US2023174507A1PendingUtilityA1
Imidazole 3-oxide derivative based acss2 inhibitors and methods of use thereof
Est. expiryMay 14, 2039(~12.8 yrs left)· nominal 20-yr term from priority
C07F 5/025C07D 207/34C07D 231/38A61K 31/506C07D 401/12C07D 231/16A61K 45/06C07D 405/10C07D 231/46C07D 413/10C07D 413/04A61K 31/4184C07D 233/70C07D 233/90C07D 401/10C07D 403/10C07D 401/04A61P 25/32C07D 231/26A61P 25/18C07D 403/04A61P 1/16A61P 37/00A61P 35/00C07D 249/06C07D 401/14A61K 31/4152C07D 263/34A61P 31/12A61K 31/497C07D 231/22A61P 25/24C07D 403/12A61P 25/00C07D 231/20A61P 37/02A61P 29/00A61K 31/422C07D 241/24A61K 31/4155C07D 207/36C07D 405/04A61K 31/5377C07D 413/12A61P 3/00A61K 31/501C07D 417/12C07D 405/12A61K 31/427A61K 31/4439C07D 409/12C07D 413/14C07D 231/14A61K 31/454C07D 213/81C07D 239/28C07D 409/04C07D 405/14
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Claims
Abstract
The present invention relates to novel ACSS2 inhibitors having activity as anti-cancer therapy, treatment of alcoholism, and viral infection (e.g., CMV), composition and methods of preparation thereof, and uses thereof for treating viral infection, alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), obesity/weight gain, anxiety, depression, post-traumatic stress disorder, inflammatory/autoimmune conditions and cancer, including metastatic cancer, advanced cancer, and drug resistant cancer of various types.
Claims
exact text as granted — not AI-modified1 - 42 . (canceled)
43 . 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 C 3 -C 10 cycloalkyl (e.g. cyclohexyl), or a single or fused C 3 -C 10 heterocyclic ring (e.g., benzofuran-2(3H)-one, benzo[d][1,3]dioxole, tetrahydrothiophene 1,1-dioxide, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran);
R 1 , R 2 and R 20 are each independently H, F, Cl, Br, I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., —CH 2 —O—CH 3 ), R 8 —(C 3 -C 8 cycloalkyl) (e.g., cyclohexyl), R 8 —(C 3 -C 8 heterocyclic ring) (e.g., CH 2 -morpholine, CH 2 -imidazole, CH 2 -indazole), CF 3 , CD 3 , OCD 3 , CN, NO 2 , —CH 2 CN, —R 8 CN, NH 2 , NHR (e.g., NH—CH 3 ), N(R) 2 (e.g., N(CH 3 ) 2 ), R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —CH 2 —N(CH 3 ) 2 , CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ), R 9 —R 8 —N(R 10 )(R 11 ) (e.g., C≡C—CH 2 —NH 2 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, NHC(O)—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), COOH, —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH(CH 3 ) 2 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 ), SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 N(CH 3 ) 2 , SO 2 NHC(O)CH 3 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)—CH 3 , methyl, 2, 3, or 4-CH 2 —C 6 H 4 —Cl, ethyl, propyl, iso-propyl, butyl, t-Bu, iso-butyl, pentyl, benzyl), C 2 -C 5 linear or branched, substituted or unsubstituted alkenyl (e.g., CH═C(Ph) 2 )), C 1 -C 5 linear, branched or cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 ), substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O—(CH 2 ) 2 -pyrrolidine, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally wherein at least one methylene group (CH 2 ) in the alkoxy is replaced with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C 3 -C 8 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(CF 3 )(NH—R 10 );
or R 2 and R 1 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);
R 3 is I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., CH 2 —O—CH 3 ) CF 3 , CD 3 , OCD 3 , CN, —CH 2 CN, —R 8 CN, NH 2 , NHR, N(R) 2 , R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ) R 9 —R 8 —N(R 10 )(R 11 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, —NHCO—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 )), C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CH 2 —O—CH 3 ), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH 3 )), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 NH(CH 3 ), SO 2 N(CH 3 ) 2 ), C 2 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH 3 )(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C 2 -C 5 linear or branched or C 3 -C 8 cyclic haloalkyl (e.g., CF 2 CH 3 , CF 2 -cyclobutyl, CF 2 -cyclopropyl, CF 2 -methylcyclopropyl, CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 , C(OH) 2 CF 3 , cyclopropyl-CF 3 ), C 2 -C 5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., CF 3 -cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C 3 -C 8 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(CF 3 )(NH—R 10 );
R 4 and R 40 are each independently H, F, Cl, Br, I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., CH 2 —O—CH 3 ) CF 3 , CD 3 , OCD 3 , CN, NO 2 , —CH 2 CN, —R 8 CN, NH 2 , NHR, N(R) 2 , R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ) R 9 —R 8 —N(R 10 )(R 11 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, —NHCO—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), COOH, —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 )), C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CH 2 —O—CH 3 ), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH 3 )), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 NH(CH 3 ), SO 2 N(CH 3 ) 2 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH 3 )(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CF 2 -cyclobutyl, CF 2 -cyclopropyl, CF 2 -methylcyclopropyl, CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 , C(OH) 2 CF 3 , cyclopropyl-CF 3 ), C 1 -C 5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., CF 3 -cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C 3 -C 8 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(CF 3 )(NH—R 10 );
or R 3 and R 4 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);
R 5 is H, C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, CH 2 SH, ethyl, iso-propyl), C 2 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 2 -C 5 linear or branched, substituted or unsubstituted alkynyl (e.g., CCH), C 1 -C 5 linear or branched haloalkyl (e.g., CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), C(═CH 2 )—R 10 (e.g., C(═CH 2 )—C(O)—OCH 3 , C(═CH 2 )—CN) substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine);
R 6 is H, C 1 -C 5 linear or branched alkyl (e.g., methyl), C(O)R, or S(O) 2 R;
R 60 is H, substituted or unsubstituted C 1 -C 5 linear or branched alkyl (e.g., methyl, CH 2 —OC(O)CH 3 , CH 2 —PO 4 H 2 , CH 2 —PO 4 H-tBu, CH 2 —OP(O)(OCH 3 ) 2 ), C(O)R, or S(O) 2 R;
R 8 is [CH 2 ] p
wherein p is between 1 and 10;
R 9 is [CH] q , [C] q
wherein q is between 2 and 10;
R 10 and R 11 are each independently H, CN, C 1 -C 5 linear or branched alkyl (e.g., methyl, ethyl), R 8 —O—R 10 (e.g., CH 2 CH 2 —O—CH 3 ), C(O)R (e.g., C(O)(OCH 3 )), or S(O) 2 R;
or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine),
wherein substitutions include: F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl (e.g. methyl, ethyl, propyl), C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 —OH, CH 2 CH 2 —OH), C 2 -C 5 linear or branched alkenyl (e.g., E- or Z-propylene), C 2 -C 5 linear or branched, substituted or unsubstituted alkynyl (e.g., CH≡C—CH 3 ), alkoxy, ester (e.g., OC(O)—CH 3 ), N(R) 2 , CF 3 , aryl, phenyl, R 8 -aryl (e.g., CH 2 CH 2 -Ph), heteroaryl (e.g., imidazole) C 3 -C 8 cycloalkyl (e.g., cyclohexyl), C 3 -C 8 heterocyclic ring (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen-phosphate (e.g., tBu-PO 4 H), dihydrogen-phosphate (i.e., OP(O)(OH) 2 ), dialkylphosphate (e.g., OP(O)(OCH 3 ) 2 ), CN and NO 2 ;
R is H, C 1 -C 5 linear or branched alkyl (e.g., methyl, ethyl), C 1 -C 5 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.
44 . The compound of claim 43 , represented by the structure of formula II:
wherein
X 1 , X 2 , X 3 , X 4 and X 5 are each independently C or N;
by the structure of formula III:
by the structure of formula IV:
by the structure of formula VIII:
wherein
R 21 and R 22 are each independently H, F, Cl, Br, I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., —CH 2 —O—CH 3 ), R 8 —(C 3 -C 8 cycloalkyl) (e.g., cyclohexyl), R 8 —(C 3 -C 8 heterocyclic ring) (e.g., CH 2 -morpholine, CH 2 -imidazole, CH 2 -indazole), CF 3 , CD 3 , OCD 3 , CN, NO 2 , —CH 2 CN, —R 8 CN, NH 2 , NHR (e.g., NH—CH 3 ), N(R) 2 (e.g., N(CH 3 ) 2 ), R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —CH 2 —N(CH 3 ) 2 , CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ), R 9 —R 8 —N(R 10 )(R 11 ) (e.g., C≡C—CH 2 —NH 2 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, NHC(O)—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), COOH, —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH(CH 3 ) 2 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 ), SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 N(CH 3 ) 2 , SO 2 NHC(O)CH 3 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)—CH 3 , methyl, 2, 3, or 4-CH 2 —C 6 H 4 —Cl, ethyl, propyl, iso-propyl, butyl, t-Bu, iso-butyl, pentyl, benzyl), C 2 -C 5 linear or branched, substituted or unsubstituted alkenyl (e.g., CH═C(Ph) 2 )), C 1 -C 5 linear, branched or cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 ), substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O—(CH 2 ) 2 -pyrrolidine, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally wherein at least one methylene group (CH 2 ) in the alkoxy is replaced with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C 3 -C 8 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(CF 3 )(NH—R 10 ); or
by the structure of formula IX:
wherein
R 1 , R 20 , R 21 and R 22 are each independently H, F, Cl, Br, I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., —CH 2 —O—CH 3 ), R 8 —(C 3 -C 8 cycloalkyl) (e.g., cyclohexyl), R 8 —(C 3 -C 8 heterocyclic ring) (e.g., CH 2 -morpholine, CH 2 -imidazole, CH 2 -indazole), CF 3 , CD 3 , OCD 3 , CN, NO 2 , —CH 2 CN, —R 8 CN, NH 2 , NHR (e.g., NH—CH 3 ), N(R) 2 (e.g., N(CH 3 ) 2 ), R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —CH 2 —N(CH 3 ) 2 , CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ), R 9 —R 8 —N(R 10 )(R 11 ) (e.g., C≡C—CH 2 —NH 2 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, NHC(O)—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), COOH, —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH(CH 3 ) 2 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 ), SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 N(CH 3 ) 2 , SO 2 NHC(O)CH 3 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)—CH 3 , methyl, 2, 3, or 4-CH 2 —C 6 H 4 —Cl, ethyl, propyl, iso-propyl, butyl, t-Bu, iso-butyl, pentyl, benzyl), C 2 -C 5 linear or branched, substituted or unsubstituted alkenyl (e.g., CH═C(Ph) 2 )), C 1 -C 5 linear, branched or cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 ), substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic alkoxy (e.g. methoxy, O—(CH 2 ) 2 -pyrrolidine, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally wherein at least one methylene group (CH 2 ) in the alkoxy is replaced with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy (e.g., OCF 3 , OCHF 2 ), C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C 3 -C 8 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), CH(CF 3 )(NH—R 10 );
or R 21 and R 1 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);
or R 21 and R 22 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); and
R 201 and R 202 are each independently H, F, Cl, Br, I, CF 3 , or C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl).
45 . A compound represented by the structure of formula VIII:
wherein
R 1 is H, methoxy, OCD 3 , F, Cl, or OCHF 2 ;
R 2 is xylyl, 2,6-difluorophenyl, 4-fluoroxylyl or isopropyl;
R 22 is F, OH, or NH 2 ;
R 20 and R 21 are both H;
R 3 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.
46 . The compound of claim 43 , selected from the following:
Compound
Number
Compound Structure
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
169
170
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
190
191
192
193
194
195
196
197
198
199
200
201
202
204
205
206
210
211
213
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.
47 . A compound represented by the structure of formula VI:
wherein
R 3 is I, OH, SH, R 8 —OH (e.g., CH 2 —OH), R 8 —SH, —R 8 —O—R 10 , (e.g., CH 2 —O—CH 3 ) CF 3 , CD 3 , OCD 3 , CN, NO 2 , —CH 2 CN, —R 8 CN, NH 2 , NHR, N(R) 2 , R 8 —N(R 10 )(R 11 ) (e.g., CH 2 —NH 2 , CH 2 —N(CH 3 ) 2 ) R 9 —R 8 —N(R 10 )(R 11 ), B(OH) 2 , —OC(O)CF 3 , —OCH 2 Ph, —NHCO—R 10 (e.g., NHC(O)CH 3 ), NHCO—N(R 10 )(R 11 ) (e.g., NHC(O)N(CH 3 ) 2 ), COOH, —C(O)Ph, C(O)O—R 10 (e.g. C(O)O—CH 3 , C(O)O—CH 2 CH 3 ), R 8 —C(O)—R 10 (e.g., CH 2 C(O)CH 3 ), C(O)H, C(O)—R 10 (e.g., C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 ), C 1 -C 5 linear or branched C(O)-haloalkyl (e.g., C(O)—CF 3 ), —C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 )), C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CH 2 —O—CH 3 ), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH 3 )), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO 2 R, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 NH(CH 3 ), SO 2 N(CH 3 ) 2 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH 3 )(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, pentyl), substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CF 2 -cyclobutyl, CF 2 -cyclopropyl, CF 2 -methylcyclopropyl, CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 , C(OH) 2 CF 3 , cyclopropyl-CF 3 ), C 1 -C 5 linear, branched or cyclic alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, O—CH 2 -cyclopropyl), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., CF 3 -cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C 3 -C 8 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(CF 3 )(NH—R 10 ).
48 . The compound of claim 47 , wherein:
R 3 is C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 )), C(O)N(R 10 )(R 11 ) (e.g., C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CH 2 —O—CH 3 ), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH 3 )), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO 2 N(R 10 )(R 11 ) (e.g., SO 2 NH(CH 3 ), SO 2 N(CH 3 ) 2 ), or substituted or unsubstituted C 1 -C 5 linear or branched or C 3 -C 8 cyclic haloalkyl (e.g., CF 3 , CF 2 CH 3 , CF 2 -cyclobutyl, CF 2 -cyclopropyl, CF 2 -methylcyclopropyl, CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )—CH(CH 3 ) 2 , C(OH) 2 CF 3 , cyclopropyl-CF 3 ).
49 . The compound of claim 47 , selected from the following:
Compound
Number
Compound Structure
171
203
207
208
209
212
214
215
50 . A pharmaceutical composition comprising a compound according to claim 43 and a pharmaceutically acceptable carrier.
51 . A method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a disease or condition selected from: cancer, human alcoholism, viral infection, alcoholic steatohepatitis (ASH), non alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a metabolic disorder, an autoimmune disease or a neuropsychiatric disease or disorder in a subject, comprising administering a compound according to claim 43 , to a subject suffering from said disease or condition, under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit said disease or condition.
52 . A method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a disease or condition selected from: cancer, human alcoholism, viral infection, alcoholic steatohepatitis (ASH), non alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a metabolic disorder, an autoimmune disease or a neuropsychiatric disease or disorder in a subject, comprising administering a compound according to claim 47 , to a subject suffering from said disease or condition, under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit said disease or condition.
53 . The method of claim 51 ,
wherein the cancer is selected from the list of: hepatocellular carcinoma, melanoma (e.g., BRAF mutant melanoma), glioblastoma, breast cancer (e.g., invasive ductal carcinomas of the breast, triple-negative breast cancer), prostate cancer, liver cancer, brain cancer, ovarian cancer, lung cancer, Lewis lung carcinoma (LLC), colon carcinoma, pancreatic cancer, renal cell carcinoma and mammary carcinoma; wherein the cancer is early cancer, advanced cancer, invasive cancer, metastatic cancer, drug resistant cancer or any combination thereof; wherein the subject has been previously treated with chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof; wherein the compound is administered in combination with an anti-cancer therapy;
wherein the viral infection is human cytomegalovirus (HCMV) infection;
wherein the metabolic disorder is selected from: obesity, weight gain, hepatic steatosis and fatty liver disease; wherein the neuropsychiatric disease or disorder is selected from: anxiety, depression, schizophrenia, autism and post-traumatic stress disorder; or any combination thereof.
54 . The method of claim 53 , wherein the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention, or any combination thereof.
55 . A method of suppressing, reducing or inhibiting tumor growth in a subject suffering from cancer, comprising administering a compound according to claim 43 , to a subject suffering from cancer, under conditions effective to suppress, reduce or inhibit tumor growth in said subject.
56 . The method of claim 55 ,
wherein the tumor growth is enhanced by increased acetate uptake by cancer cells of said cancer, wherein the tumor growth is suppressed due to suppression of lipid (e.g., fatty acid) synthesis and/or regulating histones acetylation and function induced by ACSS2 mediated acetate metabolism to acetyl-CoA;
or combination thereof.
57 . A method of suppressing, reducing or inhibiting lipid synthesis and/or regulating histones acetylation and function in a cell, comprising contacting a compound according to claim 43 with a cell under conditions effective to suppress, reduce or inhibit lipid synthesis and/or regulating histones acetylation and function in said cell.
58 . The method of claim 57 , wherein the cell is a cancer cell.
59 . A method of binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising the step of contacting an ACSS2 enzyme with an ACSS2 inhibitor compound according to claim 43 , in an amount effective to bind the ACSS2 inhibitor compound to the ACSS2 enzyme.
60 . A method of suppressing, reducing or inhibiting acetyl-CoA synthesis from acetate in a cell, comprising contacting a compound according to claim 43 with a cell, under conditions effective to suppress, reduce or inhibit acetyl-CoA synthesis from acetate in said cell.
61 . The method of claim 60 ,
wherein the cell is a cancer cell; wherein the synthesis is mediated by ACSS2; or combination thereof.
62 . A method of suppressing, reducing or inhibiting acetate metabolism in a cancer cell, comprising contacting a compound according to claim 43 with a cancer cell, under conditions effective to suppress, reduce or inhibit acetate metabolism in said cells.
63 . The method of claim 62 ,
wherein the acetate metabolism is mediated by ACSS2; wherein the cancer cell is under hypoxic stress; or combination thereof.Join the waitlist — get patent alerts
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