conflict, the present description, including definitions, will control. Furthermore, the materials, methods, and examples provided are illustrative only and are not limiting.

EQUIVALENTS

[00670] Numerous equivalents to the specific embodiments and methods described herein will be apparent to those skilled in the art, or can be ascertained with no more than routine experimentation. Such equivalents are intended to be within the scope of the present disclosure.

Claims (75)

1. The compound represented by formula (II): or a pharmaceutically acceptable salt or tautomer thereof, wherein: X represents O or OH; W represents N; L is -(C(R ⁵ ) ₂ ) _m Y ¹ (C(R ⁵ ) ₂ ) _p –; Y ¹ represents S; R ¹ is absent or represents C ₆ -C ₁₀ arylene; each R ⁵ in each instance independently represents H; each R ⁶ in each instance independently represents H; R ⁷ is A or C; A is -(C(R ⁶ ) ₂ ) _r tetrazole, C is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl, wherein said aryl is substituted with one to three substituents, each of which is independently selected from halogen and OH; R ^c represents H or -CN; R ^d is CF ₃ , -(C(R ⁶ ) ₂ ) _t C ₆ -C ₁₀ aryl; R ^f is H; R ^j is absent; each m, p, q and r is independently equal to 0, 1 or 2; each t is either 1 or 2; and represents a single bond or a double bond. 2. The compound according to claim 1, characterized in that R ^c is H. 3. The compound according to claim 1, characterized in that R ^c is -CN. 4. A compound according to any one of claims 1 to 3, characterized in that R ^d is -CF ₃ . 5. A compound according to any one of claims 1 to 3, characterized in that R ^d is -(C(R ⁶ ) ₂ ) _r C ₆ -C ₁₀ aryl. 6. A compound according to any one of paragraphs 1-5, characterized in that R ¹ is C ₆ -C ₁₀ arylene. 7. A compound according to any one of paragraphs 1-5, characterized in that R ¹ is absent. 8. A compound according to any one of paragraphs 1-7, characterized in that R ⁷ is A. 9. A compound according to any one of claims 1 to 7, characterized in that R ⁷ is C. 10. The compound according to claim 1, characterized in that R ¹ is C ₆ -C ₁₀ arylene and R ⁷ is A. 11. The compound according to claim 1, characterized in that R ¹ is absent and R ⁷ is C. 12. The compound of claim 1 or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of: Connection No. Structure I-26 I-29 I-32 I-34 13. The compound of claim 1 or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of: I-40 And I-41 14. A pharmaceutical composition capable of inhibiting the activity of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), comprising a therapeutically effective amount of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient. 15. A method for treating, preventing or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of one or more compounds according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof. 16. A method for treating, preventing or reducing the risk of a disease or disorder associated with a reduced level of nicotinamide adenine dinucleotide (NAD ⁺ ), comprising administering to a subject suffering from or predisposed to developing said disease or disorder associated with a reduced level of NAD ⁺ , a therapeutically effective amount of one or more compounds according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof. 17. The method according to any of paragraphs. 15 or 16, characterized in that said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration of the transplant, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency. 18. A method for treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of one or more compounds according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, which provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ). 19. The method according to claim 18, characterized in that said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease. 20. The method according to claim 19, characterized in that the general metabolic disorder is obesity or type II diabetes. 21. The method according to claim 19, characterized in that the renal disorder is acute kidney injury (AKI) or chronic kidney disease (CKD). 22. A method for accelerating oxidative metabolism, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of one or more compounds according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, which provides an increase in intracellular nicotinamide adenine dinucleotide (NAD ⁺ ). 23. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a medicinal product having inhibitory activity against α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). 24. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for use in the treatment, prevention or reduction of the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ). 25. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for use in treating, preventing or reducing the risk of a disorder associated with mitochondrial dysfunction. 26. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for use in accelerating oxidative metabolism. 27. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the treatment, prevention or reduction of the risk of a disease or disorder associated with α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase dysfunction (ACMSD). 28. Use of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for the treatment, prevention or reduction of the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ). 29. Use of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for treating, preventing or reducing the risk of a disorder associated with mitochondrial dysfunction. 30. Use of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for accelerating oxidative metabolism. 31. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment, prevention or reduction of the risk of a disease or disorder associated with modulation of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). 32. Use of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment, prevention or reduction of the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ). 33. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment, prevention or reduction of the risk of a disorder associated with mitochondrial dysfunction. 34. Use of a compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for accelerating oxidative metabolism. 35. A method for treating, preventing or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), comprising administering to a subject suffering from or predisposed to developing said disease or disorder, a therapeutically effective amount of the pharmaceutical composition of claim 14. 36. A method for treating, preventing or reducing the risk of a disease or disorder associated with a reduced level of nicotinamide adenine dinucleotide (NAD ⁺ ), comprising administering to a subject suffering from or predisposed to developing a disease or disorder associated with a reduced level of NAD ⁺ , a therapeutically effective amount of the pharmaceutical composition of claim 14. 37. The method according to any of paragraphs. 35 or 36, characterized in that said disease is a chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, living donor liver regeneration of the transplant, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis and alpha-1 antitrypsin deficiency. 38. A method for treating a disorder associated with mitochondrial dysfunction, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder a therapeutically effective amount of the pharmaceutical composition of claim 14. 39. The method according to claim 38, characterized in that said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a general metabolic disorder, a neurodegenerative disease, a disorder associated with aging, a renal disorder, or a chronic inflammatory disease. 40. The method according to claim 39, characterized in that the general metabolic disorder is obesity or type II diabetes. 41. The method according to claim 40, characterized in that the renal disorder is acute kidney injury (AKI) or chronic kidney disease (CKD). 42. A method for treating acceleration of oxidative metabolism, comprising administering to a subject suffering from or predisposed to developing a metabolic disorder, a therapeutically effective amount of the pharmaceutical composition according to claim 14. 43. A pharmaceutical composition according to claim 14 for use as a medicinal product having inhibitory activity against α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). 44. The pharmaceutical composition of claim 14 for use in the treatment, prevention or reduction of the risk of a disease or disorder associated with reduced levels of nicotinamide adenine dinucleotide (NAD ⁺ ). 45. The pharmaceutical composition of claim 14 for use in treating, preventing or reducing the risk of a disorder associated with mitochondrial dysfunction. 46. The pharmaceutical composition according to claim 14 for use in accelerating oxidative metabolism. 47. Use of a pharmaceutical composition according to claim 14 for the treatment, prevention or reduction of the risk of a disease or disorder associated with the modulation of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). 48. Use of a pharmaceutical composition according to claim 14 for treating, preventing or reducing the risk of a disease or disorder associated with a reduced level of nicotinamide adenine dinucleotide (NAD ⁺ ). 49. Use of a pharmaceutical composition according to claim 14 for treating, preventing or reducing the risk of a disorder associated with mitochondrial dysfunction. 50. Use of a pharmaceutical composition according to claim 14 to accelerate oxidative metabolism. 51. Use of a pharmaceutical composition according to claim 14 for the manufacture of a medicinal product for the treatment, prevention or reduction of the risk of a disease or disorder associated with the modulation of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). 52. Use of a pharmaceutical composition according to claim 14 in the manufacture of a medicinal product for the treatment, prevention or reduction of the risk of a disease or disorder associated with a reduced level of nicotinamide adenine dinucleotide (NAD ⁺ ). 53. Use of a pharmaceutical composition according to claim 14 in the manufacture of a medicinal product for the treatment, prevention or reduction of the risk of a disorder associated with mitochondrial dysfunction. 54. Use of a pharmaceutical composition according to paragraph 14 in the production of a medicinal product for accelerating oxidative metabolism.