Substituted indanone compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders

Patent metadata

Field	Value
Publication number	US-9896434-B2
Application number	US-201515301603-A
Country	US
Kind code	B2
Filing date	Apr 2, 2015
Priority date	Apr 4, 2014
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

The present invention relates to indanone compounds. The indanone compounds are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of indanone compounds as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A compound of formula I, a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing,

wherein
R30 is (CR11′R12′) n -R32, NR17R18 or OR17;
R31 is H or (CR11′R12′) m -R32;
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
R11 R12 are independently of each other H or (C 1 -C 6 )-alkyl;
or R11 and R12 together form the group ═O;

R11′ R12′ are independently H or (C 1 -C 6 )-alkyl;
R32 is (C 1 -C 6 )-alkyl, COOR13, CONR14R15, SO 2 R16 or OH;
R13 is H or (C 1 -C 6 )-alkyl;
R14, R15 are independently H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl substituted with OR17, or (C 3 -C 6 )-cycloalkyl;
R8 is H, (C 1 -C 6 )-alkyl, hydroxyl-(C 1 -C 4 )-alkyl or (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl;
wherein at each occurrence a hydrogen atom of an alkyl group is optionally replaced by a fluorine atom.

2. The compound of claim 1 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein the 3-position of the pyrrolidinone ring has (R)-configuration.

3. The compound of claim 1 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein Z is O.

4. The compound of claim 1 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein R3 is CH 2 .

5. The compound of claim 1 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein R4 is (C 3 -C 8 )-cycloalkyl.

6. The compound of claim 1 , wherein the compound is of formula Ia, a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing,

wherein
R30 is (CR11′R12′) n -R32 or OR17;
n is 0, 1 or 2;
R16 is (C 1 -C 6 )-alkyl;
R17 is H or (C 1 -C 6 )-alkyl;
R18 is H or (C 1 -C 6 )-alkyl;
R19 is H or (C 1 -C 6 )-alkyl;
R1a, R1b, and R1c are independently H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
R2a, R2b, and R2c are independently H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
Y is N;
Z is a bond, O, CR5R5′, NR6, C═O, S, SO or SO 2 ;
R5, R5′, and R6 are independently H or (C 1 -C 4 )-alkyl;
R3 is a bond or (CR7R7′) p ;
p is 0, 1, 2, 3 or 4;
R7 and R7′ are independently H or (C 1 -C 6 )-alkyl;
R4 is (C 1 -C 6 )-alkyl, OR8, (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, or phenyl;
wherein the groups (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, or phenyl, are optionally substituted with 1 to 3 groups selected from the group consisting of (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkanoyl, hydroxy, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl, oxo, F and Cl; and

R11′ and R12′ are independently H or (C 1 -C 6 )-alkyl;
R32 is COOR13, CONR14R15, SO 2 R16 or OH;
R13 is H or (C 1 -C 6 )-alkyl;
R14 and R15 are independently H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl substituted with OR17, or (C 3 -C 6 )-cycloalkyl;
R16 is (C 1 -C 6 )-alkyl;
R17 is H or (C 1 -C 6 )-alkyl;
R18 is H or (C 1 -C 6 )-alkyl;
R19 is H or (C 1 -C 6 )-alkyl;
R1a and R1c are independently H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
R2a is H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
R3 is a bond or (CR7R7′) p ;
p is 0, 1, 2, 3 or 4;
R7 and R7′ are independently H or (C 1 -C 6 )-alkyl;
R4 is (C 1 -C 6 )-alkyl, OR8, (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, or phenyl;
wherein the groups (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, or phenyl are optionally substituted with 1 to 3 groups selected from the group consisting of (C 1 -C 4 )-alkyl, (C 1-C 4 )-alkanoyl, hydroxy, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl, oxo, F and Cl; and

R8 is H, (C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl or (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl;
wherein at each occurrence a hydrogen atom of an alkyl group is optionally replaced by a fluorine atom.

7. The compound of claim 6 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R3 is a bond, CH 2 or CH 2 —CH 2 .

8. The compound of claim 6 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R3 is a bond, CH 2 or CH 2 —CH 2 ; and
R4 is (C 3 -C 8 )-cycloalkyl.

9. The compound of claim 6 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R30 is R32;
R32 is CONR14R15 or COOR13;
R14 and R15 are independently H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl substituted with OR17;
R3 is CH 2 ; and
R4 is (C 3 -C 6 )-cycloalkyl.

10. The compound of claim 6 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R30 is R32;
R32 is CONR14R15 or COOR13;
R14 and R15 are independently H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl substituted with OR17;
R1a is H or F;
R1c is H;
R2a is H;
R3 is CH 2 ; and
R4 is (C 3 -C 6 )-cycloalkyl.

11. A compound selected from the group consisting of:
5-[(3R)-3-[[6-(Cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-N,N-dimethyl-3-oxo-indane-1-carboxamide;
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide;
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N-methyl-acetamide;
2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]-N,N-dimethyl-acetamide;
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetamide; and
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide,
or a pharmaceutically acceptable salt thereof.

12. The compound
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide
or a pharmaceutically acceptable salt thereof.

13. The compound
2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide
or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising at least one compound of claim 1 , or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

• Sanofi Sa

Inventors

• Schwink Lothar
• Buning Christian
• Glombik Heiner
• Gossel Matthias
• Kadereit Dieter
• Halland Nis
• Lohmann Matthias
• Poeverlein Christoph
• Ritter Kurt

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/402

  1-aryl substituted, e.g. piretanide · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title