US 11,752,153 B2
Substituted quinazoline sulfonamides as thioredoxin interacting protein (TXNIP) inhibitors
Corinne E. Augelli-Szafran, Homewood, AL (US); Omar Moukha-Chafiq, Birmingham, AL (US); Mark J. Suto, Homewood, AL (US); Anath Shalev, Mountain Brook, AL (US); Lance Thielen, Lenexa, KS (US); Junqin Chen, Vestavia Hills, AL (US); and Gu Jing, Vestavia Hills, AL (US)
Assigned to SOUTHERN RESEARCH INSTITUTE, Birmingham, AL (US); and THE UAB RESEARCH FOUNDATION, Birmingham, AL (US)
Filed by SOUTHERN RESEARCH INSTITUTE, Birmingham, AL (US); and THE UAB RESEARCH FOUNDATION, Birmingham, AL (US)
Filed on Nov. 3, 2022, as Appl. No. 18/52,268.
Application 18/052,268 is a continuation of application No. 17/374,100, filed on Jul. 13, 2021, granted, now 11,524,010.
Application 17/374,100 is a continuation of application No. 16/470,074, granted, now 11,103,508, issued on Aug. 31, 2021, previously published as PCT/US2018/058356, filed on Oct. 31, 2018.
Claims priority of provisional application 62/579,594, filed on Oct. 31, 2017.
Prior Publication US 2023/0172932 A1, Jun. 8, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/517 (2006.01); A61K 31/5377 (2006.01); A61P 1/16 (2006.01); A61P 3/06 (2006.01); A61P 3/10 (2006.01)
CPC A61K 31/517 (2013.01) [A61K 31/5377 (2013.01); A61P 1/16 (2018.01); A61P 3/06 (2018.01); A61P 3/10 (2018.01)] 24 Claims
 
1. A method for lowering hepatic glucose production in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula selected from:

OG Complex Work Unit Chemistry
wherein n is 0, 1, or 2;
wherein p is 0, 1, 2, 3, or 4;
wherein q is 0 or 1;
wherein R1 is —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO2H, or Cy1;
wherein Cy1, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein R2 is hydrogen or C1-C4 alkyl, or wherein each of R1 and R2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein R3 is hydrogen or C1-C4 alkyl, or wherein each of R1 and R3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein R4 is hydrogen, halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy2;
wherein Cy2, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein each of R5a, R5b, R5c, and R5d is independently hydrogen, halogen, —NH2, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO2(C1-C4 alkyl), —CO2H, —CO2NH2, —NHC(O)Cy3, —NHC(O)(C1-C4 alkyl), or Cy3;
wherein Cy3, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein A is O, NR6a, or CHRb;
wherein R6a is hydrogen or C1-C4 alkyl; and
wherein R6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO2H;
wherein R7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;
wherein each occurrence of R8a and R8b, when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO2H;
or wherein p is 1 and each of R8a and R8b together comprise ═O; and
wherein R9 is hydrogen, C1-C4 alkyl, or Cy4,
wherein Cy4, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.