# US 10,118,919 B2 · 3-substituted cyclopentylamine derivatives

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- Number: US 10,118,919 B2
- Document ID: US10118919B2
- Status: Granted
- Kind: B2
- Application number: 15/696,830
- Filed: 2017-09-06
- Published: 2018-01-25
- Granted: 2018-11-06
- Earliest claimed: 2013-08-16
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Christos Tsaklakidis; Wolfgang Staehle; Birgitta Leuthner
- Web page: https://patentgrep.com/patent/US10118919B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/4245: Oxadiazoles
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 263/57: Aryl or substituted aryl radicals
- C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compounds of the formula I in which R, W, R1, R4, X1, X2, X3, X4 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.

## Claims

### Claim 1

Compounds of the formula I
in which
R denotes Ar or —C≡C—Ar,
W denotes furanyl, thiophenyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by R2,
R denotes A, [C(R3)2]nAr1 or [C(R3)2]nCyc,
R2 denotes A, [C(R3)2]nAr1, Cyc or ═O
R4 denotes H, F, Cl, Br, OH, CN, NO2, A′, OA′, SA′, SO2Me, COA′, CONH2, CONHA′ or CONA′2,
X1, X2, X3, X4 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 CH2-groups may be replaced by N-, O- and/or S-atoms and wherein 1-7 H-atoms may be replaced by R5,
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,
R5 denotes F, Cl or OH,
Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, O[C(R3)2]nHet1, Ar1, [C(R3)2]pOR3, [C(R3)2]pN(R3)2, NO2, CN, [C(R3)2]pCOOR3, CON(R3)2, [C(R3)2]pN(R3)2, N(R3)2COA, NR3SO2A, [C(R3)2]pSO2N(R3)2, S(O)nA, O[C(R3)2]mN(R3)2, NHCOOA, NHCON(R3)2 and/or COA,
Ar1 denotes phenyl or naphthyl, which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, [C(R3)2]pOR3, [C(R3)2]pN(R3)2, NO2, CN, [C(R3)2]pCOOR3, [C(R3)2]pN(R3)2, N(R3)2COA, NR3SO2A, [C(R3)2]pSO2N(R3)2, S(O)nA, O[C(R3)2]mN(R3)2, NHCOOA, NHCON(R3)2 and/or COA,
R3 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(R3)2]nOA′, [C(R3)2]nN(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, COHet1, NR3COA, NR3SO2A, SO2N(R3)2, S(O)nA, O[C(R3)2]mN(R3)2, NHCOOA, NHCON(R3)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 X1, X2, X3, X4 denote N, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 2 (depends on 1)

Compounds according to claim 1 in which
R4 denotes H or OA′,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 3 (depends on 1)

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 R5,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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(R3)2]nOA′,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 6 (depends on 1)

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(R3)2]nOA′,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 7 (depends on 1)

Compounds according to claim 1, in which
R denotes Ar —C≡C—Ar,
W denotes furanyl, thiophenyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by R2,
R1 denotes A,
R2 denotes A or Cyc,
R4 denotes H or OA′,
X1, X2, X3, X4 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 R5,
Cyc denotes cycloalkyl with 3-7 C-atoms,
A′ denotes unbranched or branched alkyl with 1-6 C-atoms,
R5 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(R3)2]nOA′,
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 X1, X2, X3, X4 denote N,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 8 (depends on 1)

Compounds according to claim 1, selected from the group
No.
Name
“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
“A6”
4′-cyano-biphenyl-4-carboxylic acid [(1R,3S)-3-(5-ethyl-
[1,3,4]oxadiazol-2-yl)-cyclopentyl]-methyl-amide
“A10”
4′-cyano-biphenyl-4-carboxylic acid [(1R,3S)-3-(5-isopropyl-
[1,3,4]oxadiazol-2-yl)-cyclopentyl]-methyl-amide
“A16”
4′-chloro-biphenyl-4-carboxylic acid methyl-[(1R,3S)-3-(5-
methyl-[1,3,4]oxadiazol-2-yl)-cyclopentyl]-amide
“A21”
4-(4-chloro-phenylethynyl)-N-methyl-N-[(1R,3S)-3-(5-methyl-
[1,3,4]oxadiazol-2-yl)-cyclopentyl]-benzamide
“A24”
biphenyl-4-carboxylic acid methyl-[(1R,3S)-3-(5-methyl-
[1,3,4]oxadiazol-2-yl)-cyclopentyl]-amide
“A25”
4′-cyano-biphenyl-4-carboxylic acid methyl-[(1R,3S)-3-(5-
methyl-[1,3,4]oxadiazol-2-yl)-cyclopentyl]-amide
“A29”
(rac)-cis-biphenyl-4-carboxylic acid [-3-(4-cyclopropyl-
[1,2,3]triazol-1-yl)-cyclopentyl]-methyl-amide
“A30”
(rac)-cis-biphenyl-4-carboxylic acid methyl-[3-(4-propyl-
[1,2,3]triazol-1-yl)-cyclopentyl]-amide
“A31”
biphenyl-4-carboxylic acid {(1R,3S)-3-[4-((S)-1-hydroxy-ethyl)-
[1,2,3]triazol-1-yl]-cyclopentyl}-methyl-amide
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 9 (depends on 1)

Medicaments comprising at least one compound of the formula I of claim 1 and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally an pharmaceutically acceptable carrier, excipient or vehicle.

### Claim 10 (depends on 1)

Medicaments comprising at least one compound of the formula I of claim 1 and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

### Claim 11 (depends on 1)

Set (kit) consisting of separate packs of
(a) an effective amount of a compound of the formula I of claim 1 and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,
and
(b) an effective amount of a further medicament active ingredient.