Pyridopyrimidine derivatives as protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9725462-B2
Application number	US-201314420003-A
Country	US
Kind code	B2
Filing date	Jul 10, 2013
Priority date	Aug 7, 2012
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Compounds of the formula I

in which R, R 1 and R 2 have the meanings indicated in claim 1 , are inhibitors of Syk, and can be employed, inter alia, for the treatment of cancer, rheumatoid arthritis and/or systemic lupus.

First claim

The invention claimed is:

1. Compounds of the formula I

in which
R denotes H, A or NR 4 R 4′ ,
R 1 denotes Ar 1 , Het 1 , CN, A or —C≡C—Ar 1 ,
R 2 denotes Het 2 , NR 3 Cyc, NR 3 CHR 3 CON(R 3 ) 2 , NR 3 [C(R 3 ) 2 ] p CR 3 (NH 2 )CH 2 OA or NR 3 [C(R 3 ) 2 ] p N(R 3 ) 2 ,
Ar 1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH 2 ) n Het 3 , [C(R 3 ) 2 ] n OR 3 , [C(R 3 ) 2 ] n N(R 3 ) 2 , NO 2 , CN, Hal, COOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 and/or S(O) m A,
Het 1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furyl,thiazolyl, triazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NA 2 and/or ═O,
Het 2 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, pyrazolyl, indazolyl, azetidinyl or octahydro-benzimidazolyl, each of which is mono-, di- or trisubstituted by Hal, A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NA 2 , (CH 2 ) n OH and/or (CH 2 ) n OA,
Het 3 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, imidazolidinyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furyl, thiazolyl or triazolyl, each of which is unsubstituted or mono- or disubstituted by A and/or ═O,
R 3 denotes H or alkyl having 1, 2, 3 or 4 C-atoms,
R 4 and R 4′ each, independently of one another, denote H or A,
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or in which one or two non-adjacent CH 2 groups may be replaced by O and/or NH,
or
cyclic alkyl having 3-7 C atoms,

Cyc denotes cyclic alkyl having 3-7 C atoms, which may be unsubstituted or monosubstituted by NH 2 , CN, CONH 2 or OH,
m denotes 0, 1 or 2,
n denotes 0, 1, 2, 3 or 4,
p denotes 1, 2, 3 or 4,
and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

2. Compounds according to claim 1 in which
Ar 1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH 2 ) n Het 3 and/or SO 2 NH 2 ,
and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

3. Compounds according to claim 1 in which
Het 1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, and/or ═O,
and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

4. Compounds according to claim 1 in which
Het 2 denotes piperidinyl or octahydro-benzimidazolyl, each of which is monosubstituted by A, (CH 2 ) n OH or (CH 2 ) n OA,
and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

5. Compounds according to claim 1 in which
R denotes H, A or NR 4 R 4 ′,
R 1 denotes Ar 1 , Het 1 , CN, A or —C≡C—Ar 1 ,
R 2 denotes Het 2 , NR 3 Cyc, NR 3 CHR 3 CON(R 3 ) 2 , NR 3 [C(R 3 ) 2 ] p CR 3 (NH 2 )CH 2 OA or NR 3 [C(R 3 ) 2 ] p N(R 3 ) 2 ,
Ar 1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH 2 ) n Het 3 and/or SO 2 NH 2 ,
Het 1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, and/or ═O,
Het 2 denotes piperidinyl or octahydro-benzimidazolyl, each of which is monosubstituted by A, (CH 2 ) n OH or (CH 2 ) n OA,
Het 3 denotes triazolyl,
R 3 denotes H or alkyl having 1, 2, 3 or 4 C-atoms,
R 4 , R 4′ each, independently of one another, denote H or A,
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or in which one or two non-adjacent CH 2 groups may be replaced by O and/or NH,
or
cyclic alkyl having 3-7 C atoms,

Cyc denotes cyclic alkyl having 3-7 C atoms, which may be unsubstituted or monosubstituted by NH 2 , CN, CONH 2 or OH,
m denotes 0, 1 or 2,
n denotes 0, 1, 2, 3 or 4,
p denotes 1, 2, 3 or 4,
and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

6. Compounds according to claim 1 , selected from the following compounds:

Nr.
name

“A1”
N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-

pyrido[4,3-d]pyrimidine-2,5-diamine

“A2”
(1R,2S)-N-[8-(1-Methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]

pyrimidin-2-yl]-cyclohexane-1,2-diamine hydrochloride

“A3”
N2-(cis-2-Amino-cyclohexyl)-8-(3-[1,2,3]triazol-2-yl-phenyl)-

pyrido[4,3-d]pyrimidine-2,5-diamine

“A4”
N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-

pyrido[4,3-d]pyrimidine-2,5-diamine

“A5”
{1-[5-Amino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]

pyrimidin-2-yl]-piperidin-4-yl}-methanol

“A6”
N2-(2-Amino-ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-pyrido

[4,3-d]-pyrimidine-2,5-diamine

“A7”
N2-(cis-2-Amino-cyclohexyl)-8-(4-tert-butyl-phenyl)-pyrido

[4,3-d]pyrimidine-2,5-diamine

“A8”
N2-(cis-2-Amino-cyclohexyl)-8-(1-isobutyl-1H-pyrazol-4-yl)-

pyrido[4,3-d]pyrimidine-2,5-diamine

“A9”
5-Amino-2-(cis-2-amino-cyclohexylamino)-pyrido[4,3-d]-

pyrimidine-8-carbonitrile

“A10”
N2-(cis-2-Amino-cyclohexyl)-8-(1H-indol-2-yl)-pyrido-

[4,3-d]pyrimidine-2,5-diamine

“A11”
2-((cis)-3-Methyl-octahydro-benzoimidazol-1-yl)-8-(1-methyl-

1H-pyraz

Assignees

• Merck Patent Gmbh

Inventors

• Burgdorf Lars
• Kuhn Daniel
• Ross Tatjana
• Deutsch Carl

Classifications

• 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

• A61P37/02

  Immunomodulators · 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