# US 7,408,063 B2 · 1,8-annelated quinoline derivatives substituted with carbon-linked triazoles as farnesyl transferase inhibitors

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- Number: US 7,408,063 B2
- Document ID: US7408063B2
- Status: Granted
- Kind: B2
- Application number: 10/498,535
- Filed: 2002-12-11
- Published: 2005-08-11
- Granted: 2008-08-05
- Earliest claimed: 2001-12-19
- Assignees: Janssen Pharmaceutica NV
- Inventors: Patrick René Angibaud; Marc Gaston Venet
- Web page: https://patentgrep.com/patent/US7408063B2

## CPC

- C07D 471/06: Peri-condensed systems
- A61K 31/47: Quinolines; Isoquinolines
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

This invention comprises the novel compounds of formula (I) wherein r, s, A, X, Y1, Y2, R1, R2, R3, and R4 have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein
-A- is a bivalent radical of formula selected from the group consisting of
—CH2—CH2—; —CH2—CH2—CH2— and —CH2—O—;
>Y1—Y2—is >C═CR5— wherein R5 is hydrogen or halo
R1 is selected from the group consisting of hydrogen or halo;
R2 is selected from the group consisting of hydrogen, halo, or cyano;
R3 is selected from the group consisting of hydrogen, N-imidazolyl, —O—R6, and —NHR8;
wherein
R6 is selected from the group consisting of hydrogen, C1-6alkyl and hydroxyC1-6alkyl;
R8 is selected from the group consisting of hydrogen and C1-6alkylcarbonyl; and
R4 is hydrogen or C1-6alkyl.

### Claim 2 (depends on 1)

A compound according to claim 1 in which R2 is halo or cyano;
R3 is selected from the group consisting of hydrogen, hydroxy, amino, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylcarbonylamino and N-imidazolyl;
and R4 is C1-2alkyl.

### Claim 3 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl -4H-1,2,4-triazol-3-yl)methyl]- benzonitrile;
7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-2,3-dihydro-1H,5H-benzo[iJ]quinolizin-5-one;
6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
6-(4-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
6-(3-bromophenyl)-8-[(4-bromophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]- acetamide;
7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl) methyl]-2,3 -dihydro-1H,5H-benzo[ij]quinolizin-5-one;
6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol -3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol -3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;
8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl )-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.

### Claim 5

An intermediate of formula (IVa):
wherein:
-A- is a bivalent radical of formula selected from the group consisting of
—CH2—CH2—; —CH2—CH2—CH2—and —CH2—O—;
>Y1—Y2—is>>C═CR5 is hydrogen or halo;
R1 is selected from the group consisting of hydrogen or halo;
R2 is selected from the group consisting of hydrogen, halo, or cyano;
R4 is C1-6alkyl, and R21 is hydrogen or C1-6alkyl.