# US 11,440,889 B2 · Analogs of fexaramine and methods of making and using

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- Number: US 11,440,889 B2
- Document ID: US11440889B2
- Status: Granted
- Kind: B2
- Application number: 17/008,866
- Filed: 2020-09-01
- Published: 2021-05-20
- Granted: 2022-09-13
- Earliest claimed: 2014-03-13
- Assignees: The Salk Institute for Biological Studies; The University of Sydney
- Applicants: Salk Institute for Biological Studies; The University of Sydney
- Inventors: Ronald M. Evans; Michael Downes; Annette Atkins; Sungsoon Fang; Jae Myoung Suh; Thomas J. Baiga; Ruth T. Yu; John F. W. Keana; Christopher Liddle
- Web page: https://patentgrep.com/patent/US11440889B2

## CPC

- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07B 59/002: {Heterocyclic compounds}
- C07C 233/63: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C 2601/14: The ring being saturated
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## 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.

## Claims

### Claim 1

A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to a formula
or a pharmaceutically acceptable salt thereof, wherein
R is selected from
Ra is selected from aryl, heteroaryl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;
Rb is selected from hydrogen, alkyl, alkenyl, or cycloalkyl;
Y is CRg, N or N—O (N-oxide);
Rc, Rd, Re and Rg are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;
Rfa and Rfb are each independently selected from hydrogen, deuterium, halide or alkyl;
La and Lb are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
Lc and Ld are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or —(C(Lc)(Ld))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 CH2 and Lc and Ld are both H, then X is not a benzopyran;
if R is
Lc and Ld are both H, and La and Lb are both H or together form a pi-bond, then X is not a benzopyran;
X is not substituted with —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; and
each Rx9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the polycyclic is selected from
or adamantane.

### Claim 3 (depends on 1)

The method of claim 1, wherein R is selected from

### Claim 4 (depends on 3)

The method of claim 3, wherein La and Lb together form a pi-bond.

### Claim 5 (depends on 1)

The method of claim 1, where the compound has a formula

### Claim 6 (depends on 1)

The method of claim 1, wherein X is pyridine or piperidine.

### Claim 7 (depends on 1)

The method of claim 1, wherein Rfa is deuterium.

### Claim 8 (depends on 5)

The method of claim 5, wherein:
the polycyclic is selected from
or adamantane;
X is pyridine or piperidine; and
Rfa is deuterium.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disorder or disease is selected from a metabolic disorder, inflammation in an intestinal region, a cell proliferation disease, alcoholic liver disease, non-alcoholic liver disease, a cholestatic disorder, an intestinal permeability disorder, a disease that causes or results from an altered intestinal microbiome, an inborn error of metabolism, a bile disorder, or an intestinal malabsorption disorder.

### Claim 10 (depends on 1)

The method of claim 1, wherein the disorder or disease is selected from obesity, diabetes, insulin resistance, dyslipidemia, necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, colon cancer, post-surgical inflammation, gastric carcinogenesis, fatty liver (steatosis), cirrhosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholestasis resulting from a drug, overlap syndrome (PBC plus autoimmune hepatitis), drug-induced cholestatic hepatitis, total parenteral nutrition (TPN)-induced cholestasis, ICU/sepsis-related cholestasis, obstetric cholestasis, graft vs. host disease, prolonged cholestasis due to hepatitis A, B or C infection, cholestasis due to cystic fibrosis, alcoholic hepatitis, progressive familial intrahepatic cholestasis (PFIC) syndromes, Alagille syndrome, biliary atresia, infectious colitis, type 1 diabetes, an intestinal permeability condition, an intestinal inflammation disorder, intestinal lesions, cirrhosis, cerebrotendinous xanthomatosis (CTX), benign biliary stricture, malignant biliary obstruction, bile acid diarrhea, short bowel syndrome, tropical sprue, environmental enteropathy, or volvulus.

### Claim 11

A compound having a formula
or a pharmaceutically acceptable salt thereof, wherein:
Y is CRg, N or N—O (N-oxide);
R is selected from
Ra is selected from aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;
Rb is selected from alkyl, alkenyl, or cycloalkyl;
Rc, Rd, Re and Rg are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, cycloalkyl, heterocyclic, acyl, hydroxyl or nitro;
Rfa and Rfb are each independently selected from hydrogen, deuterium, halide or alkyl;
X is aryl, heterocyclic or heteroaryl;
La and Lb are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
Lc and Ld are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or —(C(Lc)(Ld))s-;
s is 1, 2, 3, 4, 5 or 6;
n is 0 or 1; and
wherein X is not substituted with —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; and
each Rx9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

### Claim 12 (depends on 11)

The compound of claim 11, having a formula
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from aryl, heteroaryl, heterocyclic, alkyl, alkenyl, cycloalkyl, cycloalkenyl or polycyclic;
Y is selected from N, N—O (N-oxide) 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;
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; and
none of R5a, R5b, R5c, R5d or R5e is —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; and
each Rx9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R4a is deuterium.

### Claim 14 (depends on 12)

The compound of claim 12, wherein R is
and La and Lb together form a pi-bond.

### Claim 15 (depends on 11)

A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 16

A compound having a formula
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from
La and Lb are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
Lc and Ld are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or —(C(Lc)(Ld))s-;
s is 1, 2, 3, 4, 5 or 6;
n is 0 or 1;
Rb is selected from alkyl, alkenyl, or cycloalkyl;
Y is CRg, N or N—O (N-oxide);
Rc, Re and Rg are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, cycloalkyl, heterocyclic, acyl, hydroxyl or nitro;
Rfa and Rfb are each independently selected from hydrogen, deuterium, halide or alkyl;
Rh and Rj are each independently selected from hydrogen, deuterium, halide, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl or heteroaryl;
X is aryl, heterocyclic or heteroaryl; and
X is not substituted with —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; and
each Rx9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

### Claim 17 (depends on 16)

The compound of claim 16, wherein Rfa is deuterium.

### Claim 18 (depends on 16)

The compound of claim 16, wherein R is
and La and Lb together form a pi-bond.

### Claim 19 (depends on 16)

The compound of claim 16, wherein X is a phenyl substituted with an aryl or heteroaryl group.

### Claim 20 (depends on 16)

A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 16.