# US 9,751,874 B2 · Hydroxy containing FXR (NR1H4) modulating compounds

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- Number: US 9,751,874 B2
- Document ID: US9751874B2
- Status: Granted
- Kind: B2
- Application number: 14/971,875
- Filed: 2015-12-16
- Published: 2016-06-23
- Granted: 2017-09-05
- Earliest claimed: 2014-12-17
- Assignees: Gilead Sciences, Inc.
- Applicants: Gilead Sciences, Inc.
- Inventors: Christian Gege; Olaf Kinzel; Claus Kremoser; Aaron C. Schmitt
- Web page: https://patentgrep.com/patent/US9751874B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

## Claims

### Claim 1

A compound according to the following Formula (1), an enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutical acceptable salt thereof
wherein:
R is selected from the group consisting of hydrogen, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, halo-C1-6-alkyl, C0-6-alkylene-R7, C0-6-alkylene-O—R7, C0-6-alkylene-CN, C0-6-alkylene-NR7R8, O—C3-10-cycloalkyl, O—C1-6-alkylene-O—R7, O—C3-10-heterocycloalkyl, C0-6-alkylene-CO2R7, C0-6-alkylene-C(O)R7, C0-6-alkylene-C(O)NR7R8, C0-6-alkylene-C(O)NR7SO2R7, C0-6-alkylene-N(R7)C(O)R7, C0-6-alkylene-SOx—R7, C0-6-alkylene-SO3H, C0-6-alkylene-SO2—NR7R8, C0-6-alkylene-SO2—NR8COR7, C0-6-alkylene-N(R7)SO2—R8, and C0-6-alkylene-SO2—C3-10-heterocycloalkyl,
wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered heteroaryl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, CO2H, SO3H, O—C1-3-alkyl and O-halo-C1-3-alkyl;
R7 is independently selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl, C0-6-alkylene-C3-8-cycloalkyl, C0-6-alkylene-C3-8-heterocycloalkyl, 5- or 6-membered heteroaryl and phenyl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, OH, oxo, CO2H, C1-3-alkyl, halo-C1-3-alkyl, O—C1-3-alkyl, O-halo-C1-3-alkyl, SO3H and SO2—C1-3-alkyl;
R8 is independently selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl and C3-6-cycloalkyl;
or R7 and R8 when taken together with the nitrogen to which they are attached may complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
A is a 6-10 membered mono- or bicyclic aryl or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, wherein aryl and heteroaryl are unsubstituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O—C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C6-6-heterocycloalkyl and halo-C3-6-cycloalkyl;
Q is a C3-10-cycloalkyl ring, or C6-10-bridged cycloalkyl ring wherein the —O—CH2—Z-substituent is not directly adjacent to substituent A, wherein when Q is a bi- or multicyclic ring system, a carbon atom may optionally be replaced by a oxygen, SOx or NR7;
Z is selected from
wherein
L is selected from the group consisting of a bond, C1-3-alkylene and C1-3-alkylene-O—;
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C4-8-cycloalkyl and C4-8-heterocycloalkyl, wherein phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C4-8-cycloalkyl and C4-8-heterocycloalkyl are substituted with R2 and R3 and optionally substituted one or two times with a group selected from fluoro, chloro, CN, NH2, NH(C1-3-alkyl), N(C1-3-alkyl)2, C1-3-alkyl, fluoro-C1-3-alkyl, OH, C1-3-alkoxy, fluoro-C1-3-alkoxy, C3-6-cycloalkyl and fluoro-C3-6-cycloalkyl;
R1 is selected from the group consisting of C1-4-alkyl and C3-6-cycloalkyl, wherein C1-4-alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkoxy and fluoro-C1-3-alkoxy, and C3-6-cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkyl, fluoro-C1-3-alkyl, C1-3-alkoxy and fluoro-C1-3-alkoxy;
R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C1-3-alkyl, halo-C1-3-alkyl, C1-3-alkoxy, halo-C1-3-alkoxy, cyclopropyl and fluoro-cyclopropyl;
R4 is independently selected from the group consisting of halogen, C1-3-alkyl, halo-C1-3-alkyl, C1-3-alkoxy, halo-C1-3-alkoxy, C3-6-cycloalkyl, C1-3-alkylene-O—C1-3-alkyl and fluoro-C3-6-cycloalkyl;
R5 is selected from the group consisting of hydrogen, fluoro, CH3, CHF2 and CF3;
n is selected from 0, 1, 2, 3 and 4;
x is independently selected from 0, 1 and 2.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein
R is selected from the group consisting of CO2H, SO3H, CONR7R9, tetrazolyl, 1,2,4-oxadiazol-5(4H)-one-3-yl and SO2NHCOR7;
R7 selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl, and C1-6-alkylene-R9;
R8 selected from the group consisting of hydrogen, C1-6-alkyl and halo-C1-6-alkyl; and
R9 is selected from the group consisting of COOH, OH and SO3H.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein
A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl and benzimidazolyl, each unsubstituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O—C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl and halo-C3-6-cycloalkyl.

### Claim 4 (depends on 3)

The compound according to claim 3 wherein A is selected from the group consisting of phenyl, pyridyl, indolyl, indazolyl, benzisothiazolyl, triazolopyridinyl, benzothiazolyl, thiazolyl, oxazolyl and quinolyl, each unsubstituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O—C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl and halo-C3-6-cycloalkyl.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein R-A is selected from

### Claim 6 (depends on 1)

The compound according to claim 1 wherein Z is selected from the group consisting of:
wherein
L is selected from the group consisting of a bond, C1-3-alkylene and C1-3-alkylene-O—;
X is selected from the group consisting of CH, CF, N and NO;
R1 is selected from the group consisting of C1-4-alkyl and C3-6-cycloalkyl, wherein C1-4-alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkoxy and fluoro-C1-3-alkoxy, and C3-6-cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkyl, fluoro-C1-3-alkyl, C1-3-alkoxy and fluoro-C1-3-alkoxy;
R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C1-3-alkyl, halo-C1-3-alkyl, C1-3-alkoxy, halo-C1-3-alkoxy, cyclopropyl and fluoro-cyclopropyl; and
R5 is selected from the group consisting of hydrogen, fluoro, CH3, CHF2 and CF3.

### Claim 7 (depends on 1)

The compound according to claim 1 wherein Z is selected from
wherein
X is selected from the group consisting of CH, CF, N and NO;
R1 is selected from the group consisting of methyl, CF3, CHF2, isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted or substituted with one or two fluoro or one hydroxy;
R2 is selected from the group consisting of fluoro, chloro, CH3, CHF2, CF3, OCHF2 and OCF3;
R3 is selected from the group consisting of hydrogen, fluoro, chloro, CH3, CHF2, CF3, OCHF2 and OCF3; and
R5 is selected from the group consisting of hydrogen, fluoro, CH3, CHF2 and CF3.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein
is selected from
each optionally substituted with R4.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the compound is according to Formula (2)
wherein
A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl and benzimidazolyl, each unsubstituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O—C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl and halo-C3-6-cycloalkyl;
R is selected from the group consisting of CO2H, SO3H, CONR7R5, tetrazolyl, 1,2,4-oxadiazol-5(4H)-one-3-yl and SO2NHCOR7, wherein
R7 selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl, and C1-6-alkylene-R9;
R8 selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl; and
R9 is selected from the group consisting of COOH, OH and SO3H;
Z is selected from
X is selected from the group consisting of CH, N and NO;
R1 is selected from the group consisting of methyl, isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted or substituted with one or two fluoro or one hydroxy;
R2 is selected from the group consisting of fluoro, chloro, CH3, CHF2, CF3, OCHF2 and OCF3; and
R3 is selected from the group consisting of hydrogen, fluoro, chloro, CH3, CHF2, CF3, OCHF2 and OCF3.

### Claim 10

A compound selected from the group consisting of:
or an enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutical acceptable salt thereof.

### Claim 11 (depends on 1)

A method of treating a patient having an FXR mediated condition, the method comprising administering a compound of claim 1 to a patient in need thereof, wherein the FXR mediated condition is selected from chronic intrahepatic or some forms of extrahepatic cholestatic conditions;
liver fibrosis;
obstructive or chronic inflammatory disorders of the liver;
liver cirrhosis;
liver steatosis and associated syndromes, cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-borne forms of hepatitis;
liver failure or liver ischemia after major liver resection;
chemotherapy associated steatohepatitis (CASH);
acute liver failure; and
Inflammatory Bowel Diseases.

### Claim 12 (depends on 1)

A method of treating a patient having an FXR mediated condition, the method comprising administering a compound of claim 1 to a patient in need thereof, wherein the FXR mediated condition is selected from the group consisting of:
Type II Diabetes and clinical complications of Type I and Type II Diabetes, selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifest long term Diabetes;
Non-Alcoholic Fatty Liver Disease (NAFLD), or Non-Alcoholic Steatohepatitis (NASH);
obesity or metabolic syndrome (combined conditions of dyslipidemia, diabetes or abnormally high body-mass index); and
acute myocardial infarction, acute stroke or thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis.