US 12,479,818 B2
Treatment of fibrosis with IRE1 small molecule inhibitors
Joseph P. Vacca, Telford, PA (US); Dansu Li, Warrington, PA (US); and Sarah Elizabeth Bettigole, New York, NY (US)
Assigned to Cornell University, Ithaca, NY (US)
Appl. No. 17/611,544
Filed by Cornell University, Ithaca, NY (US)
PCT Filed May 15, 2020, PCT No. PCT/US2020/033259
§ 371(c)(1), (2) Date Nov. 15, 2021,
PCT Pub. No. WO2020/232403, PCT Pub. Date Nov. 19, 2020.
Claims priority of provisional application 62/848,327, filed on May 15, 2019.
Prior Publication US 2022/0227730 A1, Jul. 21, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/04 (2006.01); A61K 45/06 (2006.01)
CPC C07D 401/04 (2013.01) [A61K 45/06 (2013.01)] 20 Claims
OG exemplary drawing
 
1. A method of treating fibrosis in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I) is:

OG Complex Work Unit Chemistry
wherein
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2RV, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)R9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, 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,
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently halogen, —CN, —OR8, —SR8, —N(R8)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 R2 is independently halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═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;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R6 and R7 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R8 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 R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 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;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4;
provided that the compound of Formula (I) is not 2-chloro-N-(5-2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide or 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl(benzenesulfonamide.