# US 12,600,716 B2 · Compounds for modulating activity of FXR and uses thereof

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- Number: US 12,600,716 B2
- Document ID: US12600716B2
- Status: Granted
- Kind: B2
- Application number: 17/756,789
- Filed: 2020-10-12
- Published: 2022-12-08
- Granted: 2026-04-14
- Earliest claimed: 2020-10-12
- Assignees: Gannex Pharma Co., Ltd.
- Applicants: Gannex Pharma Co., Ltd.
- Inventors: Bailing Yang; Gudmundsson Kristjan; Liuyu Dong; James Chen
- Web page: https://patentgrep.com/patent/US12600716B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K 31/42: Oxazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 31/20: for DNA viruses
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are a compound for modulating the activity of FXR having a structure of formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof.

## Claims

### Claim 1

A compound for modulating the activity of FXR having a structure of formula (I), or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof:
wherein:
R1, R2 and R3 are independently selected from H, halogen, unsubstituted or halogen substituted C1-6 alkyl and unsubstituted or halogen substituted C1-6 alkoxy, provided that at least one of R1, R2 and R3 is not hydrogen, R0 is selected from unsubstituted or halogen substituted C1-6 alkyl, C3-6 cycloalkyl and C4-7 alkylcycloalkyl;
X1 and X2 are independently selected from H and halogen;
moiety —O—Z attaches to the naphthalene ring, wherein Z is a residue selected from 5-10 membered aryl and 5-10 membered heteroaryl optionally having one or more hetero atoms selected from N, O and S, wherein the 5-10 membered aryl or 5-10 membered heteroaryl is substituted by R4 and is optionally further substituted by R5;
wherein R4 is selected from —COOH, —CH2COOH, —NHSO2CF3, —SO2NH—C1-6 alkyl, —SO3H, —CONHSO2—C1-6 alkyl, —CONHSO2—C3-6 cycloalkyl, —CONHSO2-5-10 membered aryl and —CONHSO2-5-10 membered aryl substituted by C1-6 alkyl at the aryl, and wherein R5 is selected from H, C1-6 alkyl, halogen, C1-6 haloalkyl, —O—(C1-6 alkyl) and —NH—(C1-6 alkyl).

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R1, R2 and R3 are independently selected from H, halogen and C1-3 perfluoroalkoxy, and R0 is selected from isopropyl and cyclopropyl.

### Claim 3 (depends on 2)

The compound according to claim 2, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R1, R2 and R3 are independently selected from H, Cl, F and —O—CF3.

### Claim 4 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein both of R1 and R2 are Cl, and R3 is selected from H, F and —O—CH3; or R1 is —O—CF3, and both of R2 and R3 are H.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein Z is a phenyl which is substituted by R4 and is optionally substituted by R5; or Z is a 5-10 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R4 and is optionally substituted by R5.

### Claim 6 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein Z is a 5-6 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R4 and is optionally substituted by R5.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein Z is a pyridyl, which is substituted by R4 and is optionally substituted by R5.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R4 is selected from —COOH, —CH2COOH, —CONHSO2—C1-6 alkyl and —CONHSO2-C3-6 cycloalkyl.

### Claim 9 (depends on 8)

The compound according to claim 8, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R4 is —COOH or —CH2COOH.

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R5 is selected from H, C1-3 alkyl and halogen.

### Claim 11 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein Z is pyridyl; R4 is —COOH; and R5 is H or halogen.

### Claim 12 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein each halogen present in the compound is fluoro or chloro.

### Claim 13 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and a pharmaceutically acceptable auxiliary material.

### Claim 15 (depends on 14)

The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition further comprises a second therapeutic agent for the treatment of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), cholestasis liver tree, chronic liver disease, hepatitis C infection, alcoholic liver disease, hepatic fibrosis, primary sclerosing cholangitis (PSC), gallstones, bile duct atresia, lower urinary tract symptoms and benign prostatic hyperplasia (BPH), ureteral calculi, obesity, type 2 diabetes, atherosclerosis, atherosclerosis, or liver damage caused by hypercholesterolemia or hyperlipidemia.

### Claim 16 (depends on 1)

A method for treating a condition or disease mediated by FXR in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof.

### Claim 17 (depends on 16)

The method according to claim 16, further comprising administering a second therapeutic agent.

### Claim 18 (depends on 16)

The method according to claim 16, wherein the condition or the disease is selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), cholestasis liver tree, chronic liver disease, hepatitis C infection, alcoholic liver disease, hepatic fibrosis, primary sclerosing cholangitis (PSC), gallstones, bile duct atresia, lower urinary tract symptoms and benign prostatic hyperplasia (BPH), ureteral calculi, obesity, type 2 diabetes, atherosclerosis, atherosclerosis, and liver damage caused by hypercholesterolemia or hyperlipidemia.

### Claim 19 (depends on 9)

The compound according to claim 9, or a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein R4 is —COOH.