Hydroxy containing FXR (NR1H4) modulating compounds

Patent metadata

Field	Value
Publication number	US-9751874-B2
Application number	US-201514971875-A
Country	US
Kind code	B2
Filing date	Dec 16, 2015
Priority date	Dec 17, 2014
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

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.

First claim

The invention claimed is:

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, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, halo-C 1-6 -alkyl, C 0-6 -alkylene-R 7 , C 0-6 -alkylene-O—R 7 , C 0-6 -alkylene-CN, C 0-6 -alkylene-NR 7 R 8 , O—C 3-10 -cycloalkyl, O—C 1-6 -alkylene-O—R 7 , O—C 3-10 -heterocycloalkyl, C 0-6 -alkylene-CO 2 R 7 , C 0-6 -alkylene-C(O)R 7 , C 0-6 -alkylene-C(O)NR 7 R 8 , C 0-6 -alkylene-C(O)NR 7 SO 2 R 7 , C 0-6 -alkylene-N(R 7 )C(O)R 7 , C 0-6 -alkylene-SO x —R 7 , C 0-6 -alkylene-SO 3 H, C 0-6 -alkylene-SO 2 —NR 7 R 8 , C 0-6 -alkylene-SO 2 —NR 8 COR 7 , C 0-6 -alkylene-N(R 7 )SO 2 —R 8 , and C 0-6 -alkylene-SO 2 —C 3-10 -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, C 1-3 -alkyl, halo-C 1-3 -alkyl, OH, oxo, CO 2 H, SO 3 H, O—C 1-3 -alkyl and O-halo-C 1-3 -alkyl;

R 7 is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 0-6 -alkylene-C 3-8 -cycloalkyl, C 0-6 -alkylene-C 3-8 -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, CO 2 H, C 1-3 -alkyl, halo-C 1-3 -alkyl, O—C 1-3 -alkyl, O-halo-C 1-3 -alkyl, SO 3 H and SO 2 —C 1-3 -alkyl;
R 8 is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl and C 3-6 -cycloalkyl;
or R 7 and R 8 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, C 1-4 -alkyl and halo-C 1-4 -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—C 1-6 -alkyl, O-halo-C 1-6 -alkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-6 -cycloalkyl, C 6-6 -heterocycloalkyl and halo-C 3-6 -cycloalkyl;
Q is a C 3-10 -cycloalkyl ring, or C 6-10 -bridged cycloalkyl ring wherein the —O—CH 2 —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, SO x or NR 7 ;
Z is selected from

wherein
L is selected from the group consisting of a bond, C 1-3 -alkylene and C 1-3 -alkylene-O—;
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C 4-8 -cycloalkyl and C 4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C 4-8 -cycloalkyl and C 4-8 -heterocycloalkyl are substituted with R 2 and R 3 and optionally substituted one or two times with a group selected from fluoro, chloro, CN, NH 2 , NH(C 1-3 -alkyl), N(C 1-3 -alkyl) 2 , C 1-3 -alkyl, fluoro-C 1-3 -alkyl, OH, C 1-3 -alkoxy, fluoro-C 1-3 -alkoxy, C 3-6 -cycloalkyl and fluoro-C 3-6 -cycloalkyl;
R 1 is selected from the group consisting of C 1-4 -alkyl and C 3-6 -cycloalkyl, wherein C 1-4 -alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C 1-3 -alkoxy and fluoro-C 1-3 -alkoxy, and C 3-6 -cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C 1-3 -alkyl, fluoro-C 1-3 -alkyl, C 1-3 -alkoxy and fluoro-C 1-3 -alkoxy;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halo-C 1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl;
R 4 is independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, C 1-3 -alkoxy, halo-C 1-3 -alkoxy, C 3-6 -cycloalkyl, C 1-3 -alkylene-O—C 1-3 -alkyl and fluoro-C 3-6 -cycloalkyl;
R 5 is selected from the group consisting of hydrogen, fluoro, CH 3 , CHF 2 and CF 3 ;
n is selected from 0, 1, 2, 3 and 4;
x is independently selected from 0, 1 and 2.

2. The compound according to claim 1 wherein
R is selected from the group consisting of CO 2 H, SO 3 H, CONR 7 R 9 , tetrazolyl, 1,2,4-oxadiazol-5(4H)-one-3-yl and SO 2 NHCOR 7 ;
R 7 selected from the group consisting of hydrogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, and C 1-6 -alkylene-R 9 ;
R 8 selected from the group consisting of hydrogen, C 1-6 -alkyl and halo-C 1-6 -alkyl; and
R 9 is selected from the group consisting of COOH, OH and SO 3 H.

3. 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—C 1-6 -alkyl, O-halo-C 1-6 -alkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-6 -cycloalkyl and halo-C 3-6 -cycloalkyl.

4. 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—C 1-6 -alkyl, O-halo-C 1-6 -alkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-6 -cycloalkyl and halo-C 3-6 -cycloalkyl.

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

6. 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, C 1-3 -alkylene and C 1-3 -alkylene-O—;
X is selected from the group consisting of CH, CF, N and NO;
R 1 is selected from the group consisting of C 1-4 -alkyl and C 3-6 -cycloalkyl, wherein C 1-4 -alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C 1-3 -alkoxy and fluoro-C 1-3 -alkoxy, and C 3-6 -cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C 1-3 -alkyl, fluoro-C 1-3 -alkyl, C 1-3 -alkoxy and fluoro-C 1-3 -alkoxy;
R 2 and R 3 ar

Assignees

• Gilead Sciences Inc

Inventors

• Gege Christian
• Kinzel Olaf
• Kremoser Claus
• Schmitt Aaron C

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title