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

Patent metadata

Field	Value
Publication number	US-9908868-B2
Application number	US-201615284334-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Apr 4, 2014
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

The present invention relates to isoindolinone compounds. The isoindolinone 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 isoindolinone 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
X is N or C—R1a;
A is CR31R33, NR31, CR31R33-NR31 or CR31=N;
R30 is H or (CR11R12) n -R32;
R31 is H or (CR11R12) n -R32;
R33 is H or (C 1 -C 6 )-alkyl;
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, COOR13, CONR14R15, S(O) m ,R16, OH, CN, (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 6 )-alkyloxy, (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl, oxo, F and Cl;

m is 0, 1 or 2;
R13 is H or (C 1 -C 6 )-alkyl;
R14 and R15 are independently H, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )-alkyl, or
(C 1 -C 6 )-alkyl substituted with 1 to 3 groups selected from the group consisting of OR17, COOR19 and a 4-, 5- or 6-membered heterocycle;

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 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, (C 1 -C 3 )-alkyl substituted with COOR19 or CN;
R19 is H or (C 1 -C 6 )-alkyl;
Y is N or CH;
Z is a bond, 0, CR5R5′, NR6, C═0, 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 F, Cl, SF 5 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, OR8, (C 3 -C 8 )-cycloalkyl, (C s -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 Z is O.

4. 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
X is N or C—R1la;
A is CR31R33, NR31, CR31R33-NR31 or CR31=N;
R30 is H or (CR11R12) n -R32;
R31 is H or (CR11R12) n -R32;
R33 is H or (C 1 -C 6 )-alkyl;
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, COOR13, CONR14R15, S(O ) m , R16, OH, CN, (C 3 -C 8 )-cycloalkyl, 4-, 5- or 6-membered heterocycle or 5- or 6-membered heteroaryl ring;
wherein the groups (C 3 -C 8 )-cycloalkyl, 4-, 5- or 6-membered heterocycle, 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 6 )-alkyloxy, (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl, oxo, F and Cl;

m is 0, 1 or 2;
R13 is H or (C 1 -C 6 )-alkyl;
R14 and R15 are independently H, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )-alkyl, or
(C 1 -C 6 )-alkyl substituted with 1 to 3 groups selected from the group consisting of OR17, COOR19 and a 4-, 5- or 6-membered heterocycle;

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 is H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
R2a is H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN;
Y is N or CH;
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, (C 2 -C 6 )-alkenyl, OR8, (C 3 -C 8 )-cycloalkyl, (C s -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.

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

6. The compound of claim 5 , a stereoisomeric form thereof, or a physiologically acceptable salt of any of the foregoing, wherein
X is C—R1a;
A is CR31R33 or NR31;
R32 is (C 1 -C 6 )-alkyl, COOR13, CONR14R15, S(0) m R16, OH, CN, (C 3 -C 8 )-cycloalkyl, 4-, 5- or 6-membered heterocycle or 5- or 6-membered heteroaryl ring;
wherein the groups (C 3 -C 8 )-cycloalkyl, 4-, 5- or 6-membered heterocycle, 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 6 )-alkyloxy, (C 1 -C 3 )-alkyloxy-(C 1 -C 4 )-alkyl, oxo, F and Cl;

R1a is H or F;
R2a is H, F, Cl, Br, (C 1 -C 6 )-alkyl or CN; and
R4 is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, OR8, (C 3 -C 8 )-cycloalkyl, (C s -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

Assignees

• Sanofi Sa

Inventors

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

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

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