Imidazopyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9617266-B2
Application number	US-201414772430-A
Country	US
Kind code	B2
Filing date	Feb 11, 2014
Priority date	Mar 5, 2013
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

Compounds of the formula I

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

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

First claim

The invention claimed is:

1. A compound of the formula I

in which
X denotes H, CH 3 or NH 2 ,
R 1 denotes Ar or Het,
R 2 denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of which is unsubstituted or monosubstituted by A, Hal, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , [C(R 3 ) 2 ] p Ar, [C(R 3 ) 2 ] p Het 1 , CN, [C(R 3 ) 2 ] p COOR 3 , Cyc, CO[C(R 3 ) 2 ] p N(R 3 ) 2 , CO[C(R 3 ) 2 ] p Het 1 , 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 , NHCOOA, NHCON(R 3 ) 2 , NHCOO[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOO[C(R 3 ) 2 ] p Het 1 , NHCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCONH[C(R 3 ) 2 ] p Het 1 , OCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , OCONH[C(R 3 ) 2 ] p Het 1 or C(O)R 3 ,
R 3 denotes H or unbranched alkyl with 1-4 C-atoms or branched alkyl with 3-4 C-atoms,
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , O[C(R 3 ) 2 ] p N(R 3 ) 2 , [C(R 3 ) 2 ] p Het 1 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , O[C(R 3 ) 2 ] p COOR 3 , CONH 2 , CONA, CONA 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 ] p Het 1 , NHCOOA, NHCON(R 3 ) 2 , NHCOO[(R 3 ) 2 m N(R 3 ) 2 , NHCOO[(R 3 ) 2 ] p Het 1 , NHCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCONH[C(R 3 ) 2 ] p Het 1 , OCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , OCONH[C(R 3 ) 2 ] p -Het 1 , S(O) n Het 1 , CHO and/or COA,
Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benz-imidazolyl, indazolyl, quinolyl, isoquinolyl, benzoxazolyl, 1,3-benzo-dioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or furo[3,2-b]pyridyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , O[C(R 3 ) 2 ] p N(R 3 ) 2 , [C(R 3 ) 2 ] p Het 1 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , O[C(R 3 ) 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 ] p Het 1 , NHCOOA, NHCON(R 3 ) 2 , NHCOO[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOO[(R 3 ) 2 p Het 1 , NHCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCONH[C(R 3 ) 2 ] p Het 1 , OCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , OCONH[C(R 3 ) 2 ] p Het 1 , S(O) n Het 1 , CHO, COA, ═S and/or ═O,
Het 1 denotes pyrazolyl, pyridyl, pyrazinyl, indolyl, dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydro-pyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahydro-pyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p —N(R 3 ) 2 , [C(R 3 ) 2 ] p Het 2 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , O[C(R 3 ) 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 2 , O[C(R 3 ) 2 ] m N(R 3 ) 2 , O[C(R 3 ) 2 ] p Het 2 , NHCOOA, NHCON(R 3 ) 2 , NHCOO[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOO[C(R 3 ) 2 ] p Het 2 , NHCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCONH[C(R 3 ) 2 ] p Het 2 , OCONH[C(R 3 ) 2 ] m N(R 3 ) 2 , OCONH[C(R 3 ) 2 ] p Het 2 , S(O) n Het 2 , CHO, COA, ═S and/or ═O,
Het 2 denotes pyrrolidinyl, azetidinyl, azoxetanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, OA, CN, COOA, CONH 2 , S(O) n A, S(O) n Ar, COA and/or ═O,
Cyc denotes cycloalkyl alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by NH 2 ,
A denotes unbranched alkyl with 1-6 C-atoms or branched alkyl with 3-6 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 1-7 H-atoms may be replaced by F or Cl,
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,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

2. A compound according to claim 1 in which
R 2 denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of which is unsubstituted or monosubstituted by A, [C(R 3 ) 2 ] p Ar, [C(R 3 ) 2 ] p Het 1 , Cyc, [C(R 3 ) 2 ] p OR 3 , CO[C(R 3 ) 2 ] p N(R 3 ) 2 or CO[C(R 3 ) 2 ] p Het 1 ,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

3. A compound according to claim 1 in which
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p Het 1 , CONH 2 , CONA and/or CONA 2 ,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

4. A compound according to claim 1 in which
Het denotes pyrazolyl, pyridyl, indolyl, isoindolyl, indolinyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by A and/or ═O,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

5. A compound according to claim 1 in which
Het 1 denotes pyrazolyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or [C(R 3 ) 2 ] p Het 2 ,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

6. A compound according to claim 1 in which
X denotes H, CH 3 or NH 2 ,
R 1 denotes Ar or Het,
R 2 denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of which is unsubstituted or monosubstituted by A, [C(R 3 ) 2 ] p Ar, [C(R 3 ) 2 ] p Het 1 , Cyc, [C(R 3 ) 2 ] p OR 3 , CO[C(R 3 ) 2 ] p N(R 3 ) 2 or CO[C(R 3 ) 2 ] p Het 1 ,
R 3 denotes H or unbranched alkyl with 1-4 C-atoms or branched alkyl with 3-4 C atoms,
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , O[C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p Het 1 , CONH 2 , CONA and/or CONA 2 ,
Het denotes pyrazolyl, pyridyl, indolyl, isoindolyl, indolinyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by A and/or ═O,
Het 1 denotes pyrazolyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or [C(R 3 ) 2 ] p Het 2 ,
Het 2 denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or monosubstituted by A,
A denotes unbranched alkyl with 1-6 C-atoms or branched alkyl with 3-6 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 1-7 H-atoms may be replaced by F or Cl,
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,
or a pharmaceutically acceptable alcoholate, hydrate, salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

7. A compound according to claim 1 , selected from the group

No.

Assignees

• Merck Patent Gmbh

Inventors

• Hoelzemann Guenter
• Dorsch Dieter
• Wegener Ansgar
• Poeschke Oliver
• Busch Michael
• Seenisamy Jeyaprakashnarayanan

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

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