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-8-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 (II):

• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein:
• X1 is H, O, S, OR2, SH, NH, NH2, or halogen;
• X2 is O, S, OR2, SR2, NH, NHR2, or halogen;
• L is —(CH2)mCH═CH(CH2)p—, —(CH2)o—, —(CH2)mY1(CH2)p—,
• —(CH2)mY1CH═CH—, —(CH2)mC═(O)(CH2)p—, —(CH2)mC═(O)O(CH2)p—, —(CH2)mC═(O)NR3(CH2)p—, —(CH2)mNR3C═(O)(CH2)p—, phenyl, pyridinyl, or thiophenyl;
• Y1 is O, NR4, or S(O)q;
• Y2 is O, NH or S;
• R1 is C6-C10 aryl or heteroaryl, wherein the heteroaryl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, and wherein the aryl and heteroaryl are substituted with Ra and Rb, and optionally substituted with one to two Re;
• R2 is H or C1-C4 alkyl;
• R3 is H or C1-C4 alkyl;
• R4 is H or C1-C4 alkyl;
• Ra is H, C1-C4 alkyl, —(C(Rf)2)rCO2Rx, —Y2(C(Rf)2)rCO2Rx, —O(C(Rf)2)rC(O)NHRg, halogen, —(C(Rf)2)rC6-C10 aryl, —(C(Rf)2)rS—C6-C10 aryl, —(C(Rf)2)rheteroaryl, —O(C(Rf)2)rheteroaryl, —O(C(Rf)2)rheterocycloalkyl, —O(C(Rf)2)r(C3-C7)cycloalkyl, —(C(Rf)2)rP(O)(OH)ORx, —O(C(Rf)2)rP(O)(OH)ORx, —(C(Rf)2)rS(O)2OH, —O(C(Rf)2)rS(O)2OH, —(C(Rf)2)rP(O)2OH, —O(C(Rf)2)rP(O)2OH, —O(C(Rf)2)rOH, —ORY, —(C(Rf)2)rC(O)NHCN, —CH═CHCO2Rx, or —(C(Rf)2)rC(O)NHS(O)2alkyl, wherein the aryl and heteroaryl are optionally substituted with one to three substituents each independently selected from halogen and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;
• Rb is C1-C4 alkyl, —(C(Rf)2)rCO2Rx, —Y2(C(Rf)2)rCO2Rx, —O(C(Rf)2)rC(O)NHRg, halogen, —(C(Rf)2)rC6-C10 aryl, —(C(Rf)2)rS—C6-C10 aryl, —(C(Rf)2)rheteroaryl, —O(C(Rf)2)rheteroaryl, —O(C(Rf)2)rheterocycloalkyl, —(C(Rf)2)rP(O)(OH)ORx, —O(C(Rf)2)rP(O)(OH)ORx, —(C(Rf)2)rS(O)2OH, —O(C(Rf)2)rS(O)2OH, —(C(Rf)2)rP(O)2OH, —O(C(Rf)2)rP(O)2OH, —O(C(Rf)2)rOH, —ORY, —(C(Rf)2)rC(O)NHCN, —CH═CHCO2Rx, or —(C(Rf)2)rC(O)NHS(O)2alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents selected from halogen and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;
• or
• Ra and Rb when on adjacent atoms together with the atoms to which they are attached form a C6-C10 aryl ring optionally substituted with one or more —CO2H;
• Ra and Rb when on adjacent atoms together with the atoms to which they are attached form a 5- to 6-membered heteroaryl ring optionally substituted with one or more —CO2H;
• Rc is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —NO2, —ORx, or —CO2R;
• each Rd is independently at each occurrence absent, H, or methyl;
• each Re is independently at each occurrence C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —NHRz, —OH, or —CN;
• each Rf is independently H or C1-C6 alkyl;
• Rg is H, C1-C6 alkyl, OH, —S(O)2(C1-C6 alkyl), or —S(O)2N(C1-C6 alkyl)2;
• Rx is H or C1-C6 alkyl;
• each Ry and Rz is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;
• each m, p, q, and r is independently 0, 1 or 2;
• n is 0 or 1;
• o is 0, 1, 2, 3, or 4;
• and
• the dotted line is an optional double bond.