3-substituted cyclopentylamine derivatives

Patent metadata

Field	Value
Publication number	US-2016200714-A1
Application number	US-201414912287-A
Country	US
Kind code	A1
Filing date	May 12, 2014
Priority date	Aug 16, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

Compounds of the formula I

in which R, W, R 1 , R 4 , X 1 , X 2 , X 3 , X 4 and q have the meanings indicated in claim 1,

are inhibitors of fatty acid synthase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

First claim

1 . Compounds of the formula I

in which
R denotes Ar or Het, —C≡C—Ar or —C≡C—Het,
W denotes furanyl, thiophenyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by R 2 ,
R 1 denotes A, [C(R 3 ) 2 ] n Ar 1 or [C(R 3 ) 2 ] n Cyc,
R 2 denotes A, [C(R 3 ) 2 ] n Ar 1 , Cyc or=O
R 4 denotes H, F, Cl, Br, OH, CN, NO 2 , A′, OA′, SA′, SO 2 Me, COA′, CONH 2 , CONHA′ or CONA′ 2 ,
X 1 , X 2 , X 3 , X 4 each, independently of one another, denote CH or N,
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein two adjacent carbon atoms may form a double bond and/or 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 R 5 ,
Cyc denotes cycloalkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by OH, Hal or A,
A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F,
R 5 denotes F, Cl or OH,
Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, O[C(R 3 ) 2 ] n Het 1 , Ar 1 , [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , CON(R 3 ) 2 , [C(R 3 ) 2 ] p N(R 3 ) 2 , N(R 3 ) 2 COA, NR 3 SO 2 A, [C(R 3 ) 2 ] p SO 2 NR 3 ) 2 , S(O) n A, O[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOOA, NHCON(R 3 ) 2 and/or COA,
Ar 1 denotes phenyl or naphthyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, [C(R 3 ) 2 ] p OR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , NO 2 , CN, [C(R 3 ) 2 ] p COOR 3 , [C(R 3 ) 2 ] p N(R 3 ) 2 , N(R 3 ) 2 COA, NR 3 SO 2 A, [C(R 3 ) 2 ] p SO 2 N(R 3 ) 2 , S(O) n A, O[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOOA, NHCON(R 3 ) 2 and/or COA,
R 3 denotes H or unbranched or branched alkyl with 1-6 C-atoms,
Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, [C(R 3 ) 2 ] n OA′, [C(R 3 ) 2 ] n N(R 3 ) 2 , SR 3 , NO 2 , CN, COOR 3 , CON(R 3 ) 2 , COHet 1 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O) n A, O[C(R 3 ) 2 ] m N(R 3 ) 2 , NHCOOA, NHCON(R 3 ) 2 , CHO, COA, ═S, ═NH, ═NA and/or ═O (carbonyl oxygen),
Hal denotes F, Cl, Br or I,
m denotes 1, 2 or 3,
n denotes 0, 1 or 2,
p denotes 0, 1, 2, 3 or 4,
q 0, 1, 2 or 3,
with the proviso that only one or two of X 1 , X 2 , X 3 , X 4 denote N, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2 . Compounds according to claim 1 in which
R 4 denotes H or OA′,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3 . Compounds according to claim 1 , in which
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein 1-7 H-atoms may be replaced by R 5 , and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4 . Compounds according to claim 1 , in which
Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal and/or CN, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5 . Compounds according to claim 1 , in which
Het denotes a mono- or bicyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal and/or [C(R 3 ) 2 ]OA′, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6 . Compounds according to claim 1 , in which
Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, benzodioxanyl, benzothiadiazolyl, indazolyl, benzofuranyl, quinolyl, isoquinolyl, oxazolo[5,4-b]pyridyl, imidazo[1,2-a]pyrimidinyl or oxazolo[5,4-c]pyridyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or [C(R 3 ) 2 ] n OA′, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7 . Compounds according to claim 1 , in which
R denotes Ar, Het, —C≡C—Ar or —C≡C-Het, W denotes furanyl, thiophenyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by R 2 , R 1 denotes A, R 2 denotes A or Cyc, R 4 denotes H or OA′, X 1 , X 2 , X 3 , X 4 each, independently of one another, denote CH or N, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein 1-7 H-atoms may be replaced by R 5 , Cyc denotes cycloalkyl with 3-7 C-atoms, A′ denotes unbranched or branched alkyl with 1-6 C-atoms, R 5 denotes OH, Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal and/or CN, Het denotes a mono- or bicyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal and/or [C(R 3 ) 2 ] n OA′, Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, q 0, 1, 2 or 3, with the proviso that only one or two of X 1 , X 2 , X 3 , X 4 denote N, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

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

No.
Name

“A1”
4-benzoxazol-2-yl-N-methyl-N-[(1R,3S)-3-(5-propyl-

[1,3,4]oxadiazol-2-yl)-cyclopentyl]-benzamide

“A2”
biphenyl-4-carboxylic acid methyl-[(1R,3S)-3-(5-propyl-

[1,3,4]oxadiazol-2-yl)-cyclopentyl]-amide

“A3”
4-(4-fluoro-phenylethynyl)-N-methyl-N-[(1R,3S)-3-(5-propyl-

[1,3,4]oxadiazol-2-yl)-cyclopentyl]-benzamide

“A4”
4′-cyano-biphenyl-4-carboxylic acid methyl-[(1R,3S)-3-(5-

propyl-[1,3,4]oxadiazol-2-yl)-cyclopentyl]-amide

“A5”
4-benzoxazol-2-yl-N-[(1R,3S)-3-(5-ethyl-[1,3,4]oxadiazol-

2-yl)-cyclopentyl]-N-methyl-benzamide

“A6”
4′-cyano-biphenyl-4-carboxylic acid [(1R,3S)-3-(5-ethyl-

[1,3,4]oxadiazol-2-yl)-cyclopentyl]-methyl-amide

“A7”
4-(1H-benzimidazol-2-yl)-N-[(1R,3S)-3-(5-ethyl-[1,3,4]

oxadiazol-2-yl)-cyclopentyl]-N-methyl-benzamide

“A8”
N-[(1R,3S)-3-(5-ethyl-[1,3,4]oxadiazol-2-yl

Assignees

• Merck Patent Gmbh

Inventors

• Tsaklakidis Christos
• Staehle Wolfgang
• Leuthner Birgitta

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title