Macrocyclic quinazole derivatives and their use as MTKI

Patent metadata

Field	Value
Publication number	US-9688691-B2
Application number	US-201414285008-A
Country	US
Kind code	B2
Filing date	May 22, 2014
Priority date	Dec 8, 2004
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

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 —C 3-9 alkyl-, —C 1-5 alkyl-NR 13 —C 1-5 alkyl-, —C 1-5 alkyl-NR 14 —CO—C 1-5 alkyl-, —C 1-2 alkyl-NR 21 —H 2 —CO—NH—C 1-3 alkyl- or —C 1-2 alkyl-NR 23 —CO—CR 16 R 17 —NH—; X 1 represents O or —O—C 1-2 alkyl-; X 2 represents a direct bond, C 1-2 alkyl, —CO—C 1-2 alkyl or NR 12 —C 1-2 alkyl; R 1 represents hydrogen or halo; R 2 represents halo, acetylene or Het 1 R 3 represents hydrogen or cyano; R 4 represents Ar 4 —C 1-4 alkyloxy-, C 1-4 alkyloxy- or C 1-4 alkyloxy substituted with one or where possible two or more substituents selected from Het 2 , NR 7 R 8 , hydroxy and C 1-4 alkyloxy—C 1-4 alkyloxy-; R 7 represents hydrogen or C 1-4 alkyl; R 8 represents C 1-4 alkyl substituted with NR 25 R 26 or C 1-4 alkylsulfonyl; R 12 represents hydrogen or C 1-4 alkyl-; R 13 represents Ar 6 -sulfonyl or C 1-6 alkyloxycarbonyl optionally substituted with phenyl; R 16 and R 17 represents hydrogen, C 1-4 alkyl or R 16 and R 17 taken together with the carbon atom to which they are attached from a C 3-6 cycloalkyl; R 23 represents C 1-4 alkyl and R 23 represents hydrogen when R 16 and R 17 taken together with the carbon atom to which they are attached from a C 3-6 cycloalkyl; R 25 , R 26 , R 27 and R 28 each independently represent hydrogen or C 1-4 alkylcarbonyl; Het 1 represents 2-bora-1,3-dioxolanyl; Het 2 represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl wherein said Het 2 is optionally substituted with C 1-4 alkyloxycarbonyl or NR 27 R 28 —C 1-4 alkyl; Ar 4 and Ar 5 represents phenyl; Ar 6 represents phenyl optionally substituted with nitro.

First claim

The invention claimed is:

1. A compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
Z represents NH;
Y represents —C 3-9 alkyl-, —C 2-9 alkenyl-, —C 1-5 alkyl-oxy-C 1-5 alkyl-, —C 1-5 alkyl-NR 13 —C 1-5 alkyl-, —C 1-5 alkyl-NR 14 —CO—C 1-5 alkyl-, —C 1-6 alkyl-NH—CO—, —NH—CO—C 1-6 alkyl-, —CO—C 1-7 alkyl-, —C 1-7 alkyl-CO—, C 1-6 alkyl—CO—C 1-6 alkyl, —C 1-2 alkyl-NR 23 —CO—CR 16 R 17 —NH—, —C 1-2 alkyl-CO—NH—CR 18 R 19 —CO—, —C 1-2 alkyl-CO—NR 20 —C 1-3 alkyl-CO—, —C 1-2 alkyl-NR 21—CH 2 —CO—NH—C 1-3 alkyl-, —NR 22—CO—C 1-3 alkyl-NH—, —C 1-3 alkyl-NH—CO-Het 20 -, C 1-2 alkyl-CO-Het 21 -CO—, or -Het 22 -CH 2 —CO—NH—C 1-3 alkyl-;
X 1 represents O, —O—C 1-2 alkyl-, —O—N═CH—, NR 11 or —NR 11 —C 1-2 alkyl-;
X 2 represents a direct bond, C 1-2 alkyl, O, —O—C 1-2 alkyl-, CO, —CO—C 1-2 alkyl-, —O—N═CH—, NR 12 or NR 12 —C 1-2 alkyl-;
R 1 represents hydrogen, cyano, halo or hydroxy;
R 2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, C 1-4 alkyloxycarbonyl-, Het 16 -carbonyl-, C 1-4 alkyl-, C 2-6 alkynyl-, Ar 5 , Het 1 or dihydroxyborane;
R 3 represents hydrogen, cyano, halo, hydroxy, formyl, C 1-6 alkoxy-, C 1-6 alkyl-, C 1-6 alkoxy- substituted with halo, or R 3 represents C 1-4 alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo;
R 4 represents Ar 4 —C 1-4 alkyloxy-, C 1-4 alkyloxy- or R 4 represents C 1-4 alkyloxy substituted with one or where possible two or more substituents selected from hydroxy-, halo, C 1-4 alkyloxy-, C 1-4 alkyloxy-C 1-4 alkyloxy-, NR 37 R 38 -carbonyloxy-, Het 5 -carbonyloxy-, NR 7 R 8 , NR 9 R 10 -carbonyl-, Het 3 -carbonyl-, Het 13 -oxy- or Het 2 -;
R 7 represents hydrogen, hydroxy-C 1-4 alkyl- or C 1-4 alkyl;
R 8 represents C 3-6 cycloalkyl; Het 6 -carbonyl-; Het 7 -aminocarbonyl-; Het 8 ;
Het 9 -oxycarbonyl-; Het 10 -sulfonyl-; C 1-4 alkyloxycarbonyl;
mono- or di(C 1-4 alkyl)aminocarbonyl-; mono- or di(C 1-4 alkyl)aminocarbonyl substituted with C 1-4 alkylsulfonyl-; or
C 1-4 alkylcarbonyl optionally substituted with one or more substituents selected from C 1-4 alkylsulfonyl, hydroxy- and C 1-4 alkyloxy-; or
R 8 represents C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, NR 25 R 26 , aminocarbonyloxy-, C 1-4 alkylcarbonyloxy-, aminocarbonyl-, hydroxy-C 1-4 alkyloxy-, C 1-4 alkyloxy-C 1-4 alkyloxy-, and Het 11 ;

R 9 represents hydrogen or C 1-4 alkyl-;
R 10 represents Het 4 or C 1-4 alkyl- substituted with C 1-4 alkylsulfonyl-;
R 11 represents hydrogen, C 1-4 alkyl- or C 1-4 alkyl-oxy-carbonyl-;
R 12 represents hydrogen, C 1-4 alkyl-, C 1-6 alkyloxycarbonyl- or C 1-6 alkyloxycarbonyl-substituted with phenyl;
R 13 represents hydrogen, Het 14 -C 1-4 alkyl, C 1-6 alkyloxycarbonyl optionally substituted with phenyl or R 13 represents Ar 6 -sulfonyl or Het 24 -C 1-4 alkylcarbonyl;
R 14 and R 15 are each independently selected from hydrogen, C 1-4 alkyl, Het 15 -C 1-4 alkyl- or C 1-4 alkyloxyC 1-4 alkyl-;
R 16 and R 17 each independently represents hydrogen, C 1-4 alkyl or C 1-4 alkyl substituted with hydroxy-, C 3-6 cycloalkyl or phenyl; or R 16 and R 17 taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
R 18 represents hydrogen or C 1-4 alkyl optionally substituted with hydroxy or phenyl;
R 19 represents hydrogen or C 1-4 alkyl;
R 20 represents hydrogen or C 1-4 alkyl;
R 21 represents hydrogen, C 1-4 alkyl, Het 23 -C 1-4 alkylcarbonyl- or R 21 represents mono- or di(C 1-4 alkyl)amino-C 1-4 alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C 1-4 alkyloxy;
R 22 represents hydrogen or C 1-4 alkyl optionally substituted with hydroxy or C 1-4 alkyloxy;
R 23 represents C 1-4 alkyl optionally substituted with hydroxy-, C 1-4 alkyloxy- or Het 25 ; R 23 may also represent hydrogen when R 16 and R 17 taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
R 25 and R 26 each independently represent hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 27 and R 28 each independently represent hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-; or for those compounds of formula (I) wherein Het 2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl or thiomorpholinyl substituted with NR 27 R 28 —C 1-4 alkyl said R 27 and R 28 each independently represent C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 29 and R 30 each independently represent hydrogen, aminosulfonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl-, mono- or di(C 1-4 alkyl)aminosulfonyl-, or

C 1-4 alkyl- optionally substituted with one or more substituents selected from NR 31 R 32 , C 1-4 alkylsulfonyl, aminocarbonyloxy-, hydroxy-, C 1-4 alkyloxy-, aminocarbonyl- and mono- or di(C 1-4 alkyl)aminocarbonyl-, or
C 1-4 alkyloxycarbonyl optionally substituted with one or more substituents selected from hydroxy, C 1-4 alkyloxy- and C 1-4 alkylsulfonyl-, or C 1-4 alkylcarbonyl optionally substituted with one or more substituents selected from hydroxy-, C 1-4 alkyloxy- and C 1-4 alkylsulfonyl-;
R 31 and R 32 each independently represent hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 33 represents hydrogen or C 1-4 alkyl;
R 34 represents C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 35 represents hydrogen or C 1-4 alkyl;
R 36 represents C 1-4 alkylsulfonyl-, aminocarbonyl-, mono- or di(C 1-4 alkyl)aminocarbonyl-, C 1-4 alkylcarbonyl-, C 1-4 alkyloxycarbonyl- or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 37 and R 38 each independently represent hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl-, Het 12 or C 1-4 alkyl substituted with one or more substituents selected from C 1-4 alkylsulfonyl-, hydroxy- and C 1-4 alkyloxy-;
R 39 and R 40 each independently represent aminosulfonyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl-, mono- or di(C 1-4 alkyl)aminosulfonyl-, or
C 1-4 alkyl- substituted with one or more substituents selected from NR 31 R 32 ,
C 1-4 alkylsulfonyl, aminocarbonyloxy-, hydroxy-, C 1-4 alkyloxy-, aminocarbonyl- and mono- or di(C 1-4 alkyl)aminocarbonyl-, or
C 1-4 alkyloxycarbonyl optionally substituted with one or more substituents selected from hydroxy, C 1-4 alkyloxy- and C 1-4 alkylsulfonyl-, or
C 1-4 alkylcarbonyl optionally substituted with one or more substituents selected from hydroxy-, C 1-4 alkyloxy- and C 1-4 alkylsulfonyl-;

Het 1 represents thiazolyl or 2-bora-1,3-dioxolanyl wherein said Het 1 is optionally substit

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Freyne Eddy Jean Edgard
• Willems Marc
• Ten Holte Peter
• Papanikos Alexandra
• Embrechts Werner Constant Johan
• Storck Pierre Henri
• Poncelet Virginie Sophie

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/529

  forming part of bridged ring systems · CPC title

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D498/06 Primary

  Peri-condensed systems · CPC title