Imidazole 3-oxide derivative based acss2 inhibitors and methods of use thereof

A compound represented by the structure of formula I:

• A and B rings are each independently a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, indole, benzofuran, 2-, 3- or 4-pyridine, naphthalene, thiazole, thiophene, imidazole, 1-methylimidazole, benzimidazole), a single or fused C3-C10 cycloalkyl (e.g. cyclohexyl), or a single or fused C3-C10 heterocyclic ring (e.g., benzofuran-2(3H)-one, benzo[d][1,3]dioxole, tetrahydrothiophene 1,1-dioxide, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran);
• R1, R2 and R20 are each independently H, F, Cl, Br, I, OH, SH, R8—OH (e.g., CH2—OH), R8—SH, —R8—O—R10, (e.g., —CH2—O—CH3), R8—(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8—(C3-C8 heterocyclic ring) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, —CH2CN, —R8CN, NH2, NHR (e.g., NH—CH3), N(R)2 (e.g., N(CH3)2), R8—N(R10)(R11) (e.g., CH2—CH2—N(CH3)2, CH2—NH2, CH2—N(CH3)2), R9—R8—N(R10)(R11) (e.g., C≡C—CH2—NH2), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R10 (e.g., NHC(O)CH3), NHCO—N(R10)(R11) (e.g., NHC(O)N(CH3)2), COOH, —C(O)Ph, C(O)O—R10 (e.g. C(O)O—CH3, C(O)O—CH(CH3)2, C(O)O—CH2CH3), R8—C(O)—R10 (e.g., CH2C(O)CH3), C(O)H, C(O)—R10 (e.g., C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF3), —C(O)NH2, C(O)NHR, C(O)N(R10)(R11) (e.g., C(O)N(CH3)2), SO2R, SO2N(R10)(R11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)—CH3, methyl, 2, 3, or 4-CH2—C6H4—Cl, ethyl, propyl, iso-propyl, butyl, t-Bu, iso-butyl, pentyl, benzyl), C2-C5 linear or branched, substituted or unsubstituted alkenyl (e.g., CH═C(Ph)2)), C1-C5 linear, branched or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2), substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic alkoxy (e.g. methoxy, O—(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O—CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocyclic ring (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, oxadiazole, imidazole, furane, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH—R10);
• or R2 and R1 are joint together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrol, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);
• R3 is I, OH, SH, R8—OH (e.g., CH2—OH), R8—SH, —R8—O—R10, (e.g., CH2—O—CH3) CF3, CD3, OCD3, CN, —CH2CN, —R8CN, NH2, NHR, N(R)2, R8—N(R10)(R11) (e.g., CH2—NH2, CH2—N(CH3)2) R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, —NHCO—R10 (e.g., NHC(O)CH3), NHCO—N(R10)(R11) (e.g., NHC(O)N(CH3)2), —C(O)Ph, C(O)O—R10 (e.g. C(O)O—CH3, C(O)O—CH2CH3), R8—C(O)—R10 (e.g., CH2C(O)CH3), C(O)H, C(O)—R10 (e.g., C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF3), —C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2—O—CH3), C(S)N(R10)(R11) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10)(R11) (e.g., SO2NH(CH3), SO2N(CH3)2), C2-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C2-C5 linear or branched or C3-C8 cyclic haloalkyl (e.g., CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C2-C5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH2-cyclopropyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocyclic ring (e.g., oxadiazole, pyrrol, N-methyloxetane-3-amine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, isoxazole, imidazole, furane, triazole, methyl-triazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), CH(CF3)(NH—R10);
• R4 and R40 are each independently H, F, Cl, Br, I, OH, SH, R8—OH (e.g., CH2—OH), R8—SH, —R8—O—R10, (e.g., CH2—O—CH3) CF3, CD3, OCD3, CN, NO2, —CH2CN, —R8CN, NH2, NHR, N(R)2, R8—N(R10)(R11) (e.g., CH2—NH2, CH2—N(CH3)2) R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, —NHCO—R10 (e.g., NHC(O)CH3), NHCO—N(R10)(R11) (e.g., NHC(O)N(CH3)2), COOH, —C(O)Ph, C(O)O—R10 (e.g. C(O)O—CH3, C(O)O—CH2CH3), R8—C(O)—R10 (e.g., CH2C(O)CH3), C(O)H, C(O)—R10 (e.g., C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF3), —C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2—O—CH3), C(S)N(R10)(R11) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10)(R11) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH2-cyclopropyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocyclic ring (e.g., oxadiazole, pyrrol, N-methyloxetane-3-amine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, isoxazole, imidazole, furane, triazole, methyl-triazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), CH(CF3)(NH—R10);
• or R3 and R4 are joint together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole);
• R5 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, iso-propyl), C2-C5 linear or branched, substituted or unsubstituted alkenyl, C2-C5 linear or branched, substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2), R8-aryl (e.g., CH2-Ph), C(═CH2)—R10 (e.g., C(═CH2)—C(O)—OCH3, C(═CH2)—CN) substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);
• R6 is H, C1-C5 linear or branched alkyl (e.g., methyl), C(O)R, or S(O)2R;
• R60 is H, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, CH2—OC(O)CH3, CH2—PO4H2, CH2—PO4H-tBu, CH2—OP(O)(OCH3)2), C(O)R, or S(O)2R;
• R8 is [CH2]p
• wherein p is between 1 and 10;
• R9 is [CH]q, [C]q
• wherein q is between 2 and 10;
• R10 and R11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8—O—R10 (e.g., CH2CH2—O—CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R;
• or R10 and R11 are joined to form a substituted or unsubstituted C3-C8 heterocyclic ring (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine),
• wherein substitutions include:
• F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g. methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2—OH, CH2CH2—OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched, substituted or unsubstituted alkynyl (e.g., CH≡C—CH3), alkoxy, ester (e.g., OC(O)—CH3), N(R)2, CF3, aryl, phenyl, R8-aryl (e.g., CH2CH2-Ph), heteroaryl (e.g., imidazole) C3-C8 cycloalkyl (e.g., cyclohexyl), C3-C8 heterocyclic ring (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen-phosphate (e.g., tBu-PO4H), dihydrogen-phosphate (i.e., OP(O)(OH)2), dialkylphosphate (e.g., OP(O)(OCH3)2), CN and NO2;
• R is H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C1-C5 linear or branched alkoxy (e.g., methoxy), phenyl, aryl or heteroaryl,
• or two gem R substituents are joint together to form a 5 or 6 membered heterocyclic ring;
• m, n and k are each independently an integer between 0 and 4 (e.g., 0, 1 or 2);
• l is an integer between 1 and 4 (e.g., 0, 1 or 2);
• or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

A compound represented by the structure of formula VIII:

• wherein
• R1 is H, methoxy, OCD3, F, Cl, or OCHF2;
• R2 is xylyl, 2,6-difluorophenyl, 4-fluoroxylyl or isopropyl;
• R22 is F, OH, or NH2;
• R20 and R21 are both H;
• R3 is oxadiazole, oxazole, isoxazole, or tetrazole;
• or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical product or any combination thereof.

A compound represented by the structure of formula VI:

• wherein
• R3 is I, OH, SH, R8—OH (e.g., CH2—OH), R8—SH, —R8—O—R10, (e.g., CH2—O—CH3) CF3, CD3, OCD3, CN, NO2, —CH2CN, —R8CN, NH2, NHR, N(R)2, R8—N(R10)(R11) (e.g., CH2—NH2, CH2—N(CH3)2) R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, —NHCO—R10 (e.g., NHC(O)CH3), NHCO—N(R10)(R11) (e.g., NHC(O)N(CH3)2), COOH, —C(O)Ph, C(O)O—R10 (e.g. C(O)O—CH3, C(O)O—CH2CH3), R8—C(O)—R10 (e.g., CH2C(O)CH3), C(O)H, C(O)—R10 (e.g., C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF3), —C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R10)(R11) (e.g., C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2—O—CH3), C(S)N(R10)(R11) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10)(R11) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH2-cyclopropyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocyclic ring (e.g., oxadiazole, pyrrol, N-methyloxetane-3-amine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, isoxazole, imidazole, furane, triazole, methyl-triazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), CH(CF3)(NH—R10).