US 12,133,852 B2
ACSS2 inhibitors and methods of use thereof
Philippe Nakache, Ness Ziona (IL); Omri Erez, Rehovot (IL); Simone Botti, Rehovot (IL); and Andreas Goutopoulos, Boston, MA (US)
Assigned to EpiVario, Inc., Philadelphia, PA (US)
Filed by EpiVario, Inc., Philadelphia, PA (US)
Filed on Nov. 4, 2020, as Appl. No. 17/088,613.
Application 17/088,613 is a continuation in part of application No. 16/411,168, filed on May 14, 2019, granted, now 10,851,064.
Application 16/411,168 is a continuation in part of application No. PCT/IL2018/051232, filed on Nov. 15, 2018.
Application 17/088,613 is a continuation in part of application No. PCT/IL2020/050526, filed on May 14, 2020.
Application PCT/IL2020/050526 is a continuation in part of application No. 16/411,168, filed on May 14, 2019, granted, now 10,851,064.
Claims priority of provisional application 62/847,348, filed on May 14, 2019.
Claims priority of provisional application 62/586,195, filed on Nov. 15, 2017.
Prior Publication US 2022/0305010 A1, Sep. 29, 2022
Int. Cl. A61K 31/501 (2006.01); A61K 31/4152 (2006.01); A61K 31/4155 (2006.01); A61K 31/4184 (2006.01); A61K 31/422 (2006.01); A61K 31/4245 (2006.01); A61K 31/4439 (2006.01); A61K 31/497 (2006.01); A61K 31/498 (2006.01); A61K 31/635 (2006.01); A61P 35/04 (2006.01)
CPC A61K 31/501 (2013.01) [A61K 31/4152 (2013.01); A61K 31/4155 (2013.01); A61K 31/4184 (2013.01); A61K 31/422 (2013.01); A61K 31/4245 (2013.01); A61K 31/4439 (2013.01); A61K 31/497 (2013.01); A61K 31/498 (2013.01); A61K 31/635 (2013.01); A61P 35/04 (2018.01)] 17 Claims
 
1. A method of suppressing, reducing or inhibiting tumor growth in a subject comprising administering a compound represented by the structure of formula (I):

OG Complex Work Unit Chemistry
wherein
A and B rings are each independently a single or fused aromatic or heteroaromatic ring system, or a single or fused C3-C10 cycloalkyl or a single or fused C3-C10 heterocyclic ring;
R1 and R2 are each independently H, D, F, Cl, Br, I, OH, SH, R8—OH, CH2—OH, R8—SH, —R8—O—R10, —CH2—O—CH3, R8-aryl, CH2-3-methoxy-phenyl, benzyl, CH2-1-methoxy-phenyl, CH2-4-chloro-phenyl, CH2CH2-phenyl, CF3, CD3, OCD3, CN, NO2, —CH2CN, —R8CN, NH2, NHR, N(R)2, R8—N(R10)(R11), CH2—NH2, CH2—N(CH3)2, R9—R8—N(R10)(R11), C≡C—CH2—NH2, B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R10, NHC(O)CH3, NHCO—N(R10)(R11), NHC(O)N(CH3)2, COOH, —C(O)Ph, —C(O)-aryl, C(O)-1-methyl-phenyl, C(O)-4-methyl-phenyl, C(O)-3-methyl-phenyl, C(O)-phenol, C(O)-4-hydroxy-phenyl, C(O)-3-hydroxy-phenyl, C(O)-2-hydroxy-phenyl, C(O)O—R10, C(O)O—CH3, C(O)O—CH(CH3)2, C(O)O—CH2CH3, R8—C(O)—R10, CH2C(O)CH3, C(O)H, C(O)—R10, C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3, C1-C5 linear or branched C(O)-haloalkyl, C(O)—CF3, —C(O)NH2, C(O)NHR, C(O)N(R10)(R11), C(O)N(CH3)2, SO2R, SO2-Ph, SO2-toluene, SO2—CH3, SO2N(R10)(R11), SO2N(CH3)2, SO2NHC(O)CH3, substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic alkyl, methyl, 2, 3, or 4-CH2—C6H4—Cl, ethyl, propyl, iso-propyl, cyclopropyl, t-Bu, iso-butyl, pentyl, benzyl, C(CH3)(OH)Ph, CH2-3-methoxy-phenyl, CH2-1-methoxy-phenyl, CH2-4-chloro-phenyl, CH2CH2-phenyl, C1-C5 linear or branched haloalkyl, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, CF2CH-cyclopropyl, substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic alkoxy, methoxy, ethoxy, propoxy, isopropoxy, O—CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu, substituted or unsubstituted C1-C5 linear or branched or C3-C8 cyclic alkoxy wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, O-1-oxacyclobutyl, O-2-oxacyclobutyl, C1-C5 linear or branched thioalkoxy, S—CH3, C1-C5 linear or branched haloalkoxy, OCF3, OCHF2, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, cyclopropyl, cyclopentyl, substituted or unsubstituted C3-C8 heterocyclic ring, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 2-methyl-4-pyridine, 2,6-dimethyl-4-pyridine, 3,5-dimethyl-4-pyridine, 2,5-dimethyl-4-pyridine, 3-methyl-4-pyridine, 5-methyl-2-pyridine, 3-methyl-2-pyridine, 3-ethyl-2-pyridine, 3-isopropyl-2-pyridine, 3-propyl-2-pyridine, 3-phenyl-2-pyridine, 4-methyl-2-pyridine, 6-methyl-2-pyridine, 5-methyl-2-pyridine, pyrimidine, 5-methyl-pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide, substituted or unsubstituted aryl, phenyl, (wherein substitutions include: F, Cl, Br, I, C1-C5 linear or branched alkyl, methyl, ethyl, propyl, isopropyl, OH, alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2 or any combination thereof;
or R2 and R1 are joined to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic single or fused ring;
R3 and R4 are each independently H, F, Cl, Br, I, OH, SH, R8—OH, CH2—OH, R8—SH, —R8—O—R10, CH2—O—CH3, CF3, CD3, OCD3, CN, NO2, —CH2CN, —R8CN, NH2, NHR, N(R)2, R8—N(R10)(R11), CH2—NH2, CH2—N(CH3)2, R8—C(O)N(R10)(R11), CF2C(O)N[(CH3)(OCH3)], R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, —NHCO—R10, NHC(O)CH3, NHCO—N(R10)(R11), NHC(O)N(CH3)2, COOH, —C(O)Ph, C(O)O—R10, C(O)O—CH3, C(O)O—CH2CH3, R8—C(O)—R10, CH2C(O)CH3, C(O)H, C(O)—R10, C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3, C1-C5 linear or branched C(O)-haloalkyl, C(O)—CF3, —C(O)NH2, C(O)NHR, C(O)N(R10)(R11), C(O)N(CH3)2, SO2R, SO2N(R10)(R11), SO2N(CH3)2, C1-C5 linear or branched or C3-C8 cyclic, substituted or unsubstituted alkyl, methyl, C(OH)(CH3)(Ph), ethyl, propyl, iso-propyl, t-Bu, iso-butyl, 2-butyl, pentyl, tert-pentyl, 1-ethylcyclopropyl, C(CH3)(OH)Ph, C1-C5 linear or branched or C3-C8 cyclic haloalkyl, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CF2CHFCH3, CHFCHFCH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, CF2-cyclopropyl, CF2-cyclopentyl, C1-C5 linear or branched or C3-C8 cyclic haloalkenyl, CF═CH—CH3 E, Z, CF═C—(CH3)2, C1-C5 linear or branched or C3-C8 cyclic alkoxy, 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, cyclopropyl, cyclopentyl, substituted or unsubstituted C3-C8 heterocyclic ring, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, pyrrole, 1-methyl-pyrrole, imidazole, 1-methyl-imidazole, triazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, substituted or unsubstituted aryl or phenyl; wherein substitutions include: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2 or any combination thereof;
or R3 and R4 are joined to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
R5 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl, methyl, CH2SH, ethyl, iso-propyl, C1-C5 linear or branched haloalkyl, CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)—CH(CH3)2, R8-aryl, CH2-Ph, C(O)—R10, C(O)—CH3, substituted or unsubstituted aryl, phenyl, substituted or unsubstituted heteroaryl, pyridine (2, 3, and 4-pyridine); wherein substitutions include: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2 or any combination thereof;
R6 is H, C1-C5 linear or branched alkyl, methyl, C(O)R, or S(O)2R;
R8 is [CH2]p or [CF2]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, C1-C5 linear or branched alkyl, methyl, ethyl, C(O)R, or S(O)2R;
R is H, C1-C5 linear or branched alkyl, methyl, ethyl, C1-C5 linear or branched alkoxy, phenyl, aryl, toluene or heteroaryl, or two gem R substituents are joined to form a 5 or 6 membered heterocyclic ring;
m, n, l and k are each independently an integer between 0 and 4;
Q1 and Q2 are each independently S, O, N—OH, CH2, C(R)2 or N—OMe;
or its pharmaceutically acceptable salt thereof, to a subject, under conditions effective to suppress, reduce or inhibit said tumor growth in said subject.