AMINE OR (THIO)AMIDE CONTAINING LXR MODULATORS

• US 20200131144A1
• Filed: 07/18/2018
• Published: 04/30/2020
• Est. Priority Date: 07/18/2017
• Status: Abandoned Application

• Current Assignee: Phenex-FXR GmbH
• Original Assignee: Phenex-FXR GmbH
• Inventors: Gege, Christian, Birkel, Manfred, Hambruch, Eva, Deuschle, Ulrich, Kremoser, Claus
• Application Number:
  US16/605,649
• Publication Number:
  US 20200131144A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: C07C 233/87 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07D 207/335 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/82 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to derivatives of formula (I) which bind to the liver X receptor (LXRα and/or LXRβ) and act preferably as inverse agonists of LXR.

Claims

1. A compound represented by Formula (I)

2. The compound according to claim 1 wherein

R¹, R², R³ and R⁴ are independently selected from H or Me;

R⁵ and R⁶ are independently selected from H or Me or R⁵ and R⁶ together are oxo;

m and p is 1.

3. The compound according to claim 1 wherein

4. The compound according to claim 1 wherein

5. The compound according to claim 1 wherein

6. The compound according to claim 1 wherein

7. The compound according to claim 1 wherein

X is selected from a bond, C_0-6-alkylene-S(═

O)_n—

, C_0-6-alkylene-S(═

NR¹¹)(═

O)—

, C_0-6-alkylene-S(═

NR¹¹)—

, C_0-6-alkylene-O—

, C_0-6-alkylene-NR⁹¹—

, C_0-6-alkylene-S(═

O)₂NR⁹¹—

, C_0-6-alkylene-S(═

NR¹¹)(═

O)—

NR⁹¹— and

C_0-6-alkylene-S(═

NR¹¹)—

NR⁹¹—

;

Y is selected from C_1-6-alkylene, C_2-6-alkenylene, C_2-6-alkinylene, 3- to 8-membered cycloalkylene, 3- to 8-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein alkylene, alkenylene, alkinylene, cycloalkylene or heterocycloalkylene is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, C_1-4-alkyl, halo-C_1-4-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, O—

C_1-4-alkyl, O-halo-C_1-4-alkyl, NH₂, NH(C_1-4-alkyl), N(C_1-4-alkyl)₂, NH(halo-C_1-4-alkyl) and N(halo-C_1-4-alkyl)₂;

Z is selected from —

CO₂H, —

CONHO—

C_1-4-alkyl, —

CON(C_1-4-alkyl)OH, —

CONHOH, —

CONHSO₂—

C_1-4-alkyl, —

CONHSO₂—

N(C_1-4-alkyl)₂,

8. The compound according to claim 1 wherein

X is selected from a bond, O and S(═

O)₂;

Y is selected from C_1-3-alkylene, 3- to 6-membered cycloalkylene and 3- to 6-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein alkylene, cycloalkylene or heterocycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from fluoro, CN, C_1-4-alkyl, halo-C_1-4-alkyl, OH, NH₂, oxo, O—

C_1-4-alkyl and O-halo-C_1-4-alkyl; and

Z is selected from —

CO₂H, —

CONHO—

C_1-4-alkyl, —

CON(C_1-4-alkyl)OH, —

CONHOH, —

CONHSO₂—

C_1-4-alkyl, —

CONHSO₂—

N(C_1-4-alkyl)₂,

9. The compound according to claim 1 wherein

10. The compound according to claim 1 wherein

11. The compound according to claim 1 wherein

12. The compound according to claim 1 selected from

14. A method for the prophylaxis and/or treatment of diseases mediated by LXRs, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

15. The method according to claim 14 wherein the disease is selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long-term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

13. (canceled)