Substituted quinazoline sulfonamides as thioredoxin interacting protein (TXNIP) inhibitors

Patent metadata

Field	Value
Publication number	US-11752153-B2
Application number	US-202218052268-A
Country	US
Kind code	B2
Filing date	Nov 3, 2022
Priority date	Oct 31, 2017
Publication date	Sep 12, 2023
Grant date	Sep 12, 2023

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. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

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:

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 b ;
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 formula:

3. The method of claim 2 , 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 1 ; 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.

4. The method of claim 2 , wherein n equals 1.

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

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

7. The method of claim 5 , 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.

8. The method of claim 5 , 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 .

9. A method for treating hyperlipidemia 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:

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,

Assignees

• Southern Res Inst
• Uab Res Found

Inventors

• Augelli-Szafran Corinne E
• Moukha-Chafiq Omar
• Suto Mark J
• Shalev Anath
• Thielen Lance
• Chen Junqin
• Jing Gu

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/517 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title