US 11,718,628 B2
SREBP inhibitors comprising a 6-membered central ring
Michael John Green, Half Moon Bay, CA (US); and Barry Patrick Hart, Palo Alto, CA (US)
Assigned to CAPULUS THERAPEUTICS, LLC, San Francisco, CA (US)
Filed by Capulus Therapeutics, LLC, San Francisco, CA (US)
Filed on Jul. 27, 2020, as Appl. No. 16/940,212.
Application 16/940,212 is a continuation of application No. PCT/US2019/015458, filed on Jan. 28, 2019.
Claims priority of provisional application 62/744,397, filed on Oct. 11, 2018.
Claims priority of provisional application 62/623,405, filed on Jan. 29, 2018.
Prior Publication US 2021/0047340 A1, Feb. 18, 2021
Int. Cl. C07D 491/056 (2006.01); C07D 401/04 (2006.01); C07D 401/10 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 471/08 (2006.01); C07D 491/048 (2006.01); C07D 491/052 (2006.01)
CPC C07D 491/056 (2013.01) [C07D 401/04 (2013.01); C07D 401/10 (2013.01); C07D 401/14 (2013.01); C07D 405/14 (2013.01); C07D 471/08 (2013.01); C07D 491/048 (2013.01); C07D 491/052 (2013.01)] 20 Claims
 
1. A compound of Formula (X-A):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, or isotope thereof, wherein:
R1 is —C(O)OR9, —C(O)NR8R9, —S(O)2NR8R9, —NR10C(O)NR8R9, —NR10C(O)R9, —NR10S(O)2R9, —OR26, —SR9, —S(O)R9, —S(O)2R9, —NR8R9, —NR10C(O)OR9, —C(O)R26, —NR10S(O)2NR8R9, —C(O)NR10S(O)2R9, or —C(O)NR10NR8R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl of R1, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C1-10)alkyl, (C1-10)haloalkyl, cyano, oxo, —OR19, —C(O)NR19R19, —NR19C(O)R19, —NR19C(O)NR19R19, —NR19R19, —S(O)2NR19R19, —NR19S(O)2R19, —S(O)n4R20, —C(O)OR19, —C(O)R20, and —(OR38)n15OR19,
each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R38 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each n15 is independently an integer from 1 to 5, and
n4 is 0, 1, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, —OR23, —C(O)NR23R23, —NR23C(O)R23, —NR23C(O)OR23, —NR23C(O)NR23R23, —NR23R23, —S(O)2NR23R23—NR23S(O)2R24, —S(O)n6R24, —C(O)OR23, —C(O)R24, and —(OR39)n16OR23,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, —OR31, —C(O)NR31R31, —NR31C(O)R31, —NR31C(O)OR31, —NR31C(O)NR31R31, —NR31S(O)2R31, and —S(O)n9R31, wherein each R31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R39 is independently (C1-10)alkylene or (C1-10)haloalkylene, each n16 is independently an integer from 1 to 5, and
n6 is 0, 1, or 2;
R2 and R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, —OR25, —C(O)NR25R25, —NR25C(O)R25, —NR25C(O)NR25R25, —NR25R25, —S(O)2NR25R25, —NR25S(O)2R25, —S(O)n7R30, —NR25C(O)OR25R25, —C(O)OR25, and —C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more halo,
each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, 1, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein one of X1, X2, X3, and X4 is N; and
R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, —OR27, —C(O)NR27R27, —S(O)2NR27R27, —S(O)n8R28, —C(O)OR27, and —C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo,
each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0, 1 or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, —OR27, —C(O)NR27R27, —NR27C(O)R27, —NR27R27, —S(O)2NR27R27, —NR27S(O)2R27, —S(O)n8R28, and —C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, —OR27, —C(O)NR27R27, —S(O)2NR27R27, —S(O)n8R28, and —C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or —OR29, wherein each R29 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, unsubstituted (C3-10)cycloalkyl or (C3-10)halocycloalkyl, or —OR5;
wherein (C1-10)alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, —C(O)OR7, oxo, and —OR5;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, —OR5, —C(O)NR5R5, —R5C(O)NR5R5, —S(O)2NR5R5, —S(O)n1R6, or —C(O)R6;
wherein the (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl of R16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, —OR7, —C(O)OR7, —C(O)NR7R7, —NR7C(O)R7, —NR7C(O)NR7R7, —NR7R7, —S(O)2NR7R7, —NR7S(O)2R7, —S(O)n2R13, and —C(O)R13;
wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and —(OR33)n10OR32, wherein each n10 is independently an integer from 0 to 5, each R32 is independently hydrogen, (C1-10)alkyl or (C1-10)haloalkyl, and each R33 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, —C(O)OR34, —C(O)NR34R34, —NR34C(O)R34, —NR34C(O)NR34R34, —NR34R34, —S(O)2NR34R34, —NR34S(O)2R34, —S(O)n11R34, —C(O)R34, and —(OR35)n12OR34, wherein each
R34 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each n11 is independently 0, 1, or 2; each n12 is independently an integer from 0 to 5; and each R35 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each n1 is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl,
wherein the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, —OR18, —C(O)NR18R18, —NR18C(O)R18, —NR18C(O)NR18R18, —NR18R18, —S(O)2NR18R18, —NR18S(O)2R18, —S(O)n3R21, —C(O)OR18, and —C(O)R21,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, —C(O)OR36, —C(O)NR36R36, —NR36C(O)R36, —NR36C(O)NR36R36, —NR36R36, —S(O)2NR36R36, —NR36S(O)2R36, —S(O)n13R36, —C(O)R36, and —(OR37)n14OR36, wherein each R36 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each n13 is independently 0, 1, or 2; each n14 is independently an integer from 0 to 5; and each R37 is independently (C1-10)alkylene or (C1-10)haloalkylene;
wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo; and
each n3 is independently 0, 1, or 2.