Analogs of fexaramine and methods of making and using

Patent metadata

Field	Value
Publication number	US-10815203-B2
Application number	US-201916566343-A
Country	US
Kind code	B2
Filing date	Sep 10, 2019
Priority date	Mar 13, 2014
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

Abstract

Novel compounds having a formula

embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

First claim

We claim:

1. A compound, having a formula

or a pharmaceutically acceptable salt thereof, wherein
R is selected from

R a is selected from aryl, heteroaryl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;
R b is selected from hydrogen, alkyl, alkenyl, or cycloalkyl;
Y is CR g , N or N—O (N-oxide);
R c , R d , R e and R g are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;
R fa and R fb are each independently selected from hydrogen, deuterium, halide or alkyl;
L a and L b are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
L c and L d are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or (C(L c )(L d )) s -;
s is 1, 2, 3, 4, 5 or 6;
n is 0 or 1;
X is heterocyclic or heteroaryl; and

wherein
if W is CH 2 and L c and L d are both H, then X is not a benzopyran;
if R is

L c and L d are both H, and L a and L b are both H or together form a pi-bond, then X is not a benzopyran;
X is not substituted with —R x -L x -R x2 , where
R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;
L x is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)OR x6 , or C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;
R x2 is selected from —C(O)L x2 R x8 or a carboxyl bioisostere;
L x2 is a bond or NR x3 ;
R x8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —OR x9 , N(R x9 ) 2 , —C(O)R x9 , —S(O) 2 R x9 , —C(O)OR x9 , —S(O) 2 N(R x9 ) 2 or —C(O)N(R x9 ) 2 ; and
each R x9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

2. A method of treating inflammatory bowel disease in a subject, the method comprising administering to the subject an effective amount of a compound having a formula

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
R 1 is selected from aryl, heteroaryl, heterocyclic, alkenyl, cycloalkyl, cycloalkenyl or polycyclic;
R 2 is selected from alkyl, alkenyl, or cycloalkyl;
Y is selected from N, N—O or C—R 3d ;
R 3a , R 3b , R 3c and R 3d are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;
R 4a and R 4b are each independently selected from hydrogen, deuterium, halide or alkyl;
L 1 and L 2 are independently selected from hydrogen, deuterium, alkyl, cycloalkyl, or together form a pi-bond; and
R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl or nitro; or
any two adjacent groups selected together form an aryl, heteroaryl, cycloalkyl or heterocyclic ring; and

wherein
if L 1 and L 2 are both hydrogen or together form a pi-bond then
Y is N or C-halogen; or
R 1 is polycyclic; or
R 4a is D; or
R 5a is F, Cl or I; or
R 5d and R 5e together form an aryl, heteroaryl, cycloalkyl or heterocyclic ring; or
R 5b and R 5c together form an aryl, cycloalkyl, nitrogen-containing heterocyclic or nitrogen-containing heteroaryl ring; or
any combination thereof; and

none of R 5a , R 5b , R 5c , R 5d or R 5e are —R x -L x -R x2 , where
R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;
L x is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)OR x6 , or —C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;
R x2 is selected from —C(O)L x2 R x8 or a carboxyl bioisostere;
L x2 is a bond or NR x3 ;
R x8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —OR x9 , N(R x9 ) 2 , —C(O)R x9 , —S(O) 2 R x9 , —C(O)OR x9 , —S(O) 2 N(R x9 ) 2 or —C(O)N(R x9 ) 2 ; and
each R x9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

3. The method of claim 2 , wherein L 1 and L 2 together form a pi-bond.

4. The method of claim 2 , wherein R 4a is deuterium.

5. The method of claim 3 , wherein R 3d or R 5a or both are halogen.

6. The method of claim 5 , wherein R 3d or R 5a or both are F.

7. The method of claim 2 , wherein the polycyclic is selected from

or adamantane.

8. The method of claim 7 , wherein the polycyclic is

9. The method of claim 2 , wherein R 5c comprises a nitrogen-containing heteroaryl ring.

10. The method of claim 9 , wherein R 5c is selected from pyridine, pyrazole, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrimidine, pyrazine, triazine, benzopyrazole, benzimidazole, indole, quinoline, indazole, purine, quinoxaline, or acridine.

11. The method of claim 2 , wherein the compound has a formula

wherein Z is selected from N, CH, or C-alkyl;
R 6a , R 6c , R 6d and R 6g are each independently selected from H, D, halogen or alkyl; and
R 6h is selected from H, D, alkyl, cycloalkyl, aryl or heteroaryl.

12. The method of claim 11 , wherein Z is N; R 6a , R 6c , R 6d and R 6g are all H; R 6h is methyl; or a combination thereof.

13. The method of claim 2 , wherein the compound has a formula

wherein R 6a , R 6b , R 6c and R 6d are each independently selected from H, D, halogen or alkyl;
G is a lone pair of electrons, or an oxygen;
R 6e and R 6f are each independently selected from alkyl, H or cycloalkyl; and

wherein R 3d or R 5a or both are halogen; or
R 4a is D; or
R 1 is polycyclic; or
any combination thereof.

14. The method of claim 13 , wherein R 6e and R 6f are both methyl.

15. The method of claim 2 , wherein the compound is

16. The method of claim 2 , wherein the

Assignees

• Salk Inst For Biological Studi
• Univ Sydney

Inventors

• Evans Ronald M
• Downes Michael
• Atkins Annette
• Fang Sungsoon
• Suh Jae Myoung
• Baiga Thomas J
• Yu Ruth T
• Keana John F W
• Liddle Christopher

Classifications

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D231/56 Primary

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title