US 12,441,689 B2
ACSS2 inhibitors and methods of use thereof
Philippe Nakache, Ness Ziona (IL); Omri Erez, Rehovot (IL); Simone Botti, Rehovot (IL); Andreas Goutopoulos, Boston, MA (US); and Harry Finch, Bedfordshire (GB)
Assigned to EpiVario, Inc., Philadelphia, PA (US)
Appl. No. 17/609,392
Filed by EpiVario, Inc., Philadelphia, PA (US)
PCT Filed May 14, 2020, PCT No. PCT/IL2020/050524
§ 371(c)(1), (2) Date Nov. 7, 2021,
PCT Pub. No. WO2020/230134, PCT Pub. Date Nov. 19, 2020.
Application 17/609,392 is a continuation of application No. 16/411,168, granted, now 10,851,064, issued on Dec. 1, 2020, previously published as PCT/IL2020/050524, filed on May 14, 2020.
Claims priority of provisional application 62/847,348, filed on May 14, 2019.
Prior Publication US 2023/0084752 A1, Mar. 16, 2023
Int. Cl. C07D 231/22 (2006.01); A61K 31/4152 (2006.01); A61K 31/4155 (2006.01); A61K 31/4184 (2006.01); A61K 31/422 (2006.01); A61K 31/427 (2006.01); A61K 31/4439 (2006.01); A61K 31/454 (2006.01); A61K 31/497 (2006.01); A61K 31/506 (2006.01); A61K 45/06 (2006.01); A61P 3/00 (2006.01); A61P 25/00 (2006.01); A61P 29/00 (2006.01); A61P 31/12 (2006.01); A61P 35/00 (2006.01); A61P 37/02 (2006.01); C07D 231/20 (2006.01); C07D 231/26 (2006.01); C07D 233/70 (2006.01); C07D 401/04 (2006.01); C07D 401/10 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/10 (2006.01); C07D 403/12 (2006.01); C07D 405/04 (2006.01); C07D 405/10 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 409/04 (2006.01); C07D 409/12 (2006.01); C07D 413/10 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01); C07F 5/02 (2006.01)
CPC C07D 231/22 (2013.01) [A61K 31/4152 (2013.01); A61K 31/4155 (2013.01); A61K 31/4184 (2013.01); A61K 31/422 (2013.01); A61K 31/427 (2013.01); A61K 31/4439 (2013.01); A61K 31/454 (2013.01); A61K 31/497 (2013.01); A61K 31/506 (2013.01); A61K 45/06 (2013.01); A61P 3/00 (2018.01); A61P 25/00 (2018.01); A61P 29/00 (2018.01); A61P 31/12 (2018.01); A61P 35/00 (2018.01); A61P 37/02 (2018.01); C07D 231/20 (2013.01); C07D 231/26 (2013.01); C07D 233/70 (2013.01); C07D 401/04 (2013.01); C07D 401/10 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/10 (2013.01); C07D 403/12 (2013.01); C07D 405/04 (2013.01); C07D 405/10 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 409/04 (2013.01); C07D 409/12 (2013.01); C07D 413/10 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07F 5/025 (2013.01)] 13 Claims
 
1. A method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a disease or disorder selected from: cancer, human alcoholism, viral infection, alcoholic steatohepatitis (ASH), non alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic disorder, neuropsychiatric disease, inflammatory condition or autoimmune disease or disorder, comprising administering a compound to a subject suffering from said disease or disorder under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit said disease or disorder, wherein the compound is represented by the structure of formula (II):

OG Complex Work Unit Chemistry
wherein
A and B rings are each independently a single or fused aromatic or heteroaromatic ring system, a single or fused C3-C10 cycloalkyl, a single or fused C3-C10 heterocyclic ring;
C ring is selected from the following (wavy line represents a connection point):

OG Complex Work Unit Chemistry
wherein
X1, X2, X3, X4, X5, X6, X7 and X8 are each independently N, N—O, or C,
wherein at least one of X1, X2, X3, X4, X5, X6, X7 or X8 is N, and
wherein if X1, X2, X3, X4, X5, X6, X7 or X8 is N than its respective substituent is nothing;
Q3, Q6, Q7 and Q8 are each independently N, N—O, CH or C(R);
Q4 and Q5 are each independently O, NH or N(R);
R200, R400, R500, and R600 are each independently H or a C1-C5 linear or branched, substituted or unsubstituted alkyl;
R201, R202, R203, R204, R301, R302, R303, and R304 are each independently nothing, H or a C1-C5 linear or branched, substituted or unsubstituted alkyl;
R100 and R700 are each independently H, F, Cl, Br, I, OH, SH, R8—SH, —R8—O—R10, R8—(C3-C8 cycloalkyl), R8—(C3-C8 heterocyclic ring), CD3, OCD3, CN, NO2, —R8CN, N(R)2, R8—N(R10)(R11), R9—R8—N(R10)(R11), B(OH)2, —OC(O)—N(R10)(R11), —OC(O)CF3, —OCH2Ph, NHC(O)—R10, NHCO—N(R10)(R11), —C(O)Ph, C(O)O—R10, R8—C(O)—R10, C(O)—R10, C1-C5 linear or branched C(O)-haloalkyl, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched or cyclic haloalkyl, C1-C5 linear, branched or cyclic alkoxy optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, or CH(CF3)(NH—R10);
R1, R2 and R20 are each independently H, F, Cl, Br, I, OH, SH, R8—SH, —R8—O—R10, R8—(C3-C8 cycloalkyl), R8—(C3-C8 heterocyclic ring), CD3, OCD3, CN, NO2, —R8CN, N(R)2, R8—N(R10)(R11), R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, NHC(O)—R10, NHCO—N(R10)(R11), —C(O)Ph, C(O)O—R10, R8—C(O)—R10, C(O)—R10, C1-C5 linear or branched C(O)-haloalkyl, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched or cyclic haloalkyl, C1-C5 linear, branched or cyclic alkoxy, optionally wherein at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom, C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, 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;
R3, R4 and R40 are each independently H, F, Cl, Br, I, OH, SH, R8—SH, —R8—O—R10, CD3, OCD3, CN, NO2, —R8CN, N(R)2, R8—N(R10)(R11), R9—R8—N(R10)(R11), B(OH)2, —OC(O)CF3, —OCH2Ph, —NHCO—R10, NHCO—N(R10)(R11), —C(O)Ph, C(O)O—R10, R8—C(O)—R10, C(O)—R10, C1-C5 linear or branched C(O)-haloalkyl, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), C1-C5 linear or branched, substituted or unsubstituted alkyl, C1-C5 linear, branched or cyclic haloalkyl, C1-C5 linear, branched or cyclic alkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic ring, substituted or unsubstituted aryl, or 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;
R6 is H, C1-C5 linear or branched alkyl, 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, C(O)R, C(O)(OCH3), or S(O)2R;
or R10 and R11 are joint to form a substituted or unsubstituted C3-C8 heterocyclic ring;
R is H, C1-C5 linear or branched alkyl, C1-C5 linear or branched alkoxy, aryl or heteroaryl,
or two gem R substituents are joint together to form a 5 or 6 membered heterocyclic ring;
m, n, l and k are each independently an integer between 0 and 4;
Q2 is S, O, N—OH, CH2, CH(R), C(R) 2 or N—OMe;
or a pharmaceutically acceptable salt thereof.