# US 9,040,511 B2 · 3-cyano-quinoline derivatives with antiproliferative activity

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- Number: US 9,040,511 B2
- Document ID: US9040511B2
- Status: Granted
- Kind: B2
- Application number: 13/796,377
- Filed: 2013-03-12
- Published: 2013-08-01
- Granted: 2015-05-26
- Earliest claimed: 2003-12-18
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica N.V.
- Inventors: Eddy Jean Edgard Freyne; Peter Jacobus Johannes Buijnsters; Kristof Van Emelen; Werner Constant Johan Embrechts; Timothy Pietro Suren Perera
- Web page: https://patentgrep.com/patent/US9040511B2

## CPC

- C07D 215/54: attached in position 3
- A61K 31/4748: forming part of bridged ring systems (strychnine A61K31/475; morphinan derivatives A61K31/485)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 498/06: Peri-condensed systems
- 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

## Abstract

The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O—; X2 represents a direct bond, —NR11—C1-2alkyl-, —NR11—CH2—, —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen, hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R3 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R10 represents hydrogen; R11 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R12 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

## Claims

### Claim 1

A method of treating ovarian cancer, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound
having the formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
Z represents O, NH or S;
Y represents —C3-9alkyl-, —C3-9alkenyl-, —C1-5alkyl-oxy-C1-5alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-5alkyl-NR13—CO—C1-5alkyl-, —C1-5alkyl-CO—NR14—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO-, —CO—NH—C1-6alkyl-, —NH—CO—C1-6alkyl-, —CO—C1-7alkyl-, —C1-7alkyl-CO—, C1-6alkyl-CO—C1-6alkyl, —C1-2alkyl-NH—CO—CH2R15—NH—;
X1 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR10, —NR10—C1-2alkyl-, NR16—CO—, NR16—CO—C1-2alkyl, —O—N═CH— or C1-2alkyl;
X2 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR11, NR11—C1-2alkyl-, NR17—CO—, NR17—CO—C1-2alkyl, Het20-C1-2alkyl, —O—N═CH— or C1-2alkyl;
R1 represents hydrogen, cyano, halo, hydroxy, formyl, C1-6alkoxy-, C1-6alkyl-, C1-6alkoxy- substituted with halo,
C1-4-alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo;
R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het16-carbonyl-, C1-4-alkyloxycarbonyl-, C1-4-alkylcarbonyl-, aminocarbonyl-, mono- or di(C1-4-alkyl)aminocarbonyl-, Het1, formyl, C1-4-alkyl-, C2-6alkynyl-, C3-6cycloalkyl-, C3-6cycloalkyloxy-, C1-6alkoxy-, Ar5, Ar1-oxy-, dihydroxyborane, C1-6alkoxy- substituted with halo,
C1-4-alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR4R5,
C1-4-alkylcarbonyl- wherein said C1-4-alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C1-4-alkyl-oxy-;
R3 represents hydrogen, hydroxy, Ar3-oxy, Ar4—C1-4-alkyloxy-, C1-4-alkyloxy-, C2-4alkenyloxy- optionally substituted with Het12 or R3 represents C1-4-alkyloxy substituted with one or where possible two or more substituents selected from C1-4-alkyloxy-, hydroxy, halo, Het-, —NR6R7, -carbonyl- NR8R9 or Het3-carbonyl-;
R4 and R5 are each independently selected from hydrogen or C1-4-alkyl;
R6 and R7 are each independently selected from hydrogen, C1-4-alkyl, Het8, aminosulfonyl-, mono- or di (C1-4-alkyl)-aminosulfonyl, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxycarbonyl-C1-4-alkyl-, C3-6cycloalkyl, Het9-carbonyl-C1-4-alkyl-, Het10-carbonyl-, polyhydroxy-C1-4-alkyl-, Het11-C1-4-alkyl- or Ar2—C1-4-alkyl-;
R8 and R9 are each independently selected from hydrogen, C1-4-alkyl, C3-6cycloalkyl, Het4, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl- or polyhydroxy-C1-4-alkyl-;
R10 represents hydrogen, C1-4-alkyl, Het5, Het6-C1-4-alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het7-C1-4-alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4-alkyloxyC1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4-alkyloxy-;
R11 represents hydrogen, C1-4-alkyl, C1-4-alkyl-oxy-carbonyl-, Het17, Het18-C1-4-alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het19-C1-4-alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4-alkyloxyC1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-;
R12 represents hydrogen, C1-4-alkyl, Het13, Het14-C1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4-alkyloxy-;
R13 and R14 are each independently selected from hydrogen, C1-4-alkyl, Het15-C1-4-alkyl- or C1-4alkyloxyC1-4-alkyl-;
R15 represents hydrogen or C1-4-alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
R16 and R17 are each independently selected from hydrogen, C1-4-alkyl, Het21-C1-4-alkyl or C1-4alkyloxyC1-4-alkyl;
Het1 represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het1 is optionally substituted amino, C1-4-alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl- mono- or di(C1-4-alkyl)amino- or amino-carbonyl-;
Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4-alkyl-, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxy-C1-4-alkyl-oxy-C1-4alkyl-, mono- or di(C1-4-alkyl)amino-, mono- or di(C1-4-alkyl)amino-C1-4-alkyl-, aminoC1-4-alkyl-, mono- or di(C1-4-alkyl)amino-sulfonyl-, aminosulfonyl-;
Het3, Het4 and Het8 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het3, Het4 or Het8 is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C1-4-alkyl-, C3-6cycloalkyl-C1-4-alkyl-, aminosulfonyl-, mono- or di(C1-4-alkyl)aminosulfonyl or amino-C1-4-alkyl-;
Het5 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het5 optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
Het6 and Het7 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het6 and Het7 are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
Het9 and Het10 each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het9 or Het10 is optionally substituted C1-4-alkyl, C3-6cycloalkyl-C1-4-alkyl- or amino-C1-4-alkyl-;
Het11 represents a heterocycle selected from indolyl or
Het12 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het12 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4-alkyl-, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxy-C1-4-alkyl-oxy-C1-4alkyl-, mono- or di(C1-4-alkyl)amino- or mono- or di(C1-4-alkyl)amino-C1-4-alkyl-;
Het13 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het13 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-allyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
Het14 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het14 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-allyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-;
Het15 and Het21 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycles are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-;
Het16 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C1-4-alkyl; and
Het17 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het17 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
Het18 and Het19 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het18 and Het19 are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
Het20 represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl or pyrazolidinyl wherein said Het20 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-; and
Ar1, Ar2, Ar3, Ar4 and Ar5 each independently represent phenyl optionally substituted with cyano, C1-4-alkylsulfonyl-, C1-4-alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C1-4alkyl, aminosulfonyl-, hydroxy-, C1-4-alkyloxy- or C1-4-alkyl.

### Claim 2 (depends on 1)

The method of claim 1 wherein in the compound:
Z represents NH;
Y represents —C3-9alkyl-, —C2-9alkenyl-, —C1-5alkyl-oxy-C1-5alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-5alkyl-NR13—CO—C1-5alkyl-, —C1-6alkyl-NH—CO-, —CO—C1-7alkyl-, —C1-7alkyl-CO— or C1-6alkyl-CO—C1-6alkyl;
X1 represents O, —O—C1-2alkyl-, —O—N═CH—, NR16—CO, —NR16—CO—C1-2alkyl-, NR10 or —NR10—C1-2alkyl;
X2 represents a direct bond, O, —O—C1-2alkyl-, —O—N═CH—, Het20-C1-2alkyl, C1-2alkyl, NR17—CO, —NR17—CO—C1-2alkyl-, NR11 or NR11—C1-2alkyl;
—NR11—CH2—, Het20-C1-2alkyl, NR17—CO, —NR17—CO—C1-2alkyl-C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—;
R1 represents hydrogen, cyano, halo or hydroxy;
R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, C1-4-alkyloxycarbonyl-, Het16-carbonyl-, C2-6alkynyl-, Ar5 or Het1;
R3 represents hydrogen, hydroxy, C1-4-alkyloxy-, Ar4—C1-4-alkyloxy or R3 represents C1-4-alkyloxy substituted with one or where possible two or more substituents selected from C1-4-alkyloxy- or Het2-;
R10 represents hydrogen, C1-4alkyl- or C1-4-alkyl-oxy-carbonyl-;
R11 represents hydrogen, C1-4alkyl- or C1-4-alkyl-oxy-carbonyl-;
R12 represents Het14-C1-4-alkyl;
R16 represents hydrogen, C1-4alkyl-, Het21-C1-4-alkyl or C1-4-alkyl-oxy-C1-4-alkyl;
R17 represents hydrogen, C1-4alkyl-, Het21-C1-4-alkyl or C1-4-alkyl-oxy-C1-4-alkyl;
Het1 represents thiazolyl optionally substituted amino, C1-4-alkyl, hydroxy-C1-4-alkyl-, phenyl, phenyl-C1-4-alkyl-, C1-4alkyl-oxy-C1-4alkyl- mono- or di(C1-4alkyl)amino- or amino-carbonyl-;
Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C1-4alkyl-;
Het14 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het14 is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C1-4alkyl-;
Het16 represents a heterocycle selected from piperidinyl, morpholinyl or pyrrolidinyl;
Het20 represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl or piperidinyl;
Het21 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het21 is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C1-4alkyl-;
Ar4 represents phenyl optionally substituted with cyano, hydroxy-, C1-4-alkyloxy or C1-4alkyl;
Ar5 represents phenyl optionally substituted with cyano, hydroxy, C1-4alkyloxy or C1-4alkyl.

### Claim 3 (depends on 1)

The method of claim 1 wherein in the compound:
Z represents NH;
Y represents —C3-9alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-5alkyl-NR13—CO—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-;
X1 represents a direct bond, NR10, —NR10—C1-2alkyl-, —NR10—CH2—, —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—;
X2 represents a-O—, NR11, NR17—CO, NR17—CO—C1-2 alkyl or Het20-C1-2 alkyl;
R1 represents hydrogen or halo;
R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5;
R3 represents hydrogen, hydroxy, C1-4-alkyloxy-, Ar4—C1-4-alkyloxy or R3 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-;
R10 represents hydrogen;
R11 represents hydrogen, C1-4alkyl- or C1-4-alkyl-oxy-carbonyl-;
R12 represents Het14-C1-4-alkyl;
R13 represents hydrogen;
R17 represents hydrogen;
Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C1-4alkyl-;
Het14 represents morpholinyl;
Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl;
Het20 represents pyrrolidinyl or piperidinyl;
Ar4 represents phenyl;
Ar5 represents phenyl optionally substituted with cyano.

### Claim 4 (depends on 1)

The method of claim 1 wherein in the compound:
the R1 substituent is at position 4′, the R2 substituent is at position 5′ and the R3 substituent at position 7 of the structure of formula (I).