Pyridazinone derivatives

Patent metadata

Field	Value
Publication number	US-9376426-B2
Application number	US-201414169891-A
Country	US
Kind code	B2
Filing date	Jan 31, 2014
Priority date	Jan 7, 2009
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

Compounds of the formula (I) in which D, R 1 , R 2 , R 3 , R 4 have the meanings indicated in Claim 1 , are inhibitors of tyrosine kinases, in particular of Met kinase, and can be employed, inter alia, for the treatment of tumors.

First claim

The invention claimed is:

1. A method for the treatment of a solid tumor cancer of: the stomach, the kidneys, the head and neck, the oesophagus, the thyroid, the intestines, the liver, the brain, the urogenital tract, the lung, the pancreas, the colon or the breast; comprising administering to a host in need thereof a Met kinase inhibiting effective amount of a compound of formula I

in which
D denotes a five- or six-membered unsaturated or aromatic heterocycle having 1 to 3 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal and/or A,
R 1 denotes OH, OA, O[C(R 5 ) 2 ] n Ar, O[C(R 5 ) 2 ] n Het, O[C(R 5 ) 2 ] p N(R 5 ) 2 , N(R 5 ) 2 , NR 5 [C(R 5 ) 2 ] n Ar, NR 5 [C(R 5 ) 2 ] n Het, NR 5 [C(R 5 ) 2 ] p N(R 5 ) 2 , COOR 5 , CON(R 5 ) 2 , CONR 5 [C(R 5 ) 2 ] p N(R 5 ) 2 , CONR 5 [C(R 5 ) 2 ] p OR 5 , CONR 5 [C(R 5 ) 2 ] n Het, COHet or COA,
R 2 denotes H, A, Hal, OH, OA, N(R 5 ) 2 , N═CR 5 N(R 5 ) 2 , SR 5 , NO 2 , CN, COOR 5 , CON(R 5 ) 2 , NR 5 COA, NR 5 SO 2 A, SO 2 N(R 5 ) 2 , S(O) m A, [C(R 5 ) 2 ] n N(R 5 ) 2 , [C(R 5 ) 2 ] n Het, O[C(R 5 ) 2 ] p N(R 5 ) 2 , O[C(R 5 ) 2 ] n Het, S[C(R 5 ) 2 ] p N(R 5 ) 2 , S[C(R 5 ) 2 ] n Het, NR 5 [C(R 5 ) 2 ] p N(R 5 ) 2 , —NR 5 [C(R 5 ) 2 ] n Het, NHCON(R 5 ) 2 , NHCONH[C(R 5 ) 2 ] p N(R 5 ) 2 , NHCONH[C(R 5 ) 2 ] n Het, NHCO[C(R 5 ) 2 ] p —N(R 5 ) 2 , NHCO[C(R 5 ) 2 ] n Het, CON(R 5 ) 2 , CONR 5 [C(R 5 ) 2 ] p N(R 5 ) 2 , CONR 5 [C(R 5 ) 2 ] n Het, COHet, COA, O[C(R 5 ) 2 ] n NR 5 COZ, O[C(R 5 ) 2 ] n NR 2 COHet 1 , O[C(R 5 ) 2 ] n Cyc[C(R 5 ) 2 ] n N(R 5 ) 2 , O[C(R 5 ) 2 ] n Cyc[C(R 5 ) 2 ] n OR 5 , O[C(R 5 ) 2 ] n Cyc[C(R 5 ) 2 ] n Het 1 ,

O[C(R 5 ) 2 ] n CR 5 (NR 5 ) 2 COOR 5 , O[C(R 5 ) 2 ] n NR 5 CO[C(R 5 ) 2 ] n NR 5 COA, O[C(R 5 ) 2 ] n NR 5 COOA, O[C(R 5 ) 2 ] n CO—NR 5 -A, O[C(R 5 ) 2 ] n CO—NR 5 -[C(R 5 ) 2 ] n Het 1 , O[C(R 5 ) 2 ] n CONH 2 , O[C(R 5 ) 2 ] n CONHA, O[C(R 5 ) 2 ] n CONA 2 , O[C(R 5 ) 2 ] n CO—NR 5 -[C(R 2 ) 2 ] n N(R 5 ) 2 or OCOA,
Z denotes CR 5 (NR 5 ) 2 CR 5 (OR 5 )A,
R 3 denotes H or A,
R 4 denotes H, A or Hal,
R 5 denotes H or A′,
A denotes unbranched or branched alkyl having 1-10 C atoms,
in which 1-7 H atoms may be replaced by OH, F, Cl and/or Br, and/or in which one or two CH 2 groups may be replaced by O, NH, S, SO, SO 2 and/or CH═CH groups,
or

cyclic alkyl having 3-7 C atoms, in which 1-7 H atoms may be replaced by OH, F, Cl and/or Br,
A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F,
Cyc denotes cycloalkylene having 3-7 C atoms,
Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 5 , N(R 5 ) 2 , SR 5 , NO 2 , CN, COOR 5 , CON(R 5 ) 2 , NRSCOA, NR 5 SO 2 A, SO 2 N(R 5 ) 2 , S(O) m A, CO-Het 1 , [C(R 5 ) 2 ] n N(R 5 ) 2 , [C(R 5 ) 2 ] n Het 1 , O[C(R 5 ) 2 ] p —N(R 5 ) 2 , O[C(R 5 ) 2 ] n Het 1 , NHCOOA, NHCON(R 5 ) 2 , NHCOO[C(R 5 ) 2 ] p N(R 5 ) 2 , NHCOO[C(R 5 ) 2 ] n Het 1 , NHCONH[C(R 5 ) 2 ] p N(R 5 ) 2 , NHCONH[C(R 5 ) 2 ] n Het 1 , OCONH[C(R 5 ) 2 ] p N(R 5 ) 2 and/or OCONH[C(R 5 ) 2 ] n Het 1 ,
Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 5 , N(R 5 ) 2 , SR 5 , NO 2 , CN, COOR 5 , CON(R 5 ) 2 , NRSCOA, NR 5 SO 2 A, SO 2 N(R 5 ) 2 , S(O) m A, CO-Het 1 , [C(R 5 ) 2 ] n N(R 5 ) 2 , [C(R 5 ) 2 ] n Het 1 , O[C(R 5 ) 2 ] p N(R 5 ) 2 , O[C(R 5 ) 2 ] n Het 1 , NHCOOA, NHCON(R 5 ) 2 , NHCOO[C(R 5 ) 2 ] p N(R 5 ) 2 , NHCOO[C(R 5 ) 2 ] n Het 1 , NHCONH[C(R 5 ) 2 ] p N(R 5 ) 2 , NHCONH[C(R 5 ) 2 ] n Het 1 , OCONH[C(R 5 ) 2 ] p N(R 5 ) 2 , OCONH[C(R 5 ) 2 ] n Het 1 , CO-Het 1 , CHO, COA, ═S, ═NH, ═NA and/or ═O (carbonyl oxygen),
Het 1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which may be mono- or disubstituted by A, OA, OH, Hal and/or ═O (carbonyl oxygen),
Hal denotes F, Cl, Br or I,
m denotes 0, 1 or 2,
n denotes 0, 1, 2, 3 or 4,
p denotes 2, 3, 4, 5, or 6,
q denotes 1, 2, 3, 4 or 5,
or a pharmaceutically usable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

2. The method according to claim 1 in which
R 1 denotes OH, OA, O[C(R 5 ) 2 ] n Ar, N(R 5 ) 2 , CON(R 5 ) 2 or NR 5 [C(R 5 ) 2 ] n Ar.

3. The method according to claim 1 in which
R 2 denotes [C(R 5 ) 2 ] n Het or O[C(R 5 ) 2 ] p N(R 5 ) 2 .

4. The method according to claim 1 in which
R 3 denotes H or methyl.

5. The method according to claim 1 , in which
Ar denotes phenyl.

6. The method according to claim 1 , in which
A denotes unbranched or branched alkyl having 1-6 C atoms,
in which 1-5 H atoms may be replaced by F,
and/or in which one or two CH 2 groups may be replaced by O.

7. The method according to claim 1 , in which
R 4 denotes H.

8. The method according to claim 1 , in which
Het denotes a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by [C(R 5 ) 2 ] n Het 1 .

9. The method according to claim 1 , in which
Het denotes pyrazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl or isoxazolyl, where the radicals may also be mono- or disubstituted by [C(R 5 ) 2 ] n Het 1 .

10. The method according to claim 1 in which
Het 1 denotes piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals may also be mono- or disubstituted by ═O and/or A.

11. The method according to claim 1 , in which
D denotes thiazolediyl, thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazinediyl, pyrazinediyl, pyridinediyl or pyrimidinediyl,
where the radicals may also be mono-, di- or trisubstituted by Hal and/or A.

12. The method according to claim 1 , in which
R 1 denotes OH, OA, O[C(R 5 ) 2 ] n Ar, N(R 5 ) 2 , CON(R 5 ) 2 or NR 5 [C(R 5 ) 2 ] n Ar,
R 2 denotes [C(R 5 ) 2 ] n Het or O[C(R 5 ) 2 ] p N(R 5 ) 2 ,
R 3 denotes H or methyl,
R 4 denotes H,
R 5 denotes H or A′,
A denotes unbranched or branched alkyl having 1-6 C atoms,
in which 1-5 H atoms may be replaced by F,
and/or in which one or two CH 2 groups may be replaced by O,

A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F,
Ar denotes phenyl,
Het denotes a monocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by [C(R 5 ) 2 ] n Het 1 ,
Het 1 denotes piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, oxazolidinyl or imidazolidinyl, where the radicals may also be mono- or disubstituted by ═O and/or A,
D denotes thiazolediyl, thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, pyrazolediyl, imidazolediyl, thiadiazolediyl, pyridazinediyl, pyrazinediyl, pyridinediyl or pyrimidinediyl,
where the radicals may also be mono-, di- or trisubstituted by Hal and/or A,

Hal denotes F, Cl, Br or I,
n denotes 0, 1, 2, 3 or 4, and
p denotes 2, 3, 4, 5, or 6.

13. The method according to claim 1 in which
R 1 denotes OH, OA, O[C(R 5 ) 2 ] n Ar, N(R 5 ) 2 , CON(R 5 ) 2 or NR 5 [C(R 5 ) 2 ] n Ar,
R 2 denotes [C(R 5 ) 2 ] n Het or O[C(R 5 ) 2 ] p N(R 5 ) 2 ,
R 3 denotes H or methyl,
R 4 denotes H,
R

Assignees

• Merck Patent Gmbh

Inventors

• Dorsch Dieter
• Schadt Oliver
• Stieber Frank
• Blaukat Andree

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title