US 12,071,426 B2
IRE1 small molecule inhibitors
Joseph P. Vacca, Telford, PA (US); and Sarah Elizabeth Bettigole, New York, NY (US)
Assigned to Cornell University, Ithaca, NY (US)
Appl. No. 17/299,684
Filed by Cornell University, Ithaca, NY (US)
PCT Filed Dec. 2, 2019, PCT No. PCT/US2019/063921
§ 371(c)(1), (2) Date Jun. 3, 2021,
PCT Pub. No. WO2020/117635, PCT Pub. Date Jun. 11, 2020.
Claims priority of provisional application 62/774,794, filed on Dec. 3, 2018.
Prior Publication US 2022/0356168 A1, Nov. 10, 2022
Int. Cl. C07D 401/14 (2006.01); C07D 471/04 (2006.01)
CPC C07D 401/14 (2013.01) [C07D 471/04 (2013.01)] 23 Claims
 
1. A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

OG Complex Work Unit Chemistry
wherein,
Y1, Y2, Y3, and Y4 are each independently selected from N and CR8; Z1 is independently selected from N and CR7; Z2 is independently selected from N and CR7A, and Z3 is independently selected from N and CR7B; wherein at least one of Y1, Y2, Y3, Y4, Z1, Z2 and Z3 are N and not more than two of Y1, Y2, Y3, and YA are N;
X1, X2, and X3 are each independently selected from N and CR4;
R1 is halogen, —CN, —OR10, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
R2 is hydrogen, —CN, —OR10, —SR10, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cyclooalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R4 is independently H, halogen, —CN, —OR10, —SR10, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R11)2, —NR10S(═O)2R3, —C(═O)R9, —OC(═O)R9, —C(═O)OR10, —OC(═O)OR9, —N(R11)2, —OC(═O)N(R11)2, —NR1ºC(═O)R9, —NR1ºC(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R5 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cyclooalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R6 is independently halogen, —CN, —OR10, —SR10, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R11)2, —NR10S(═O); R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR10, —OC(═O)OR9, —N(R11)2, —OC(═O)N(R11)2, —NR1ºC(═O)R9, —NR1ºC(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7, R7A, and R7B are independently H, —CN, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
each R8 is independently H, halogen, —CN, —OR10, —SR10, —N(R11)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R′ is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R10 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R11 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R1 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle; and
q is 0, 1, 2, 3, or 4.
 
19. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein
R1 is chlorine;
R2 is unsubstituted C1-C4alkyl or unsubstituted —O—C1-C4alkyl;
R3 is hydrogen or unsubstituted C1-C4alkyl;
R4 is hydrogen;
R5 is hydrogen or unsubstituted C1-C4alkyl;
R6 is absent as q is zero;
Z1 is N or CR7 wherein R7 is H;
Z2 is N or CR7A wherein R7A is H;
Z3 is N or CR7B wherein R7B is unsubstituted C1-C4alkyl;
Y1 is N or CR8,
Y2 is N or CR8,
Y3 is N or CR8;
Y4 is Nor CR8;
R8 is hydrogen;
X1 is N or CR4;
X2 is N or CR4; and
X3 is N or CR4; wherein at least one of Y1, Y2, Y3, Y4, Z1, Z2, and Z3 are N and not more than two of Y1, Y2, Y3, and Y4 are N.