IP Library › Granted Patent US 11,103,508

Granted Patent B2

US 11,103,508 · App. 16/470,074 · Granted Aug 31, 2021

Substituted quinazoline sulfonamides as thioredoxin interacting protein (TXNIP) inhibitors

Inventors: Corinne E. Augelli-Szafran (Homewood, AL); Omar Moukha-Chafiq (Birmingham, AL); Mark J. Suto (Homewood, AL); Anath Shalev (Mountain Brook, AL); Lance Thielen (Lenexa, KS); Junqin Chen (Vestavia Hills, AL); Gu Jing (Vestavia Hills, AL)

Assignees: SOUTHERN RESEARCH INSTITUTE; THE UAB RESEARCH FOUNDATION

A61K31/517 A61K31/5377 A61P1/16 A61P3/06 A61P3/10

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,103,508
App. No.: 16/470,074
Granted: Aug 31, 2021
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

In one aspect, compounds and compositions that inhibit TXNIP expression and/or that lower hepatic glucose production and methods of identifying, making, and using same are disclosed. The disclosed compounds and compositions can be useful for disorders associated with elevated TXNIP and/or elevated glucagon levels such as, for example, diabetes and associated disorders. Further provided are methods for treating hyperlipidemia or fatty liver disease, optionally associated with elevated TXNIP and/or elevated glucagon levels.

Claims (194)

1. A method for treating diabetes or a diabetes related disorder associated with elevated TXNIP or elevated glucagon in a mammal, the method comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula selected from:

wherein n is 0, 1, or 2;

wherein p is 0, 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 1 is —NH 2 , —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)CO 2 H, or Cy 1 ;

wherein Cy 1 , 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, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein R 2 is hydrogen or C1-C4 alkyl, or wherein each of R 1 and R 2 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, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein R 3 is hydrogen or C1-C4 alkyl, or wherein each of R 1 and R 3 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, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein Cy 2 , 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, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ;

wherein Cy 3 , 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, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl; and

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O; and

wherein R 9 is hydrogen, C1-C4 alkyl, or Cy 4 ,

wherein Cy 4 , 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, —NH 2 , —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.

2. The method of claim 1 , wherein the compound has a structure represented by a formula:

3. The method of claim 2 , wherein p is 0 or 1; R 1 is —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 8a is hydrogen and R 8b is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

4. The method of claim 1 , wherein the compound has a structure represented by a formula selected from:

5. The method of claim 1 , wherein p is 1.

6. A method for inhibiting TXNIP expression or lowering glucagon levels in a mammal, the method comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula selected from:

wherein n is 0, 1, or 2;

wherein p is 0, 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl; and

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O; and

wherein R 9 is hydrogen, C1-C4 alkyl, or Cy 4 ,

or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 , wherein the compound has a structure represented by a formula:

8. The method of claim 7 , wherein p is 0 or 1; R 1 is —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 8a is hydrogen and R 8b is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

9. The method of claim 6 , wherein the compound has a structure represented by a formula selected from:

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein n is 0, 1, or 2;

wherein p is 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl; and

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O; and

wherein R 9 is hydrogen, C1-C4 alkyl, or Cy 4 ,

or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 10 , wherein p is 1; R 1 is —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 8a is hydrogen and R 8b is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

12. The pharmaceutical composition of claim 10 , wherein n is 1.

13. The pharmaceutical composition of claim 10 , wherein R 5c is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

14. The pharmaceutical composition of claim 10 , wherein Cy 3 , when present, is C3-C6 cycloalkyl or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein n is 0, 1, or 2;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein each of R 5a , R 5b , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ;

wherein R 5c is hydrogen, halogen, —NH 2 , —OH, —CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl;

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H; and

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

provided that when R 5b is morpholinyl and R 1 is thiophenyl or thiazolyl, then q is 1 and at least one of R 5a , R 5c , and R 5d is not hydrogen,

or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 15 , wherein R 1 is —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 5c is hydrogen, halogen, —NH 2 , —OH, —CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

17. The pharmaceutical composition of claim 15 , wherein n is 1.

18. The pharmaceutical composition of claim 15 , wherein R 5c is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

19. The pharmaceutical composition of claim 15 , wherein each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula selected from:

wherein n is 0, 1, or 2;

wherein p is 0, 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl; and

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O; and

wherein R 9 is hydrogen, C1-C4 alkyl, or Cy 4 ,

or a pharmaceutically acceptable salt thereof.

21. A compound having a structure represented by a formula:

wherein n is 0, 1, or 2;

wherein p is 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 1 is —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)CO 2 H, or Cy 1 ;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl;

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; and

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O;

provided that when R 1 is methyl and each of R 3 and R 4 is hydrogen then each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, fluorine, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 3 , and

provided that when n is 1, p is 1, q is 0, A is CHR 6b , and R 1 is methyl, then at least two of R 4 , R 5a , R 5b , R 5c , and R 5d are not hydrogen, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , wherein p is 1; R 1 is —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 8a is hydrogen and R 8b is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

23. The compound of claim 21 , wherein R 5c is fluorine.

24. The compound of claim 21 , wherein R 1 is methyl, each of R 3 and R 4 is hydrogen, and each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 3 .

25. The compound of claim 21 , wherein R 1 is methyl, each of R 3 and R 4 is hydrogen, and R 5b is fluorine.

26. The compound of claim 21 , wherein R 5c is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

27. The compound of claim 21 , wherein Cy 3 , when present, is C3-C6 cycloalkyl or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

28. A compound having a structure represented by a formula:

wherein n is 0, 1, or 2;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein R 5c is hydrogen, halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl;

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H; and

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

provided that when R 5b is morpholinyl and R 1 is thiophenyl or thiazolyl, then q is 1 and at least one of R 5a , R 5c , and R 5d is not hydrogen;

provided that when q is 0 then Cy 1 is not aryl; and

provided that at least one of R 5a , R 5b , R 5c , and R 5d is not hydrogen,

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 28 , wherein R 1 is —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , and R 5d is independently hydrogen, halogen, —NH 2 , —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 5c is hydrogen, halogen, —NH 2 , —OH, —CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO 2 (C1-C4 alkyl), —CO 2 H, —CO 2 NH 2 , —NHC(O)Cy 3 , —NHC(O)(C1-C4 alkyl), or aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

30. The compound of claim 28 , wherein n is 1.

31. The compound of claim 28 , wherein R 5c is hydrogen, halogen, —NH 2 , —OH, —C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

32. The compound of claim 28 , wherein each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.

33. A compound having a structure represented by a formula selected from:

wherein n is 0, 1, or 2;

wherein p is 0, 1, 2, 3, or 4;

wherein q is 0 or 1;

wherein R 4 is hydrogen, halogen, —NH 2 , —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 ;

wherein A is O, NR 6a , or CHR 6b ;

wherein R 6a is hydrogen or C1-C4 alkyl; and

wherein R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO 2 H;

wherein R 7 is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;

wherein each occurrence of R 8a and R 8b , when present, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO 2 H;

or wherein p is 1 and each of R 8a and R 8b together comprise ═O; and

wherein R 9 is hydrogen, C1-C4 alkyl, or Cy 4 ,

or a pharmaceutically acceptable salt thereof.

34. A method for treating diabetes or a diabetes related disorder associated with elevated TXNIP or elevated glucagon in a mammal, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 10 .

35. A method of lowering hepatic glucose production in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at a pharmaceutical composition of claim 10 .

36. The method of claim 35 , wherein the mammal has diabetes or a diabetes related disorder.

37. A method for treating hyperlipidemia in a mammal, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 10 .

38. A method for treating fatty liver disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 10 .

39. The method of claim 38 , wherein the fatty liver disease is nonalcoholic fatty liver disease.

Assignments (4)

CONFIRMATORY LICENSE Recorded Aug 11, 2023

From: UNIVERSITY OF ALABAMA AT BIRMINGHAM

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 064572/0224 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 12, 2020

From: SHALEV, ANATH; THIELEN, LANCE; CHEN, JUNQIN; JING, GU

To: THE UAB RESEARCH FOUNDATION

Reel/Frame 052925/0456 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 12, 2020

From: AUGELLI-SZAFRAN, CORINNE E.; MOUKHA-CHAFIQ, OMAR; SUTO, MARK J.