ANALOGS OF FEXARAMINE AND METHODS OF MAKING AND USING

摘要

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.

主权项

1. A compound, having a formulaor a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
R1 is selected from aryl, heteroaryl, heterocyclic, alkenyl, cycloalkyl, cycloalkenyl or polycyclic; R2 is selected from alkyl, alkenyl, or cycloalkyl; Y is selected from N, N—O or C—R3d; R3a, R3b, R3c and R3d are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro; R4a and R4b are each independently selected from hydrogen, deuterium, halide or alkyl; L1 and L2 are independently selected from hydrogen, deuterium, alkyl, cycloalkyl, or together form a pi-bond; and R5a, R5b, R5c, R5d and R5e 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; andwherein
none of R5a, R5b, R5c, R5d or R5e are —Rx-Lx-Rx2, where
Rx is selected from O, NRx3, sulfonyl or S;Rx3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;Lx is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CRx4Rx5;Rx4 and Rx5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)ORx6, or C(O)NRx6Rx7;Rx6 and Rx7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;Rx2 is selected from —C(O)Lx2Rx8 or a carboxyl bioisostere;Lx2 is a bond or NRx3;Rx8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —ORx9, N(Rx9)2, —C(O)Rx9, —S(O)2Rx9, —C(O)ORx9, —S(O)2N(Rx9)2 or —C(O)N(Rx9)2; andeach Rx9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl; andif L1 and L2 are both hydrogen or together form a pi-bond then
Y is N or C-halogen; orR1 is polycyclic; orR4a is D; orR5a is F, Cl or I; orR5d and R5e together form an aryl, heteroaryl, cycloalkyl or heterocyclic ring; orR5b and R5e together form an aryl, cycloalkyl, nitrogen-containing heterocyclic or nitrogen-containing heteroaryl ring; orany combination thereof.