Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase

A method of treating, preventing, or reducing the risk of a disease or disorder associated with α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) dysfunction comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with ACMSD dysfunction a therapeutically effective amount of a compound represented by Formula (I):

• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein:
• X is O, OH, or Cl;
• L is —(CH2)mCH2CH2—, —(CH2)mY(CH2)p—, —(CH2)mC(O)(CH2)p—, —(CH2)mC(O)O(CH2)p—, —(CH2)mC(O)NR2(CH2)p—, or —(CH2)mNR2C(O)(CH2)p;
• Y is O, N or S(O)q,
• R1 is C6-C10 aryl or heteroaryl, wherein the aryl and heteroaryl are substituted with Ra and Rb, and optionally substituted with one or more Re;
• R2 is H or C1-C6 alkyl:
• one of Ra and Rb is hydrogen and the other is —(CH2)rCO2Rx, —OCH2CO2Rx, —(CH2)rtetrazole, —(CH2)roxadiazolone, —(CH2)rtetrazolone, —(CH2)rthiadiazolol, —(CH2)r isoxazol-3-ol, —(CH2)rP(O)(OH)ORx, —(CH2)rS(O)2OH, —(CH)rC(O)NHCN, or —(CH2)rC(O)NHS(O)2alkyl;
• Rc is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —ORx, —CO2Rx, or NO2;
• Rd is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle;
• each Rx is independently at each occurrence hydrogen or C1-C6 alkyl;
• each Re is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —ORy, C1-C6 haloalkyl, —NHRz, —OH, or —CN;
• Rf is H or absent;
• each Ry and Rz is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• each m and p independently is 0, 1 or 2, wherein m+p<3;
• q is 0, 1, or 2;
• r is 0 or 1;
• and
• the dotted line is an optional double bond;
• with the proviso that Rc is not hydrogen or —CN when X is O, L is —SCH2— and Rd is optionally substituted phenyl, Rc is not C1-C6 alkyl when X is O, L is —SCH2— and Rd is methyl, and that Rc is not —CN when X is O, L is —SCH2— and Rd is 2-furyl.

A method of treating, preventing, or reducing the risk a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD+) levels comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD+ levels a therapeutically effective amount of a compound represented by Formula (I):

• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein:
• X is O, OH, or Cl;
• L is —(CH2)mCH2CH2—, —(CH2)mY(CH2)p—, —(CH2)mC(O)(CH2)p—, —(CH2)mC(O)O(CH2)p—, (CH2)mC(O)NR2(CH2)p—, or —(CH2)mNR2C(O)(CH2)p—;
• Y is O, N or S(O)q;
• R1 is C6-C10 aryl or heteroaryl, wherein the aryl and heteroaryl are substituted with Ra and Rb, and optionally substituted with one or more Re;
• R2 is H or C1-C6 alkyl:
• one of Ra and Rb is hydrogen and the other is —(CH2)rCO2Rx, —OCH2CO2Rx, —(CH2)rtetrazole, —(CH2)roxadiazolone, —(CH2)rtetrazolone, —(CH2)rthiadiazolol, —(CH2)r isoxazol-3-ol, —(CH2)rP(O)(OH)ORx, —(CH2)rS(O)2OH, —(CH2)rC(O)NHCN, or —(CH2)rC(O)NHS(O)2alkyl;
• Rc is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —ORx, —CO2Rx, or NO2:
• Rd is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle;
• each Rx is independently at each occurrence hydrogen or C1-C6 alkyl:
• each Re is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —ORy, C1-C6 haloalkyl, —NHRz, —OH, or —CN;
• Rf is H or absent;
• each Ry and Rz is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• each m and p independently is 0, 1 or 2, wherein m+p<3;
• q is 0, 1, or 2;
• r is 0 or 1;
• and
• the dotted line is an optional double bond;
• with the proviso that Rc is not hydrogen or —CN when X is O, L is —SCH2— and Rd is optionally substituted phenyl, Rc is not C1-C6 alkyl when X is O, L is —SCH2— and Rd is methyl, and that Rc is not —CN when X is O, L is —SCH2— and Rd is 2-furyl.

A method of treating, preventing, or reducing the risk of a disorder associated with mitochondrial dysfunction comprising administering to the subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of a compound represented by Formula (I):

• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein:
• X is O, OH, or Cl;
• L is —(CH)mCH2CH2—, —(CH2)mY(CH2)p—, —(CH2)mC(O)(CH2)p—, —(CH2)mC(O)O(CH2)p—, —(CH2)mC(O)NR2(CH2)p—, or —(CH2)mNR2C(O)(CH2)p;
• Y is O, N or S(O)q;
• R1 is C6-C10 aryl or heteroaryl, wherein the aryl and heteroaryl are substituted with Ra and Rb, and optionally substituted with one or more Re;
• R2 is H or C1-C6 alkyl:
• one of Ra and Rb is hydrogen and the other is —(CH2)rCO2Rx, —OCH2CO2Rx, —(CH2)rtetrazole, —(CH2)roxadiazolone, —(CH2)rtetrazolone, —(CH2)rthiadiazolol, —(CH2)r isoxazol-3-ol, —(CH2)rP(O)(OH)ORx, —(CH2)rS(O)2OH, —(CH2)rC(O)NHCN, or —(CH2)rC(O)NHS(O)2alkyl;
• Rc is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —ORx, —CO2Rx, or NO2;
• Rd is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle;
• each Rx is independently at each occurrence hydrogen or C1-C6 alkyl:
• each Re is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —ORy, C1-C6 haloalkyl, —NHRz, —OH, or —CN;
• Rf is H or absent;
• each Ry and Rz is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• each m and p independently is 0, 1 or 2, wherein m+p<3;
• q is 0, 1, or 2;
• r is 0 or 1;
• and
• the dotted line is an optional double bond;
• with the proviso that Rc is not hydrogen or —CN when X is O, L is —SCH2— and Rd is optionally substituted phenyl, Rc is not C1-C6 alkyl when X is O, L is —SCH2— and Rd is methyl, and that Rc is not —CN when X is O, L is —SCH2— and Rd is 2-furyl.

A method of promoting oxidative metabolism comprising administering to the subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of a compound represented by Formula (I):

• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein:
• X is O, OH, or Cl;
• L is —(CH2)mCH2CH2—, —(CH2)mY(CH2)p—, —(CH2)mC(O)(CH2)p—, —(CH2)mC(O)O(CH2)p—, —(CH2)mC(O)NR2(CH2)p—, or —(CH2)mNR2C(O)(CH2)p;
• Y is O, N or S(O)q,
• R1 is C6-C10 aryl or heteroaryl, wherein the aryl and heteroaryl are substituted with Ra and Rb, and optionally substituted with one or more Re;
• R2 is H or C1-C6 alkyl;
• one of Ra and Rb is hydrogen and the other is —(CH2)rCO2Rx, —OCH2CO2Rx, —(CH2)rtetrazole, —(CH2)roxadiazolone, —(CH2)rtetrazolone, —(CH2)rthiadiazolol, —(CH2)r isoxazol-3-ol, —(CH2)rP(O)(OH)ORx, —(CH2)rS(O)2OH, —(CH2)rC(O)NHCN, or —(CH2)rC(O)NHS(O)2alkyl:
• Rc is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —ORx, —CO2Rx, or NO2:
• Rd is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle;
• each Rx is independently at each occurrence hydrogen or C1-C6 alkyl:
• each Re is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —ORy, C1-C6 haloalkyl, —NHRz, —OH, or —CN;
• Rf is H or absent;
• each Ry and Rz is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• each m and p independently is 0, 1 or 2, wherein m+p<3;
• q is 0, 1, or 2;
• r is 0 or 1;
• and
• the dotted line is an optional double bond;
• with the proviso that Rc is not hydrogen or —CN when X is O, L is —SCH2— and Rd is optionally substituted phenyl, Rc is not C1-C6 alkyl when X is O, L is —SCH2— and Rd is methyl, and that Rc is not —CN when X is O, L is —SCH2— and Rd is 2-furyl.