Substituted fused heterocycles as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders

Patent metadata

Field	Value
Publication number	US-9758520-B2
Application number	US-201615284213-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Apr 4, 2014
Publication date	Sep 12, 2017
Grant date	Sep 12, 2017

Abstract

The present invention relates to substituted fused heterocyclic compounds.
The substituted fused heterocyclic 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 substituted fused heterocyclic 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
A is N or C;
B is CO, N or CH;
E is N or C;
G is N or CR30;
wherein at least one of the groups A, B, E and G is N;

R30 is H or (CR11R12) n -R32;
R11 and R12 are independently H or (C 1 -C 6 )-alkyl;
n is 0, 1, 2 or 3;
R32 is (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, 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;
or R14 and R15, together with the N-atom to which they are attached, form a 4-, 5- or 6-membered heterocycle, optionally containing an additional ring member selected from the group consisting of 0, S and NR18;
wherein the 4-, 5- or 6-membered heterocycle may be is optionally substituted with 1 to 3 groups selected from the group consisting of (C 1 -C 4 )-alkyl and OR17;

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;
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 or CH;
Z is a bond, 0, 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, 4-, 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl ring;
wherein the groups (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, 4-, 5- or 6-membered heterocycle, phenyl, 5- or 6-membered heteroaryl ring 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.

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 Y is N.

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

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

6. 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.

7. 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
A is N or C;
B is CO, N or CH;
E is N or C;
G is N or CR30;
wherein at least one of the groups A, B, E and G is N;

R30 is H or (CR11R12) n -R32;
R11 and R12 are independently H or (C 1 -C 6 )-alkyl;
n is 0, 1, 2 or 3;
R32 is (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, 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;
or R14 and R15, together with the N-atom to which they are attached, form a 4-, 5- or 6-membered heterocycle, optionally containing an additional ring member selected from the group consisting of O, S and NR18;
wherein the 4-, 5- or 6-membered heterocycle is optionally substituted with 1 to 3 groups selected from the group consisting of (C 1 -C 4 )-alkyl and OR17;

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;
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, 4-, 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl ring;
wherein the groups (C 3 -C 8 )-cycloalkyl, (C 5 -C 8 )-bicycloalkyl, 4-, 5- or 6-membered heterocycle, phenyl, 5- or 6-membered heteroaryl ring 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.

8. The compound of claim 7 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R30 is (CR11R12) n -R32;
n is 0, 1 or 2;
R32 is (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, COOR13, CONR14R15 or OH;
R3 is CH 2 ; and
R4 is (C 3 -C 8 )-cycloalkyl which may be optionally substituted with 1 to 3 groups selected from the group consisting of (C 1 -C 4 )-alkyl and F;
wherein at each occurrence a hydrogen atom of an alkyl group is optionally replaced by a fluorine atom.

9. The compound of claim 7 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R30 is (CR11R12) n -R32;
n is 0, 1 or 2;
R32 is (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, COOR13, CONR14R15 or OH;
R3 is CH 2 ; and
R4 (C 3 -C 8 )-cycloalkyl;
wherein at each occurrence a hydrogen atom of an alkyl group is optionally replaced by a fluorine atom.

10. The compound of claim 7 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
R30 is CH 2 CONR14R15;
R1a and R1c are independently H or F;
R2a is H;
R3 is CH 2 ; and
R4 is (C 3 -C 8 )-cycloalkyl.

11. A compound selected from the group consisting of:
(3R)-3-[[6-(Cyclopropylmethoxy)-3-pyridyl]oxy]-1-(2-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-2-one;
(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-2-one;
(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-imidazo[1,2-a]pyridin-6-yl-pyrrolidin-2-one;
methyl 2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-1-methyl-3-oxo-imidazo[1,5-a]pyridin-2-yl]acetate;
(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-([1,2,4]triazolo[4,3-a]pyridin-6-yl)pyrrolidin-2-one;
2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetic acid;
methyl 2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetate;
methyl 6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyr

Assignees

• Sanofi Sa

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title