Pyrido-pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9283225-B2
Application number	US-201214234356-A
Country	US
Kind code	B2
Filing date	Jun 15, 2012
Priority date	Aug 10, 2011
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

Compounds of the formula I

in which Het, R 3 and R 4 have the meanings indicated in Claim 1,
are inhibitors of RON and can be employed, for the treatment of cancer.

First claim

The invention claimed is:

1. A compound of the formula I

in which:
Het denotes imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or triazolyl, each of which is substituted by R 1 and R 2 ,
R 1 denotes Ar 1 ,
R 2 denotes A′,
R 3 denotes F or Cl,
R 4 denotes H, CH 2 Ar 2 or A,
Ar 1 denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CONH 2 , COOH, COOA, CN, CHO, COA, SO 2 A, NHCOA and/or, SO 2 NH 2 ,
Ar 2 denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CONH 2 , COOH, COOA, CN, CHO, COA, SO 2 A, NHCOA and/or, SO 2 NH 2 ,
A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-7 H atoms may be replaced by F,
A denotes unbranched or branched alkyl having 1-10 C atoms, in which one or two non-adjacent CH and/or CH 2 groups may be replaced by N, O, S atoms and/or by —CH═CH— groups and/or in addition 1-7 H atoms may be replaced by F,
and pharmaceutically usable salts, tautomers and stereoisomers thereof.

2. A compound according to claim 1 , in which:
Het denotes 1-R 1 -5-R 2 -1H-pyrazol-4-yl
and pharmaceutically usable salts, tautomers and stereoisomers thereof.

3. A compound according to claim 1 , in which:
Ar 1 denotes phenyl,
and pharmaceutically usable salts, tautomers and stereoisomers thereof.

4. A compound according to claim 2 , in which:
Ar 1 denotes phenyl,
and pharmaceutically usable salts, tautomers and stereoisomers thereof.

5. A compound according to claim 1 in which:
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by OH and/or OA, and pharmaceutically usable salts, tautomers and stereoisomers thereof.

6. A compound according to claim 2 in which:
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by OH and/or OA, and pharmaceutically usable salts, tautomers and stereoisomers thereof.

7. A compound according to claim 3 , in which:
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by OH and/or OA, and pharmaceutically usable salts, tautomers and stereoisomers thereof.

8. A compound according to claim 4 , in which:
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by OH and/or OA, and pharmaceutically usable salts, tautomers and stereoisomers thereof.

9. A compound according to claim 1 , in which:
A denotes unbranched or branched alkyl having 1-6 C atoms, in which one or two non-adjacent CH and/or CH 2 groups may be replaced by N and/or O atoms and/or in addition 1-7 H atoms may be replaced by F and pharmaceutically usable salts, tautomers and stereoisomers thereof.

10. A compound according to claim 1 , in which:
Het denotes 1-R 1 -5-R 2 -1H-pyrazol-4-yl
R 1 denotes Ar 1 ,
R 2 denotes A′,
R 3 denotes F or Cl,
R 4 denotes H, CH 2 Ar 2 or A,
Ar 1 denotes phenyl,
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by OH and/or OA,
A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-7 H atoms may be replaced by F,
A denotes unbranched or branched alkyl having 1-6 C atoms, in which one or two non-adjacent CH and/or CH 2 groups may be replaced by N and/or O atoms and/or in addition 1-7 H atoms may be replaced by F,
and pharmaceutically usable salts, tautomers and stereoisomers thereof.

11. A compound according to claim 1 , selected from the group consisting of:

compound

nr.
name

“A1”
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[3-fluoro-4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-

d]pyrimidin-5-yloxy)-phenyl]-amide

“A2”
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

{3-fluoro-4-[3-(4-methoxy-benzyl)-2-oxo-1,2,3,4-

tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy]-phenyl}-amide

“A3”
5-methyl-1-phenyl-1H-pyrazole-4-carboxylic

acid [3-fluoro-4-(2-oxo-1,2,3,4-tetrahydro-

pyrido[2,3-d]pyrimidin-5-yloxy)-phenyl]-amide

“A4”
5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid

{3-fluoro-4-[3-(4-methoxy-benzyl)-2-oxo-1,2,3,4-

tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy]-

phenyl}-amide

and pharmaceutically usable salts, tautomers and stereoisomers thereof.

12. Process for the preparation of compounds of the formula I according to claim 1 and pharmaceutically usable salts, tautomers and stereoisomers thereof, characterized in that:
a) a compound of the formula II
Het-CO-L  II

in which Het has the meanings indicated in claim 1 and
L denotes Cl, Br, I or a free or reactively functionally modified OH group,

is reacted with a compound of the formula III

in which R 3 and R 4 have the meaning indicated in claim 1 , and/or
a base or acid of the formula I is converted into one of its salts.

13. A medicament comprising at least one compound of the formula I according to claim 1 or pharmaceutically usable salts, tautomers and stereoisomers thereof and optionally excipients or adjuvants.

Assignees

• Staehle Wolfgang
• Schadt Oliver
• Knuehl Christine
• Friese-Hamim Manja
• Huck Bayard R
• Goutopoulos Andreas
• Brugger Nadia
• Merck Patent Gmbh

Inventors

• Staehle Wolfgang
• Schadt Oliver
• Knuehl Christine
• Friese-Hamim Manja
• Huck Bayard R
• Goutopoulos Andreas
• Brugger Nadia

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · 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

• A61P31/04

  Antibacterial agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title