Pyrrolopyrrolidinone compounds

Patent metadata

Field	Value
Publication number	US-9365576-B2
Application number	US-201313900061-A
Country	US
Kind code	B2
Filing date	May 22, 2013
Priority date	May 24, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

The invention relates to compounds of formula (I):

as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.

First claim

We claim:

1. A compound of formula (I) or a salt thereof,

wherein:
A is selected from the group consisting of:

B is selected from the group consisting of:

each R 1 is independently selected from the group consisting of halo and methyl;
R 1a is selected from the group consisting of H, halo and (C 1 -C 4 )alkyl;
R 2 is selected from the group consisting of chloro, fluoro, trifluoromethyl, methyl and cyano;
R 3 is selected from the group consisting of ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl and cyclopentyl, or R 3 is:

wherein R 22 is selected from the group consisting of OH, OCH 3 , NH 2 , NHMe, NMe 2 , NHCOMe and NHCOH;
R 5 is selected from the group consisting of:
H,
(C 1 -C 4 )alkyl-, said (C 1 -C 4 )alkyl- being optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH and ═O,
(C 1 -C 4 )alkyl-O—C(O)—(CH 2 ) m —, and
cyano;

R 6 is selected from the group consisting of:
H,
(C 1 -C 4 )alkyl,
(C 1 -C 4 )alkoxy,
halo,
cyano, and
R 9 (R 10 )N—(CH 2 ) m —;

R 7 is selected from the group consisting of: H, halo and (C 1 -C 4 )alkyl;
each R 8 is independently selected from the group consisting of H, (C 1 -C 4 )alkyl, —CHF 2 , hydroxyethyl- and methoxyethyl-;
each R 9 is independently selected from the group consisting of H, methyl or ethyl;
each R 10 is independently selected from the group consisting of H, (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkyl wherein said (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkyl are each independently optionally substituted by 1 or 2 substituents independently selected from the group consisting of methoxy, ethoxy, hydroxy, halo and S(O) v R y ;
or R 9 and R 10 , together with the N atom to which they are attached, can join to form a saturated 5 or 6 membered heterocyclic ring further comprising ring carbon atoms and optionally one ring heteroatom independently selected from N, O and S;
R 11 is H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or halo;
R 12 is H or halo;
R 13 is selected from the group consisting of hydroxy, (C 1 -C 2 )alkoxy, NH 2 , —C(O)OH, —NH(C(O)—CH 3 ) and —C(O)— NH(CH 3 );
R 14 is selected from the group consisting of H, —C(O)—NR 9 (R 10 ), (C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl;
R 23A is selected from the group consisting of H, halo and (C 1 -C 4 )alkyl;
R 23B is selected from the group consisting of H and (C 1 -C 4 )alkyl;
R 4a is selected from the group consisting of:

R 15 is independently selected from the group consisting of OCH 3 , OCD 3 , OH, CH 2 CH 3 , OCF 3 and H;
R 16 is selected from the group consisting of H, —C(O)NR 9 R 10 , halo, CN, —O—(C 1 -C 4 )alkyl, —C(O)—morpholinyl-4-yl, tetrazolyl, —C(O)OH, —CH 2 C(O)OH, —S(O) v ,NR 9 R 10 , —CH 2 C(O)NR 9 R 10 , S(O) v R y , OCF 3 , hydroxy-azetidin-1-yl-carbonyl, —CH 2 NR 9 R 10 , —CH 2 NR 9 —C(O)R 10 , CH 2 CN, methyl-imidazolyl-, —CH 2 C(O)O—(C 1 -C 4 )alkyl, —N(R 9 )—C(O)—(C 1 -C 4 )alkyl, —NR 9 R 10 and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted by 1 or 2 OH;
R 17 is selected from the group consisting of H, O(C 1 -C 4 )alkyl, —CH 2 C(O)O—(C 1 -C 4 )alkyl,—CH 2 C(O)OH, —CH 2 C(O)NR 9 R 10 , —CH 2 CN, —NR 9 R 10 , —C(O)NR 9 R 10 , —CH 2 NR 9 R 10 and —C(O)O—(C 1 -C 4 )alkyl;
R 18 is selected from the group consisting of O(C 1 -C 4 )alkyl, OCD 3 , H, —NR 9 R 10 , CH 2 NR 9 R 10 and azetidin-1-yl, said azetidin-1-yl being optionally substituted with OH or both CH 3 and OH;
R 20 is selected from the group consisting of CH 3 , H and —CH 2 CH 3 ;
R 4b is selected from the group consisting of H, CN, halo, (C 1 -C 4 )alkyl, —C(O)OH, CH 2 C(O)OH and —C(O)O—(C 1 -C 4 )alkyl;
R y is selected from the group consisting of H, (C 1 -C 4 )alkyl and NR 9 R 10 ;
m is 0, 1 or 2; and
v is 0, 1 or 2;
and wherein * indicates the point of attachment to the remainder of the molecule.

2. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein A is selected from the group consisting of:

3. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein A is selected from the group consisting of:

4. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein B is:

5. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein R 3 is isopropyl.

6. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein R 4a is selected from the group consisting of:

7. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein R 4a is selected from the group consisting of:

8. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein R 5 is selected from the group consisting of H and (C 1 -C 2 )alkyl.

9. The compound of the formula (I) or salt thereof as defined in claim 1 , wherein R 4b is H.

10. A compound or a salt thereof, selected from the group consisting of:
1: 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1 H-pyrrolo[3,4-b]pyrrol-4-one
2: 3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methyl-benzamide
3: 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-fluoro-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one
4: 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one
5: 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one
6: 5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(4-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one
7: 3-[(S)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methyl-benzamide
8: 3-[(R)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methyl-benzamide
9: 5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one
10: 3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-N-methyl-benzamide
11: 5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-ph

Assignees

• Cotesta Simona
• Furet Pascal
• Guagnano Vito
• Holzer Philipp
• Kallen Joerg
• Mah Robert
• Masuya Keiichi
• Schlapbach Achim
• Stutz Stefan
• Vaupel Andrea
• Novartis Ag

Inventors

• Cotesta Simona
• Furet Pascal
• Guagnano Vito
• Holzer Philipp
• Kallen Joerg
• Mah Robert
• Masuya Keiichi
• Schlapbach Achim
• Stutz Stefan
• Vaupel Andrea

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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