Pyridine-and pyrazine derivatives

Patent metadata

Field	Value
Publication number	US-9273029-B2
Application number	US-201214118845-A
Country	US
Kind code	B2
Filing date	Apr 11, 2012
Priority date	May 23, 2011
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

Compounds of the formula (I) in which R, R 1 and X have the meanings indicated in claim 1 , are inhibitors of TBK1 and IKKε and can be employed, inter alia, for the treatment of cancer and inflammatory diseases

First claim

The invention claimed is:

1. Compounds of the formula I

in which:
X denotes CH,
R denotes Ar or Het,
R 1 denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, para-pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimid-azolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl or furo[3,2-b]pyridyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, OR 5 , CN, COOA, COOH, CON(R 5 ) 2 and/or NR 5 COA′,
Ar denotes phenyl, biphenyl or naphtyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, Het 1 , (CH 2 ) n OR 5 , (CH 2 ) n N(R 5 ) 2 , NO 2 , CN, (CH 2 ) n COOR 5 , CON(R 5 ) 2 , CONH(CH 2 ) q NHCOOA′, CON[R 5 (CH 2 ) n Het 1 ], NR 5 COA, NHCOOA, NR 5 SO 2 A, COR 5 , SO 2 Het 2 , SO 2 N(R 5 ) 2 and/or S(O) p A,
Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzo-dioxolyl, benzothiophenyl, benzofuranyl or imidazopyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, COA, (CH 2 ) p Het 2 , OH, OA, Hal, (CH 2 ) p N(R 5 ) 2 , NO 2 , CN, (CH 2 ) p COOR 5 , (CH 2 ) p CON(R 5 ) 2 , NR 5 COA, (CH 2 ) p COHet 2 and/or (CH 2 ) p phenyl,
Het 1 denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, Hal, CN and/or (CH 2 ) p COOR 5 ,
Het 2 denotes dihydropyrrolyl, pyrrolidinyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted by OH and/or A,
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,
R 5 denotes H or unbranched or branched alkyl having 1-6 C atoms, in which 1-7 H atoms may be replaced by F,
Hal denotes F, Cl, Br or I,
n denotes 0, 1, 2, 3 or 4,
p denotes 0, 1 or 2,
q denotes 1, 2, 3 or 4,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2. Compounds according to claim 1 , in which:
R 1 denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, each of which is unsubstituted or monosubstituted by Hal, A, OR 5 , COOA, COOH, CON(R 5 ) 2 and/or NR 5 COA′,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compounds according to claim 1 , in which:
Ar denotes phenyl, biphenyl or naphtyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het 1 , COR 5 , CON(R 5 ) 2 , CONH(CH 2 ) q NHCOOA′, CON[R 5 (CH 2 ) n Het 1 ], NHCOOA, (CH 2 ) n N(R 5 ) 2 , (CH 2 ) n OR 5 , (CH 2 ) n COOR 5 , SO 2 Het 2 and/or SO 2 N(R 5 ) 2 ,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compounds according to claim 2 , in which:
Ar denotes phenyl, biphenyl or naphtyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het 1 , COR 5 , CON(R 5 ) 2 , CONH(CH 2 ) q NHCOOA′, CON[R 5 (CH 2 ) n Het 1 ], NHCOOA, (CH 2 ) n N(R 5 ) 2 , (CH 2 ) n OR 5 , (CH 2 ) n COOR 5 , SO 2 Het 2 and/or SO 2 N(R 5 ) 2 ,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. Compounds according to claim 1 , in which:
Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstituted or mono- or disubstituted by A, (CH 2 ) p Het 2 , (CH 2 ) p CON(R 5 ) 2 and/or (CH 2 ) p phenyl,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to claim 2 , in which:
Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstituted or mono- or disubstituted by A, (CH 2 ) p Het 2 , (CH 2 ) p CON(R 5 ) 2 and/or (CH 2 ) p phenyl,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. Compounds according to claim 3 , in which:
Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstituted or mono- or disubstituted by A, (CH 2 ) p Het 2 , (CH 2 ) p CON(R 5 ) 2 and/or (CH 2 ) p phenyl,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

8. Compounds according to claim 1 , in which:
Het 1 denotes pyrazolyl or imidazolyl, each of which is unsubstituted or monosubstituted by A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

9. Compounds according to claim 2 , in which:
Het 1 denotes pyrazolyl or imidazolyl, each of which is unsubstituted or monosubstituted by A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

10. Compounds according to claim 3 , in which:
Het 1 denotes pyrazolyl or imidazolyl, each of which is unsubstituted or monosubstituted by A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

11. Compounds according to claim 4 , in which:
Het 1 denotes pyrazolyl or imidazolyl, each of which is unsubstituted or monosubstituted by A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

12. Compounds according to claim 1 , in which:
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted by OH and/or A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

13. Compounds according to claim 2 , in which:
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted by OH and/or A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

14. Compounds according to claim 3 , in which:
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted by OH and/or A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

15. Compounds according to claim 4 , in which:
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted by OH and/or A,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

16. Compounds according to claim 5 , in which:
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or monosubstituted b

Assignees

• Hoelzemann Guenter
• Eggenweiler Hans-Michael
• Karra Srinivasa R
• Merck Patent Gmbh

Inventors

• Hoelzemann Guenter
• Eggenweiler Hans-Michael
• Karra Srinivasa R

Classifications

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title