Triazolopyrazine derivatives

Patent metadata

Field	Value
Publication number	US-2015051202-A1
Application number	US-201314382678-A
Country	US
Kind code	A1
Filing date	Feb 14, 2013
Priority date	Mar 7, 2012
Publication date	Feb 19, 2015
Grant date	—

Abstract

Compounds of the formula I

in which R 1 , R 2 and R 4 have the meanings indicated in Claim 1,

are inhibitors of GCN2, and can be employed, inter alia, for the treatment of cancer.

First claim

1 . Compounds of the formula I

in which
R 1 denotes Ar, COHet or Het,
R 2 denotes H, Ar 1 , NHHet or Het,
R 3 denotes H or A′,
R 4 denotes H, A, Ar 1 , Het, Hal, NHAr 1 or CN,
Ar denotes phenyl or naphthyl which is unsubstituted or mono- or disubstituted by Hal, A, Cyc, [C(R 3 ) 2 ] p OA, [C(R 3 ) 2 ] p OH, CN, NHCOHet 1 , NHCOA, NHCO[C(R 3 ) 2 ] p Cyc, CONH[C(R 3 ) 2 ] p Cyc, [C(R 3 ) 2 ] p N(R 3 ) 2 , [C(R 3 ) 2 ] p Het 1 , NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O) n A, COHet 1 , O[C(R 3 ) 2 ] m N(R 3 ) 2 and/or O[C(R 3 ) 2 ] p Het 1 ,
Ar 1 denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, A, phenyl, CONH 2 , [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , [C(R 3 ) 2 ] p —CN, [C(R 3 ) 2 ] p Het 1 and/or O[C(R 3 ) 2 ] p Het 1 ,
Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl, dihydroindolyl, 2,3-dihydro-benzo[1,4]dioxinyl or furo[3,2-b]pyridyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p —N(R 3 ) 2 , [C(R 3 ) 2 ] p Het 1 , NO 2 , CN, [C(R 6 ) 2 ] p COOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O) n A, COHet 1 , O[C(R 3 ) 2 ] m N(R 3 ) 2 , O[C(R 3 ) 2 ] p Het 1 and/or ═O,
Het 1
denotes dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl, pyridyl or piperazinyl, which is unsubstituted or mono- or disubstituted by Hal, CN, OH, OA, COOA, CONH 2 , S(O) n A, S(O) n Ar, COA, A and/or ═O,

A
denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N-, O- and/or S-atoms and wherein 1-7H-atoms may be replaced by F or Cl,

Cyc
denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3 ) 2 ] p OH or CN,

A′
denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-atoms,

Hal
denotes F, Cl, Br or I,

n
denotes 0, 1 or 2,

m
denotes 1, 2 or 3,

p denotes 0, 1, 2, 3 or 4,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2 . Compounds according claim 1 in which
R 1 denotes Ar, COHet or Het,
R 2 denotes H, Ar 1 , NHHet or Het,
R 3 denotes H or A′,
R 4 denotes H, A, Ar 1 , Het, Hal, NHAr 1 or CN,
Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, A, Cyc, [C(R 3 ) 2 ] p OA, [C(R 3 ) 2 ] p OH, CN, NHCOHet 1 , NHCOA, NHCO[C(R 3 ) 2 ] p Cyc, CONH[C(R 3 ) 2 ] p Cyc, [C(R 3 ) 2 ] p Het 1 , SO 2 N(R 3 ) 2 , NR 3 SO 2 A, O[C(R 3 ) 2 ] p Het 1 , COHet 1 , and/or S(O) n A,
Ar 1 denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, A, phenyl, CONH 2 , [C(R 3 ) 2 ] p CN, [C(R 3 ) 2 ] p OR 3 and/or [C(R 3 ) 2 ] p Het 1 ,
Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl, dihydroindolyl, 2,3-dihydro-benzo[1,4]dioxinyl or furo[3,2-b]pyridyl which is unsubstituted or mono-, di- or trisubstituted by A, [C(R 3 ) 2 ] p Het 1 , [C(R 3 ) 2 ] p N(R 3 ) 2 and/or ═O,
Het 1
denotes dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl, pyridyl or piperazinyl, which is unsubstituted or mono- or disubstituted by A,

A
denotes unbranched or branched alkyl with 1-10 C-atoms, and wherein 1-7H-atoms may be replaced by F or Cl,

Cyc
denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3 ) 2 ] p OH or CN,

A′
denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-atoms,

Hal
denotes F, Cl, Br or I,

n
denotes 0, 1 or 2,
p denotes 0, 1, 2, 3 or 4,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3 . Compounds according to claim 1 , selected from the group

No.
Name

“A1”
(4-methanesulfonyl-phenyl)-[5-(1-methyl-1H-indazol-5-yl)-

[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-amine

“A2”
(3-methoxy-phenyl)-[5-(1-methyl-1H-indazol-5-yl)-

[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-amine

“A3”
[5-(1-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-

pyridin-3-yl-amine

“A4”
[5-(1-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-

[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine

“A5”
3,3-dimethyl-6-[5-(1-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-

a]pyrazin-2-ylamino]-1,3-dihydro-indol-2-one

“A6”
(2-dimethylaminomethyl-1H-benzoimidazol-5-yl)-[5-(1-methyl-1H-

indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-amine

“A7”
3-(5-quinolin-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino)-

benzenesulfonamide

“A8”
[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-(5-quinolin-3-yl-

[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-amine

“A9”
3,3-dimethyl-6-(5-quinolin-3-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-

ylamino)-1,3-dihydro-indol-2-one

“A10”
(2-dimethylaminomethyl-1H-benzoimidazol-5-yl)-(5-quinolin-3-yl-

[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-amine

“A11”
(4-methanesulfonyl-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-

[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-amine

“A12”
[5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-

pyridin-3-yl-amine

“A13”
3,3-dimethyl-6-[5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-

Assignees

• Merck Patent Gmbh

Inventors

• Schiemann Kai
• Deutsch Carl
• Hoelzemann Guenter
• Kuhn Daniel
• Wegener Ansgar
• Swinnen Dominique
• Comas Horacio

Classifications

• 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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P37/06

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