ZA200509541B - Macrocyclic quinazoline derivatives as antiproliferative agents - Google Patents
Macrocyclic quinazoline derivatives as antiproliferative agents Download PDFInfo
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- ZA200509541B ZA200509541B ZA200509541A ZA200509541A ZA200509541B ZA 200509541 B ZA200509541 B ZA 200509541B ZA 200509541 A ZA200509541 A ZA 200509541A ZA 200509541 A ZA200509541 A ZA 200509541A ZA 200509541 B ZA200509541 B ZA 200509541B
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- het
- salkyl
- 4alkyl
- hydroxy
- optionally substituted
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 238000001783 near-resonance Rayleigh scattering spectroscopy Methods 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
: Nn
MACROCYCLIC QUINAZOLINE DERIVATIVES AS ANTIPROLIFERATIVE AGENTS
-
This invention relates to quinazoline derived macrocycles that have been found to possess anti-proliferative activity, such as anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body, for example in the manufacture of medicaments for use in hyper proliferative disorders such as atherosclerosis, restenosis and cancer. The invention also relates to processes for the manufacture of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of anti-proliferative effect .
In particular, the compounds of the present invention were found to inhibit tyrosine kinase enzymes, also called tyrosine kinases. Tyrosine kinases are a class of enzymes, which catalyse the transfer of the terminal phosphate of adenosine triphosphate to the phenolic hydroxyl group of a tyrosine residue present in the target protein. It is known, that several oncogenes; involved in the transformation of a cell into a malignant tumour cell, encode tyrosine kinase enzymes including certain growth factor receptors such as EGF, FGF, IGF-IR, IR, PDGF and VEGF. This family of receptor tyrosine kinases and in particular the EGF family of receptor tyrosine kinases are frequently present in common human cancers such as breast cancer, non-small cell lung cancers including adenocarcinomas and squamous cell cancer of the lung, bladder cancer, oesophageal cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, cancer of the prostate, Jeukaeiftia and ovarian, bronchial or pancreatic cancer, which are examples of cell proliferation disorders. oo
Accordingly, it has been recognised that the selective inhibition of tyrosine kinases will be of value in the treatment of cell proliferation related disorders. Support for this view is provided by the development of Herceptin® (Trastuzumab) and
Gleevec™ (imatinib mesylate) the first examples of target based cancer drugs.
Herceptin® (Trastuzumab) is targeted against Her2/neu, a receptor tyrosine kinase found to be amplified up to 100-fold in about 30% of patients with invasive breast cancer. In clinical trials Herceptin® (Trastuzumab) proved to have anti-tumour activity against breast cancer (Review by LK. Shawer et al, “Smart Drugs: Tyrosine kinase inhibitors in cancer therapy”, 2002, Cancer Cell Vol.1, 117), and accordingly provided the proof of principle for therapy targeted to receptor tyrosine kinases. The second example, Gleevec™ (imatinib mesylate), is targeted against the abelson tyrosine kinase (BcR-Abl), a constitutively active cytoplasmic tyrosine kinase present in virtually all : patients with chronic myelogenous leukaemia (CML) and 15% to 30% of adult patients with acute lymphoblastic leukaemia. In clinical trials Gleevec™ (imatinib mesylate) showed a spectacular efficacy with minimal side effects that led to an approval within 3 months of submission. The speed of passage of this agent through clinical trials and regulatory review has become a case study in rapid drug development (Drucker BJ. & Lydon N., “Lessons leamed from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukaemia.”, 2000, J.Clin.Invest. 105, 3).
Further support is given by the demonstration that EGF receptor tyrosine kinase inhibitors, specifically attenuates the growth in athymic nude mice of transplanted carcinomas such as human mammary carcinoma or human squamous cell carcinoma (Review by T.R. Burke Jr., Drugs of the Future, 1992, 17, 119). Asa consequence, there has been considerable interest in the development of drugs to treat different cancers that target the EGFR receptor. For example, several antibodies that bind to the extracellular domain of EGFR are undergoing clinical trials, including ‘15 Erbitux™ (also called (C225, Cetuximab), which was developed by Imclone Systems . and is in Phase III clinical trials for the treatment of several cancers. Also, several . promising orally active drugs that are potent and relatively specific inhibitors of the
EGFR tyrosine kinase are now well advanced in clinical trials. The AstraZeneca compound ZD1839, which is now called IRESSA® and approved for the treatment of advanced non-small-cell lung cancer, and the OSI/Genentech/Roche compound OSI- : 774, which is now called Tarceva™ (erlotinib) , have shown marked efficacy against several cancers in human clinical trials (Morin M.J., “From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumour and anti- angiogenic agents, 2000, Oncogene 19, 6574).
In addition to the above, EGF receptor tyrosine kinases has been shown to be implicated in non-malignant proliferative disorders such as psoriasis (Elder et al.,
Science, 1989, 243; 811). Itis therefore expected that inhibitors of EGF type receptor tyrosine kinases will be useful in the treatment of non-malignant diseases of excessive cellular proliferation such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
It is disclosed in International Patent Application WO96/33980 and in J. Med. Chem, 2002, 45, 3865 that certain 4 anilino substituted quinazoline derivatives may be useful as inhibitors of tyrosine kinase and in particular of the EGF type receptor tyrosine kinases. Unexpectedly it was found that Quinazoline derivatives of the present formula (I) that are different in structure, show to have tyrosine kinase inhibitory activity.
It is accordingly an object of the present invention to provide further tyrosine kinase inhibitors useful in the manufacture of medicaments in the treatment of cell proliferative related disorders.
This invention concerns compounds of formula (I) x2 3 R!
AN 5 / z aN Rr? = N Nz 3 wt 7 Xu 2 ® g Ny : : the N-oxide forms, the pharmaceutically acceptable addition salts and the .stereochemically isomeric forms thereof, wherein :
Z represents O, CHp, NH or S; in particular Z represents NH;
YY represents -Cs.galkyl-, -Cs.galkenyl-, -Cs.galkynyl-, -C3.7alkyl-CO-NH- optionally substituted with amino, mono- or di(Ci4alkyl)amino or Cy4alkyloxycarbonylamino-, -C3.7alkenyl-CO-NH- optionally substituted with amino, mono- or di(C,4alkyl)amino or Cj4alkyloxycarbonylamino- , -C3 salkynyl-CO-NH- optionally substituted with amino, mono- or di(C4alkyl)amino or Cyalkyloxycarbonylamino-, _C,.salkyl-oxy-Cy.salkyl-, -C salkyl-NR *-Cy.salkyl-, -Cy.salkyl-NR*-CO-C; salkyl-, -Cy.salkyl-CO-NR-C, salkyl-, -C;.6alkyl-CO-NH-, -C,.¢alkyl-NH-CO-, -Cy.5alkyl-NH-CS-Het®-, -Cy.salkyl-NH-CO-Het™-, C;.2alkyl-CO-Het?! -CO-,
Het2-CH,-CO-NH-C, salkyl-, -CO-NH-C, salkyl-, -NH-CO-C; alkyl, -CO-C)qalkyl-, -C1.7alkyl-CO-, -C1.6alkyl-CO-Cy.¢alkyl-, .C;.zalkyl-NH-CO-CR'R""-NH-, -C;.,alkyl-CO-NH-CR'*R"-CO-, -Cy.,alkyl-CO-NR?-C; salkyl-CO-, -C;.zalkyl-NR*!-CHp-CO-NH-Cy salkyl-, or
NR%Z-CO-Cy.3alkyl-NH- ;
X! represents a direct bond, O, -O-C1.2alkyl-, CO, -CO- Cralkyl-, NR,
NR!'.Cy,alkyl-, -CHp-, -O-N=CH- or -Ci.zalkyl-;
X2 represents a direct bond, O, -O-Ci.2alkyl-, CO, -CO- Cy.2alkyl-, NR'Z,
NR'%.C, salkyl-, -CHy-, -O-N=CH- or -C;.zalkyl-; sR’ represents hydrogen, cyano, halo, hydroxy, formyl, C,¢alkoxy-, Crsalkyl-, halo-phenyl-carbonylamino-,
C;.¢alkoxy- substituted with halo,
C1.4alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo;
RZ represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'®-carbonyl-,
C,4alkyloxycarbonyl-, Cisalkylcarbonyl-, aminocarbonyl-, mono-or di(C, 4alkyl)aminocarbonyl-, Het', formyl, Cy.salkyl-, Ca.salkynyl-,
Cs.ecycloalkyl-, Ca¢cycloalkyloxy-, Ci.salkoxy-, Ar, Ar'-oxy-, dihydroxyborane ,
C;.¢alkoxy- substituted with halo, 15 . Ci4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR’R®, :
Cisalkylcarbonyl- wherein said Cy.4alkyl is optionally substituted with one or : where possible two or more substituents selected froin hydroxy or
C;alkyl-oxy-; a R’ represents hydrogen, C4alkyl, or Cy4alkyl substituted with one or more substituents selected from halo, Cy4alkyloxy-, amino-, mono-or di(Cj4alkyl)amino-, Ci 4alkyl-sulfonyl- or phenyl;
R* represents hydrogen, hydroxy, Ar-oxy, Ar*-C 4alkyloxy-, Ci4alkyloxy-,
C,.4alkenyloxy- optionally substituted with Het'? or R* represents Cj_salkyloxy substituted with one or where possible two or more substituents selected from
C1.salkyloxy-, hydroxy, halo, Het’, _NR'R®, <carbonyl- NR°R'? or
Het*-carbonyl-;
R’ and R® are each independently selected from hydrogen or Cy4alkyl;
R” and R® are each independently selected from hydrogen, C;4alkyl, Het®, aminosulfonyl-, mono- or di (C14alkyl)-aminosulfonyl, hydroxy-Cj.salkyl-,
C4alkyl-oxy-Ci.salkyl-, hydroxycarbonyl-Cy.salkyl-, Cs.scycloalkyl,
Het -carbonyl-C; 4alkyl-, Het'*-carbonyl-, polyhydroxy-Ci.salkyl-,
Het'!-Cy4alkyl- or Ar’-C; alkyl;
R® and R!° are each independently selected from hydrogen, Ci4alkyl, Cs.scycloalkyl,
Het?, hydroxy-Ci4alkyl-, Cs salkyloxyCialkyl- or polyhydroxy-Ci.salkyl-;
R!! represents hydrogen, C, alkyl, Het’, Het’-Cy4alkyl-, C,4alkenylcarbonyl- optionally substituted with Het’-Cy_4alkylaminocarbonyl-, Caalkenylsulfonyl-,
Cj4alkyloxyC)salkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or
Ciaalkyloxy-;
R!? represents hydrogen, Ci4alkyl, C;.4alkyl-oxy-carbonyl-, Het'3-C; qalkyl-, phenyl-C.salkyl-oxy-carbonyl-, Het!”, C,4alkenylcarbonyl- optionally substituted with Het'%-C;4alkylaminocarbonyl-, Cz4alkenylsulfonyl-,
C14alkyloxyC salkyl- or R'? represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or Cj.4alkyloxy-;
RP represents hydrogen, C.qalkyl, Het", Het"-C; 4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C4alkyloxy-;
R™ and R' are each independently selected from hydrogen, C;.alkyl,
Het!®-C; 4alkyl- or C;4alkyloxyCiqalkyl-; 15. - R' and R" each indepedently represents hydrogen or Cy4alkyl optionally substituted “ with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
R'® and RY each indepedently represents hydrogen or Cialkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
R® and R* each independently represents hydrogen or C1.4alkyl optionally substituted with hydroxy or Cy.4alkyloxy;
R? represents hydrogen, Cisatkyl, Het>-C,4alkylcarbonyl- or
R? represents mono-or di(Ci.alkyl)amino-C; salkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C;.salkyloxy;
Het! represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het! is optionally substituted with amino, C;alkyl, hydroxy-Ci4alkyl-, phenyl, phenyl-Cj_alkyl-,
Cj4alkyl-oxy-C4alkyl- mono- or di(C;.4alkyl)amino- or amino-carbonyl-;
Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, Cialkyl-, hydroxy-Cy.salkyl-, C)4alkyl-oxy-Cialkyl-, hydroxy-Cjalkyl-oxy-Csalkyl-, mono- or di(C;4alkyl)amino-, mono- or di(C,4alkyl)amino-C; 4alkyl-, aminoC4alkyl-, mono- or di(Cy.salkyl)amino-sulfonyl-, aminosulfonyl-;
Het®, Het" and Het® each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het®, Het* or Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, Ciaalkyl-,
Cs.¢cycloalkyl-C).salkyl-, aminosulfonyl-, mono- or di(C;4alkyl)aminosuifonyl or amino-C, 4alkyl-;
Het’ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
Ci4alkyl, Cs cycloalkyl, hydroxy-Cj.salkyl-, C14alkyloxyCialkyl or polyhydroxy-Ci4alkyl-;
Het® and Het’ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C4alkyl, Csgcycloalkyl, hydroxy-Cj.salkyl-, CiaalkyloxyC4alkyl or polyhydroxy-Ci.4alkyl-; .. ., Het’ and Het!’ each independently represent a heterocycle selected from furanyl, _piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridiny} or pyrrolidinyl wherein said Het’ or Het? is optionally substituted Cy.salkyl, C.scycloalkyl-Cy.salkyl- or : amino-Cj4alkyl-; : ee ~—
Het!! represents a heterocycle selected from indolyl or ZZ
Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het'? is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C;4alkyl-, hydroxy-C;4alkyl-, Cialkyl-oxy-C;4alkyl-, hydroxy-C;4alkyl-oxy-C salkyl-, mono- or di(C;4alkyl)amino- or mono- or di(C4alkyl)amino-Ci.4alkyl-;
Het? represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
Ci4alkyl, Cs.scycloalkyl, hydroxy-C,4allkyl-, C;4alkyloxyC;.salkyl or polyhydroxy-Cy-salkyl-;
Het! represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C;alkyl, Cs.¢cycloalkyl, hydroxy-Ci.saltkyl-,
C;4alkyloxyC;4alkyl or polyhydroxy-C;.4alkyl-;
Het! represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C4alkyl, Cscycloalkyl, hydroxy-Cj4alkyl-,
CisalkyloxyC,.4alkyl or polyhydroxy-Ci.4alkyl-;
Het! 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 Ci4alkyl; and
Het!” represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
Cialkyl, Ca.scycloalkyl, hydroxy-Ci.satkyl-, CialkyloxyCi.salkyl or polyhydroxy-Cjsalkyl-;
Het!® and Het'® each independently represent a heterocycle selected from morpholinyl, pyrrolidiny}, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cj4alkyl,
Cs.¢cycloalkyl, . . hydroxy-Cj4alkyl-, Ci4alkyloxyCi4alkyl or polyhydroxy-Ci.4alkyl-;
Het®®, Het?! and Het?” each independently represent a heterocycle selected from : pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted . with one or where possible two or more substituents selected from hydroxy, :
C4alkyl, hydroxy-C;salkyl- or polyhydroxy-Cj 4alkyl-; :
Het? represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or - piperidinyl optionally substituted with one or where possible two or more substituents selected from Cj.4alkyl, Cs¢cycloalkyl, hydroxy-Ci4alkyl-,
C14alkyloxyCi.salkyl or polyhydroxy-Cisalkyl-;
Ar, Ar, Ar, Ar* and AP each independently represent phenyl optionally substituted with cyano, C;alkylsulfonyl-, C, qalkylsulfonylamino-, aminosulfonylamino-, hydroxy-Ci.salkyl, aminosulfonyl-, hydroxy-, Cj4alkyloxy- or Ci4alkyl.
As used in the foregoing definitions and hereinafter, - halo is generic to fluoro, chloro, bromo and iodo; - C, alkyl defines methyl or ethyl; - C, jalkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, for example, methyl, ethyl, propyl and the like; -C, alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1- methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like;
- C,_salkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, 1- methylbutyl, 2,2-dimethylpropyl, 2,2-dimethylethyl and the like; - C, ¢alkyl is meant to include C,.salkyl and the higher homologues thereof having 6 carbon atoms such as, for example hexyl, 1,2-dimethylbutyl, 2-methylpentyl and the like; - C, ;alkyl is meant to include C,.alkyl and the higher homologues thereof having 7 carbon atoms such as, for example 1,2,3-dimethylbutyl, 1,2-methylpenty! and the like; - Cs.salkyl defines straight and branched chain saturated hydrocarbon radicals having from 3 to 9 carbon atoms such as propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like; - Cp4alkeny! defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 4 carbon atoms such as, for example vinyl, 2- propenyl, 3-butenyl, 2-butenyl and the like; - - Caalkenyl defines straight and branched chain hydrocarbon radicals containing one : y double bond and having from 3 to 9 carbon atoms such as, for example 2-propenyl, 3- . butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; - Ca¢alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 2 to 6 carbon atoms such as, for example, 2-propynyl, 3- “ butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexyny! and the like; - Cs¢cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; - Ci4alkyloxy defines straight or branched saturated hydrocarbon radicals such as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy, 2-methylpropyloxy and the like; - C1¢alkyloxy is meant to include C;4alkyloxy and the higher homologues such as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy, 2-methylpropyloxy and the like; - polyhydroxy-Cj4alkyl is generic toa Ci 4alkyl as defined hereinbefore, having two, three or were possible more hydroxy substituents, such as for example trifluoromethyl.
As used in the foregoing definitions and hereinafter, the term formyl refers to a 3s radical of formula ~CH(=0). When X' represent the divalent radical -O-N=CH-, said radical is attached with the carbon atom to the R®, R* bearing cyclic moiety of the compounds of formula (I) and when X? represents the divalent radical ~O-N=CH-,
said radical is attached with the carbon atom to the R', R? bearing phenyl moiety of the compounds of formula (I).
The heterocycles as mentioned in the above definitions and hereinafter, are meant to include all possible isomeric forms thereof, for instance pyrrolyl also includes 2H- pyrrolyl; triazolyl includes 1,2 A-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2 ,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3 4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.
Further, the heterocycles as mentioned in the above definitions and hereinafter may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; . when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is : .triazolyl, it may be 1,2 4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4- triazol-1-yl and 1,3 4-triazol-2-yl; when it is benzothiazolyl, it may be 2- benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl and " 7-benzothiazolyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydrox yacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butane-dioic acid), maleic, fumnaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base addition salt forms which the compounds of formula (I) are able to form. Examples of such base addition salt forms are, for example, the sodium, potassium, calcium salts, and also the salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g. arginine, lysine.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term stereochemically isomeric forms as used hereinbefore defines the possible different isomeric as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture ith each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric forms. .
Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. . ~The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (T) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. :
A first group of compounds according to the present invention consists of those compounds of formula (I) wherein one or more of the following restrictions apply;
Z represents O, NH or S;
Y represents -Cs.oalkyl-, -C3_galkenyl-, -C,.salkyl-oxy-Cy.salky 1-, -Cy.5alkyl-NR3-C; salkyl-, -Cy.salkyl-NR*-CO-Cysalkyl-,
Cy.5alkyl-CO-NR'3-C; salkyl-, -C.salkyl-CO-NH-, -C; alkyl-NH-CO-, -CO-NH-C, ¢alkyl-, -NH-CO-C;.¢alkyl-, -CO-C.7alkyl-, -Ci7alkyl-CO-, -C1.¢alkyl-CO-Cy.salkyl-, -C,.zalkyl-NH-CO-CHR '*-NH-;
X! represents a direct bond, O, -O-Cy.zalkyl-, CO, -CO- Cialkyl-, NR",
NR'-C,.zalkyl-, -CH;-, -O-N=CH- or -Ci.2alkyl-;
X? represents a direct bond, 0, -O-Cy.zalkyl-, CO, -CO- Crzalkyl-, NR",
NR!2.C, 5alkyl-, -CH,-, -O-N=CH- or -C;.zalkyl-; y rR represents hydrogen, cyano, halo, hydroxy, formyl, C,¢alkoxy-, Cr.alkyl-,
C,salkoxy- substituted with halo,
C1salkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'S-carbonyl-,
Ci4alkyloxycarbonyl-, Cj «alkylcarbonyl-, aminocarbonyl-, mono-or di(C4alkyl)aminocarbonyl-, Het, formyl, Cy4alkyl-, C,.salkynyl-,
Cs.cycloalkyl-, Csecycloalkyloxy-, Ci.¢alkoxy-, AP, Ar'-oxy-, dihydroxyborane ,
C,.¢alkoxy- substituted with halo,
Cialkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NRRS,
Ciualkylcarbonyl- wherein said C4alkyl is optionally substituted with one or : where possible two or more substituents selected from hydroxy or
Ci4alkyl-oxy-;
RS represents hydrogen, C 14alkyl, or Cy4alkyl substituted with one or more : substituents selected from halo, C;.salkyloxy-, amino-, mono-or - di(Cy.4alkyl)amino-, : " Cjgalkyl-sulfonyl- or phenyl; :
Rr? represents hydrogen, hydroxy, Ar’-oxy, Ar*-C,4alkyloxy-, Cy 4alkyloxy-,
C,.qalkenyloxy- optionally substituted with Het'? or R* represents C;4alkyloxy : substituted with one or where possible two or more substituents selected from
C4alkyloxy-, hydroxy, halo, Het>-, NR'RS, -carbonyl- NR’R! or
Het>-carbonyl-;
R® and R® are each independently selected from hydrogen or Ci.salkyl; os R’ and R® are each independently selected from hydrogen, Cy4alkyl, Het®, aminosulfonyl-, mono- or di (C)4alkyl)-aminosulfonyl, hydroxy-Ci.4alkyl-,
C«alkyl-oxy-Cj.salkyl-, hydroxycarbonyl-C;.4alkyl-, Cs.scycloalkyl,
Het’-carbonyl-Cy4alkyl-, Het'%-carbonyl-, polyhydroxy-Ci.4alkyl-,
Het!!-C, 4alkyl- or Ar*-Cyaalkyl-;
R? and R'° are each independently selected from hydrogen, C;4alkyl, Cs.scycloalkyl,
Het*, hydroxy-C4alkyl-, C4alkyloxyCi4alkyl- or polyhydroxy-C;4alkyl-;
RY represents hydrogen, Cyalkyl, Het’, Het’-C;4alkyl-, Czalkenylcarbonyl- optionally substituted with Het'-C) 4alkylaminocarbonyl-, Cz 4alkenylsulfonyl-,
C,.4alkyloxyCi.4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or
Cj4alkyloxy-;
R™ represents hydrogen, Cy.4alkyl, Ci4alkyl-oxy-carbonyl-, Het', Het'®-C; salkyl-,
C..salkenylcarbonyl- optionally substituted with Het!’-C; salkylaminocarbonyl-,
C,.4alkenylsulfonyl-, C;4alkyloxyCi.salkyl- or R!? represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or Cialkyloxy-;
R" represents hydrogen, Cisalkyl, Het'?, Het'*-C;4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C;alkyloxy-;
R™ and R'® are each independently selected from hydrogen, Cy.4alkyl,
Het'*-C, 4alkyl- or C;4alkyloxyCisalkyl-;
R'® represents hydrogen or Cy alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoy] or guanidino;
Het! represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, - furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, +. oxadiazolyl, pyridiny! or pyrrolidinyl wherein said Het' is optionally substituted with amino, Cysalkyl, hydroxy-Ci4alkyl-, phenyl, phenyl-Cj_salkyl-, : . Cjalkyl-oxy-Cj4alkyl- mono- or di(C,4alkyl)amino- or amino-carbonyl-; : :
Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, ' 20 . pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het? is optionally . substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C;4alkyl-, hydroxy-Cj4alkyl-, C;4alkyl-oxy-C;4alkyl-, hydroxy-C;4alkyl-oxy-Ci4alkyl-, mono- or di(C;.4alkyl)amino-, mono- or di(C,_salkyl)amino-C; salkyl-, aminoC,4alkyl-, mono- or di(C;.4alkyl)amino-sulfonyl-, aminosulfonyl-;
Het’, Het* and Het® each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het®, Het* or Het® is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, Cysalkyl-,
Cs .scycloalkyl-Cialkyl-, aminosulfonyl-, mono- or di(C;-salkyD)aminosulfonyl or amino-Cj4alkyl-;
Het’ represent a heterocycle selected from pyrrolidinyl or piperidiny! optionally substituted with one or where possible two or more substituents selected from
C4alkyl, Cs ¢cycloalkyl, hydroxy-Cj4alkyl-, C,4alkyloxyC;4alkyl or polyhydroxy-Cj.salkyl-;
Het® and Het’ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C.4alkyl, Ca.scycloalkyl, + hydroxy-C4alkyl-, CyalkyloxyCi.salkyl or polyhydroxy-Cjalkyl-;
Het’ and Het'® each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, . imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het’ or Het'® is optionally substituted C1alkyl, Cs.scycloalkyl-Cialkyl- or amino-Cjalkyl-; ~ =
Het! represents a heterocycle selected from indolyl or Z
Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, Ci4alkyl-, hydroxy-Ci4alkyl-, Cj «alkyl-oxy-Cj.salkyl-, hydroxy-Cj.salkyl-oxy-Ci4alkyl-, mono- or di(C;4alkyl)amino- or mono- or - di(Cy4alkyl)amino-Crealkyl-; :
Het" represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally oi . «substituted with one or where possible two or more substituents selected from :
C;4alkyl, Cs ¢cycloalkyl, hydroxy-C,sallkyl-, C14alkyloxyCy4alkyl or : polyhydroxy-C; 4alkyl-;
Het represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cj_alkyl, Cs.scycloalkyl, hydroxy-C;4allkyl-,
Ci4alkyloxyCsalkyl or polyhydroxy-Ci4alkyl-;
Het" represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C;4alkyl, Cascycloalkyl, hydroxy-C.salkyl-,
C4alkyloxyCi alkyl or polyhydroxy-C,salkyl-;
Het'S 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 C;.4alkyl; and
Het!” represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
C,alkyl, Csscycloalkyl, hydroxy-C.salkyl-, C,4alkyloxyC,4alkyl or polyhydroxy-Cj4alkyl-;
Het'® and Het'® each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cy.4alkyl,
Cs.ecycloalkyl, hydroxy-C;.salkyl-, C14alkyloxyCialkyl or polyhydroxy-Cisalkyl-;
Ar, AP, AP, Art and AP each independently represent phenyl optionally substituted with cyano, Cy4alkylsulfonyl-, C;«alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C.4alkyl, aminosulfonyl-, hydroxy-, Cy4alkyloxy- or Cj4alkyl.
An interesting group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply :
Z represents NH;
Y represents -Cs oalkyl-, -C,.galkenyl-, -Cy.salkyl-oxy-Ci.salkyl-, -Cy.salkyl-NRP-Cy salkyl-, -C,.salkyl-NR"*-CO-C; salkyl-, -Cy-¢alkyl-NH-CO-, i -NH-CO-C,.calkyl-, -CO-Cyqalkyl-, -Cj7alkyl-CO-, C;.6alkyl-CO-Cj.¢alkyl, + -Cyalkyl-NH-CO-CR'R"-NH-, -Cy.2alkyl-CO-NH-CR*R"*-CO-, . "C, alkyl-CO-NR?-Cy 3alkyl-CO-, -Cy.zalkyl-NR*'-CHy-CO-NH-C;.salkyl-, ’ | NR?-CO-C, salkyl-NH-, -Cy salkyl-NH-CO-Het™-, Ci2alkyl-CO-Het”'-CO-,or = -Het™CH,-CO-NH-Cpsalkyl : X! represents O, -0-Cysalkyl-, -O-N=CH-, NR" or -NR!'-C; alkyl-; in a particular g embodiment X' represents NR!!-, -O- or -O0-CHy-; :
X? represents a direct bond, O, -O-Cizalkyl-, -O-N=CH-, NR'2 or NR'%-C, ,alkyl-; in a particular embodiment X? represents a direct bond, -Ci.patkyl-, -0-Cizalkyl, —0- or -O-CH»-; R represents hydrogen, cyano, halo or hydroxy, preferably halo;
R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,
Cj 4alkyloxycarbonyl-, Het'S-carbonyl-, Cy4alkyl-, C2.salkynyl-, AP or Het';
In a further embodiment R? represents hydrogen, cyano, halo, hydroxy,
Cs ¢alkynyl- or Het'; in particular R? represents hydrogen, cyano, halo, hydroxy, or Ar’;
R? represents hydrogen; rR? represents hydrogen, hydroxy, Cj4alkyloxy- or R* represents Cy.salkyloxy substituted with one or where possible two or more substituents selected from
C4alkyloxy- or Het;
RZ represents hydrogen, Ci.salkyl- or Cy4alkyl-oxy-carbonyl-;
RY representshydrogen or Het'*-C; alkyl, in particular morpholinyl-Cjalkyl;
RM and R® represents hydrogen;
RI® represents hydrogen or Ci.4alkyl substituted with hydroxy;
RY represents hydrogen or Ci4alkyl, in particular hydrogen or methyl;
R'® represents hydrogen or Ci.4alkyl optionally substituted with hydroxy or phenyl;
R' represents hydrogen or Ci4alkyl, in particular hydrogen or methyl, even more particular hydrogen;
R? represents hydrogen or Ci.4alkyl, in particular hydrogen or methyl;
R* represents hydrogen, C;alkyl, Het®-C,4alkylcarbonyl- or
R? represents mono-or di(C4alkyl)amino-Cysalkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C,4alkyloxy; R% represents hydrogen or C;4alkyl optionally substituted with hydroxy or
Ci-qalkyloxy;
Het’ represents thiazolyl optionally substituted with amino, Cj-salkyl, hydroxy-Ci. salkyl-, phenyl, phenyl-C;4alkyl-, C,4alkyl-oxy-C1.4alkyl- mono- or di(Ci. _ salkyl)amino- or amino-carbonyl-; 15. " Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or “4 pyrrolidinyl wherein said Het? is optionally substituted with one or where ©, ..possible two or more substituents selected from hydroxy, amino or C;.4alkyl-; Co
In a further embodiment Het? represents a heterocycle selected from morpholinyl ; .or piperidiny! optionally substituted with Cj4alkyl-, preferably methyl;
Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cj.salkyl-; :
Het'? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het? js optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cialkyl-;
Het'® represents a heterocycle selected from piperidinyl or pyrrolidinyl;
Het? represents pyrrolidinyl, 2-pyrrolidinonyl, piperidinyl or hydroxy-pyrrolidinyl, preferably pyrrolidinyl or hydroxy-pyrrolidinyl; .
Het?! represents pyrrolidinyl or hydroxy-pyrrolidinyl; Het® represents pyrrolidinyl, piperazinyl or piperidinyl.
A particular group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply :
Z represents NH;
Y represents -Csgalkyl-, -Cygalkenyl-, -C3.7alkyl-CO-NH optionally substituted with amino, mono — or di(C;salkyl)amino or C;4alkyloxycarbonylamino-, -C; salkenyl-CO-NH- optionally substituted with amino, mono- or di(C;salkyl)amino- or C4alkyloxycarbonylamino-,
C1.salkyl-NR'>-C, salkyl-, .C, salkyl-NR*-CO-C, salkyl-, -Ci.alkyl-CO-NH-, -C,.salkyl-CO NR">-C.salkyl-, -C,.salkyl-NH-CO-Bet*’-, -C2alkyl-CO-Het*'-CO-, .C, 2alky)-NH-CO-CR'*R"-NH-, -C,.,alkyl-CO-NH-CR'*R?-CO-, -C1.,alkyl-CO-NR¥-C; salkyl-CO-, or —NR*.CO-C,.3alkyl-NH-; even more particular Y represents —Cs.oalkyl-, -Cy.salkyl-NR-Csalkyl-, -C,.salkyl-NR!-CO-C; salkyl-, -C,.salkyl-NH-CO-Het*'-, -C}.,alkyl-CO-Het?-CO-, or -Cy.,alkyl-NH-CO-CR'°R"-NH-; X' represents a direct bond, O or -0-Cy.0alkyl-;
X? represents a direct bond, -CO-Cy.alkyl-, NR!?, -NR'%-C, zalkyl-, -O-N=CH- or ~C;.22lkyl-; even more particular X? represents —CO-C)zalkyl- or
NR'2-C} palkyl-;
R! represents hydrogen or halo, preferably hydrogen, chloro, fluoro or bromo; R? represents hydrogen or halo, preferably hydrogen, chloro, fluoro or bromo; .R3 represents hydrogen;
CRY represents hydrogen or Ci4alkyloxy, preferably Ci4alkyloxy, even more - . preferably methoxy; : :
R'2 represents hydrogen or Cy4alkyl, preferably hydrogen or methyl;
RR! represents hydrogen or Ci4alkyl;
R* represents hydrogen; :
R" represents hydrogen;
R'6 and R" each independently represent hydrogen or Cj4alkyl;
R'® and R!® each independently represent hydrogen or C,4alkyl optionally substituted with phenyl or hydroxy;
R? and R¥ each independently represent hydrogen or C,.4alkyl optionally substituted with Cj 4alkyloxy;
Het®, Het?! and Het? each independently represent a heterocycle selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally substituted with hydroxy.
A preferred group of compounds consists of those compounds of formula (1) wherein one or more of the following restrictions apply :
Z represents NH;
Y represents -Cs.galkyl-, -Casalkenyl-, -Cj.salkyl-oxy-Cj.salkyl-, -C,_salkyl-NR-C, salkyl-, -C;.¢alkyl-NH-CO-, -CO-Ci.7alkyl-, -C1.7alkyl-CO- or
C, calkyl-CO-C galkyl;alkyl-NH-CO-Het™-, -C;.2alkyl-CO-Het*'-CO-,
C, alkyl-NE-CO-CR*R"-NH-, -Cy zalkyl-CO-NH-CR*R ®-CO-, -Cy.p2lkyl-
CO-NR¥-C
X! represents O, -O-C; alkyl, -O-N=CH-, NR" or -NR".-Cy.;alkyl-; in a particular embodiment X' represents -NR''-, -O- or -0-CHz-; 5X represents a direct bond, O, -O-Cy.alkyl-, -O-N=CH-, NR" or NR'%.C;.palkyl-; in a particular embodiment X> represents a direct bond, C;.palkyl-, -O-Cy.aalkyl, —O- or -O-CH~;
R! represents hydrogen, cyano, halo or hydroxy, preferably halo;
R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,
C).4alkyloxycarbonyl-, Het'S-carbonyl-, C;4alkyl-, Czalkynyl-, Ar or Het;
In a further embodiment rR? represents hydrogen, cyano, halo, hydroxy,
Cp.alkynyl- or Het; in particular R? represents hydrogen, cyano, halo, hydroxy, or Ar; ~ R® represents hydrogen;
R* represents hydrogen, hydroxy, Cy4alkyloxy- or R* represents Cqalkyloxy substituted with one or where possible two or more substituents selected from . Ci4alkyloxy- or Het’; : :
R'? represents hydrogen, C1.4alkyl- or C,4alkyl-oxy-carbonyl-; *
R™ represents Het'*-Cy 4alkyl, in particular morpholinyl-Cisalkyl;
Het! represents thiazolyl optionally substituted with amino, C;4alkyl, hydroxy-C;. ; salkyl-, phenyl, phenyl-C;.salkyl-, Ci 4alkyl-oxy-Cj4alkyl- mono- or di(C;- salkyl)amino- or amino-carbonyl-; :
Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Calkyl-;
In a further embodiment Het? represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with Ci.alkyl-, preferably methyl;
Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Ci4alkyl-;
Het'? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het'? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cy_salkyl-;
Het'¢ represents a heterocycle selected from piperidinyl or pyrrolidinyl.
A further group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply :
Z represents NH;
Y represents -Cs.salkyl-, -C.salkyl-NR-Cy.salkyl-, -C¢alkyl-NH-CO-, -CO-Ci.yalkyl- or -C17alkyl-CO-;
X! represents -NR'-, ~O- or ~O-CHy-; X2represents a diréct bond, -NR'%, _NR'.C, ,alkyl-, -CO-, -O- or -O-CHz-;
R! represents halo; in particular R' represents chloro, fluoro or bromo and is at position 5’;
R? represents hydrogen, cyano, halo, hydroxy, or Ar;
R® represents hydrogen; R*represents C;4alkyloxy substituted with one or where possible two or more substituents selected from C,4alkyloxy- or Het’;
R" represents Cj.salkyl or R!? represents C,.4alkyl-oxy-carbonyl;
RY represents Het'*-Cyalkyl;
Het? represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C,.salkyl-; * Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or : -. pyrrolidinyl wherein said Het? is optionally substituted with one or where . possible two or more substituents selected from hydroxy, amino or Cyalkyl-; 2
Het' represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or . pyrrolidinyl wherein said Het'? is optionally substituted with one or where ‘ possible two or more substituents selected from hydroxy, amino or Cialkyl-;
Het'* represents morpholinyl.
In a further embodiment of the present invention the compounds of formula (I) are selected from the group consisting of ; 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17- bromo-8,9,10,11,12,13,14, 19-octahydro-20-methoxy- 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17- bromo-8,9,10,11,12,13,14, 19-octahydro-20-methoxy-13-methyl- benzamide, 4-fluoro-N-(8,9,10,1 1,12,13-hexahydro-20-methoxy-4,6- ethanediylidene-19H-pyrimido[4,5-b] [6,13,1]benzodioxaazacyclopentadecin- 16-yl)- 4 6-ethanediylidene-8H,14H-pyrimido[4.5- b][6,12,1]benzodioxaazacyclohexadecine, 18-chloro-9,10,11,12,15,20- hexahydro-21-methoxy- 4,6-ethanediylidene-8H-pyrimido[4,5-b} [6,1,11]benzoxadiazacyclohexadecin-
11(12H)-one, 18-chloro-9,10,13,14,15,20-hexahydro-21-methoxy- 4 6-cthanediylidene-14H-pyrimido{4,5-b] [6,9 .12,1]benzotrioxaazacyclohexadecine, 18-chloro-8,9,11,12,15,20-hexahydro-2 1-methoxy- 4 6-ethanediylidenepyrimido[4,5-blpyrrolo[2, 1- k] [6,1,9,12]benzoxatriazacyclopentadecin-1 1(8H)-one, 19~chloro- 9,10,11a,12,13 ,14,16,21-octahydro-22-methoxy- 4,6-ethanediylidenepyrimido[4,5-b] [6,1,9, 12]benzoxatriazacyclopentadecin-1 1(8H)- one, 17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl- 4 6-ethanediylidenepyrimido [4,5-b}[6,1,9, 12]benzoxatriazacyclopentadecin-1 1(8H)- one, 17-chloro-9,10,12,13,14,19-hexahydro-20-methoxy- 4 6-ethanediylidene-12H-pyrimido [4,5-b][6,1,10,1 3]benzoxatriazacyclohexadecin- 12-one, 18-chloro-8,9,10,11 13,14,15,20-octahydro-21-methoxy-14-methyl- 4,6-ethanediylidene-8H-pyrimido[4,5-b] [6,1,9, 13]benzoxatriazacyclohexadecin- 11(12H)-one, 18-chloro-9 ,10,13,14,15,20-hexahydro-21-methoxy- 4 6-ethanediylidenepyrimido[4,5-b] [6,1 .10,14]benzoxatriazacycloheptadecin- ++ 12(13H)-one, 19-chloro-8,9,10,1 1,14,15,16,21-octahydro-22-methoxy- : 4,6-ethenopyrimido[4,5-b] [6,1,9, 12Jbenzoxatriazacyclopentadecine-9,12(8H, 13H)- . dione, \7-chloro-10,11,14,19-tetrahydro-20-methoxy-
4 6-etheno-8H-pyrimido(4,5-blpyrrolo[2,1- : 1][6,1 ,10,13]benzoxatriazacyclohexadecine- 12,15(14H)-dione, 20-chloro- 9,10,11,12a,13,17 ,22-heptahydro-23-methoxy-
4 6-ethanediylidene-12H-pyrimido[4,5-b]pyrrolo(2, 1- 1]{6,1,10,13Tbenzoxatriazacyclohexadecin-12-one, 20-chloro- 8.9,10,11,12a,13,14,15,17 ,22-decahydro-23-methoxy-
4 6-ethenopyrimido([4,5-b) [6,1,9, 14]benzoxatriazacycloheptadecine-9,14(8H, 15H)- dione, 19-chloro-10,11,12,13 ,16,21-hexahydro-22-methoxy-
4,6-etheno-8H-pyrimido[4,5-b] [6,19,1 3]benzoxatriazacyclohex adecine- 9,13(10H,14H)-dione, 18-chloro-11 ,12,15,20-tetrahydro-21-methoxy-
4 6-ethenopyrimidof4,5-b](6,1,11, 14]benzoxatriazacycloheptadecine- 11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,2 1-hexahydro-22-methoxy-
4,6-ethenopyrimidof4,5-b][6,1,11 ,16]benzoxatriazacyclononadecine- 11,16(8H,17H)-dione, 21-chloro-9,10,12,13,14,15,18,23-octahydro-24- methoxy-
4 6-etheno-8H-pyrimido[4,5-b] [6,1,11,15]benzoxatri azacyclooctadecine- 11,15(12H,16H)-dione, 20-chloro-9,10,13,14, 17,22-hexahydro-23-methoxy-
4 6-ethenopyrimido[4 ,5-b1[6,1 ,12]benzoxadiazacyclopentadecine, 17-bromo-16- fluoro-8,9,10,11,12,13,14, 19-octahydro-20-methoxy-
4,6-ethanediylidenepyrimido(4,5-b} [6,1,9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 17 -chloro-10,11,14, 19-tetrahydro-20-methoxy-11 -methyl- 4.6-ethanediylidenepyrimidof4,5-b) [6, 1,9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 17-chloro-10,1 1,14,19-tetrahydro-20-methoxy- 11-(1- methylethyl)-
4 6-ethanediylidenepyrimido[4,5-b} [6,1,9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 17-chloro-10,11 ,14,19-tetrahydro-20-methoxy-11- (phenylmethyl)-
4,6-ethanediylidene-8H-pyrimido[4,5-b] [6, 1,9,12]benzoxatriazacyclohexadecine- 11,14-dione, 18-chloro-9,10,12,13,15,20-hexahydro-21-methoxy-12-(1- methylethyl)-
4 6-ethanediylidene-8H-pyrimido[4,5-b] [6,1,9, 12]benzoxatriazacyclohexadecine- 11,14-dione, 18-chloro-9, 10,12,13,15,20-hexahydro-21-methoxy-12,12- dimethyl-
4,6-ethanediylidene-8H-pyrimido [4,5-b] [6;1,9,12]benzoxatriazacyclohexadecine-
7 11,14-dione, 18-chloro-9,10,12,13,1 5,20-hexahydro-21-methoxy-12-(2-
. methylpropyl)- 4, 6-ethanediylidenepyrimido[4,5-b][6,1,10,1 3]benzoxatriazacycloheptadecine- : . 12,15-dione, 19-chloro-8,9,10,11, 13 ,14,16,21-octahydro-22-methoxy-13-(2- Cr methylpropyl)- 4,6-ethanediylidene-8H-pyrimido[4,5-b]{6,1.9, 12)benzoxatriazacyclohexadecine- 11,14-dione, 18-chloro-9,10,12, 13,15,20-hexahydro-21-methoxy- 4,6-ethanediylidenepyrimido{4,5-b][6, 1,10,13]benzoxatriazacycloheptadecine- 12,15-dione, 19-chloro-8,9,10,1 1,13,14,16,21-octahydro-22-methoxy- 4,6-ethanediylidenepyrimido[4,5-b][6.1,9, 12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 10,11 ,14,19-tetrahydro-20-methoxy-1 1-methyl- 4,6-ethanediylidenepyrimido[4,5-b][6,1.9, 12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 10,1 1,14,19-tetrahydro-20-methoxy-1 1-(1-methylpropyl)- 9,1 1-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2- i]{6,1 9,12]benzoxatriazacyclopentadecine-14,19(5H, 13H)-dione, 16,17,18,182,20,21-hexahydro-22-methoxy- 4,6-ethanediylidenepyrimido[4,5-b][6,1 9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 10,1 1,14,19-tetrahydro-20-methoxy- 4 6-ethanediylidene-8H-pyrimido([4,5-b] [6,1,9,13]benzoxatriazacyclohexadecine- 9,13(10H,14H)-dione, 11, 12,15,20-tetrahydro-21-methoxy- 4 6-ethanediylidenepyrimido[4,5-b][6,1 ,9,14]benzoxatriazacycloheptadecine- 9,14(8H,15H)-dione, 10,11,12,13, 16,21-hexahydro-22-methoxy-
4 6-ethanediylidenepyrimido({4,5-b]pyrrolo[2,1- k1[6,1,9,12]benzoxatriazacyclopentadecin-11 (8H)-one, 19-chloro-18-fluoro- 9,10,1 1a,12,13,14,16,21-octahydro-22-methoxy- 4,6-ethanediylidene-8H-pyrimido[4,5-b][6,1,10, 13]benzoxatriazacyclohexadecine, 18-chloro-9,10,11,12,13, 14,15,20-octahydro-21-methoxy-14-methyl- 4,6-ethanediylidenepyrimido[4,5-b][6,1.9, 12]benzoxatriazacyclopentadecin-1 1(8H)- one, 17—chloro-16-fluoro-9,10,12,13,14,19-hexahydro-20-methoxy-13-methyl- 4,6-ethanediylidene-12H-pyrimido [4,5-b][6,1 ,10,13]benzoxatriazacyclohexadecin- 12-one, 18-chloro-17-fluoro-8 9,10,11,13,14,15 ,20-octahydro-21-methoxy-14- methyl- 4 6-ethanediylidenepyrimido [4,5-b][6,1.9,12]benzoxatriazacyclopentadecin-1 1(8H)- one, 17-chloro-16-fluoro-9,10,12,13, 14,19-hexahydro-20-methoxy- 4,6-ethanediylidene-12H-pyrimido[4,5-b] [6,1, 10,13]benzoxatriazacyclohexadecin- 12-one, 18-chloro-17-fluoro-8,9,10,11,13,14, 15,20-octahydro-21-methoxy- . 4,6-ethanediylidene-12H-pyrimido [4,5-b][6,1 ,10,13]benzoxatriazacyclohexadecin- : "12-one, 18-chloro-8,9,10,11,13,14, 15,20-octahydro-21-methoxy- "9,1 1-ethanediylidenepyrimido[4,5-b]pyrrolo[1,2- . 1]6,1,9, 12]benzoxatriazacyclopentadecine-14, 19(5H,13H)-dione, 3-chioro- 16,17,18,1 8a,20,21-hexahydro-22-methoxy- ’
4.,6-ethanediylidenepyrimido[4,5-b][6,1,9, 12]benzoxatriazacyclopentadecine- . 9,12(8H,13H)-dione, 17-chloro-10,11, 14,19-tetrahydro-20-methoxy-10-methyl-
4 6-ethanediylidenepyrimido[4,5-b][6,1 ,9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 17-chloro-10,1 1,14,19-tetrahydro-11-(1-hydroxyethyl)-20- methoxy-
4 6-ethanediylidenepyrimido[4,5-b][6,1,11, 14}benzoxatriazacycloheptadecine- 11,14(8H,15H)-dione, 19-chloro-9,10, 12,13,16,21-hexahydro-22-methoxy-13- (1-methylpropyl)-
4 6-ethanediylidenepyrimido[4,5-b]{6.1 ,9,12]benzoxatriazacyclopentadecine- 9,12(8H,13H)-dione, 17-chloro-10,1 1,14,19-tetrahydro-11-(hydroxymethyl)-20- methoxy-
4,6-ethanediylidenepyrimido[4,5-b][6.1,11 ,14]benzoxatriazacycloheptadecine- 11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-13- (hydroxymethyl)-22-methoxy-
4,6-ethanediylidenepyrimido[4,5-b][6,1,11 ,14]benzoxatriazacycloheptadecine- 11,14(8H,15H)-dione, 19-chloro-9,10,12,13,16,21-hexahydro-22-methoxy-13- methyl-
4 6-ethanediylidene-8H-pyrimido[4,5-b] [6,1,9,12]benzoxatriazacyclohexadecine-
Claims (7)
1. A compound having the formula ya A R' Y JS ] n xX 7 / z No = SN3 a —t 7X 7 2 ® 8 1 the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein # Zrepresents O, CH, NHorS§; in particular Z represents NH; : % Y represents -Cs.oalkyl-, -Cs.0alkenyl-, -Cs.0alkynyl-, -Cs.7alkyl-CO-NH- optionally 10% substituted with amino, mono- or di(C;4alkyl)amino or Ci_alkyloxycarbonylamino-, : Co -C3.qalkenyl-CO-NH- optionally substituted with amino, mono- or : di(C;4alkyl)amino or C,salkyloxycarbonylamino- , }
-C3._7alkynyl-CO-NH- optionally substituted with amino, mono- or di(Cs. “ salkyl)amino or C,4alkyloxycarbonylamino-, -Crsalkyl-oxy-Cy.salkyl-, -Cy_salkyl-
NR.C, salkyl-, -Cy_salkyl-NR'*-CO-C} salkyl-,
-C}.salkyl-CO-NR"-C; salkyl-, -C.¢alkyl-CO-NH-, -C;.¢alkyl-NH-CO-,
-C1.salkyl-NH-CS-Het?-, -C, salkyl-NH-CO-Het*’-, Cy palkyl-CO-Het*'-CO-, “Het?-CH,-CO-NH-C}.salkyl-, -CO-NH-C; ¢alkyl-, -NH-CO-C, salkyl-, -CO-C;.qalkyl-, -Cy.7alkyl-CO-, -C, ¢alkyl-CO-Cj salkyl-,
-C}.2alky}-NH-CO-CR *R""-NH-, -C}.zalkyl-CO-NH-CR *R®-CO-,
-C1.,alkyl-CO-NR?-C) salkyl-CO-, -C.zalkyl-NR*'-CH,-CO-NH-C salkyl-, or -NR*-CO-C}salkyl-NH- ; X! represents a direct bond, O, -O-C; salkyl-, CO, -CO- Cy qalkyl-, NR", : -NR''-C;.,alkyl-, -CHj-, -O-N=CH- or -Czalkyl-; X? represents a direct bond, O, -O-C;.zalkyl-, CO, -CO- C;.palkyl-, NR", -NR!2.C; »alkyl-, -CHy-, -O-N=CH- or -C}2alkyl-; R! represents hydrogen, cyano, halo, hydroxy, formyl, Cy.salkoxy-, Ci.calkyl-, halo-phenyl-carbonylamino-, C1-¢alkoxy- substituted with halo,
C;4alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'%-carbonyl-, Cwalkyloxycarbonyl-, C;.salkylcarbonyl-, aminocarbonyl-, mono-or di(C;4alkyl)aminocarbonyl-, Het', formyl, Cy-4alkyl-, Cs.¢alkynyl-, Cs.ecycloalkyl-, Csscycloalkyloxy-, Ci-salkoxy-, Ar, Ar'-oxy-, dihydroxyborane ,
C,.salkoxy- substituted with halo,
C.4alky substituted with one or where possible two or more substituents selected from halo, hydroxy or NR’RS, Cialkylcarbonyl- wherein said C;4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or Ci-salkyl-oxy-; R? represents hydrogen, C1.salkyl, or Cy4alkyl substituted with one or more substituents selected from halo, C;4alkyloxy-, amino-, mono-or di(C;4alkyl)amino-, :
15. C\4alkyl-sulfonyl- or phenyl; . Se R* represents hydrogen, hydroxy, Ar-oxy, Ar*-C4alkyloxy-, Ciaalkyloxy-, oo _ tw Caualkenyloxy- optionally substituted with Het'? or R* represents Cy qalkyloxy A substituted with one or where possible two or more substituents selected from N . Craalkyloxy-, hydroxy, halo, Het, -NR'R®, -carbonyl- NR’R'® or Het’-carbonyl-; RS and R® are each independently selected from hydrogen or Cy.salkyl; ' R” and R® are each independently selected from hydrogen, Ci.salkyl, Het’, : aminosulfonyl-, mono- or di (C;4alkyl)-aminosulfonyl, hydroxy-Ci.4alkyl-, C4alkyl-oxy-Ci4alkyl-, hydroxycarbonyl-C,4alkyl-, Cs.ecycloalkyl, Het’-carbonyl-C.qalkyl-, Het'carbonyl-, polyhydroxy-Cialkyl-, Het''-Cy salkyl- or Ar*-Cj.4alkyl-; R? and R'° are each independently selected from hydrogen, C;4alkyl, Cs.gcycloalkyl, Het?, hydroxy-C, 4alkyl-, Cj 4alkyloxyC,.salkyl- or polyhydroxy-Cj4alkyl-; RY represents hydrogen, Cy.salkyl, Het’, Het®-Cj4alkyl-, C; salkenylcarbonyl- optionally substituted with Het’-C;4alkylaminocarbonyl-, C,4alkenylsulfonyl-,
C1.4alkyloxyC, 4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or Ci4alkyloxy-; R'2 represents hydrogen, Cy alkyl, C, salkyl-oxy-carbonyl-, Het'®-Cy_salkyl-, phenyl-C.salkyl-oxy-carbonyl-, Het'’, C; salkenylcarbonyl- optionally substituted with Het'*-C; 4alkylaminocarbonyl-, Cz.qalkenylsulfonyl-, C;4alkyloxyC; 4alkyl- or R'? represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C.4alkyloxy-;
R'? represents hydrogen, Ci.4alkyl, Het", Het'*-C, 4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or Cj.salkyloxy-; R and RY are each independently selected from hydrogen, Ciaalkyl, Het'>-C,4alkyl- or C;4alkyloxyCi.4alkyl-; RS and RY each indepedently represents hydrogen or C;.4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R'® and RY each indepedently represents hydrogen or C;4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R? and R? each independently represents hydrogen or Cy.4alkyl optionally substituted with hydroxy or Cj4alkyloxy; . RH represents hydrogen, C.4alkyl, Het?-C,4alkylcarbonyl- or . 3 R* represents mono-or di(Cialkyl)amino-C; salkyl-carbonyl- optionally : iE substituted with hydroxy, pyrimidinyl, dimethylamine or Ci4alkyloxy; = . - Het represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, SE furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, “i : ‘oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het! is optionally substituted i with amino, C;.4alkyl, hydroxy-Cj.salkyl-, phenyl, phenyl-Cyalkyl-, C14alkyl-oxy-Cj4alkyl- mono- or di(C,4alkyl)amino- or amino-carbonyl-; Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, Cy.salkyl-, hydroxy-Ci4alkyl-, Ci.4alkyl-oxy-Cj.salkyl-, - hydroxy-C; 4alkyl-oxy-C;4alkyl-, mono- or di(C,.4alkyl)amino-, mono- or di(C.salkyl)amino-Ci4alkyl-, aminoC;.4alkyl-, mono- or di(C).salkyl)amino-sulfonyl-, aminosulfonyl-; Het’, Het* and Het® each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridiny! or pyrrolidinyl wherein said Het’, Het® or Het® is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C;4alkyl-,
Cs.¢cycloalkyl-Cysalkyl-, aminosulfonyl-, mono- or di(C;-4alkyl)aminosulfonyl or amino-Cj4alkyl-; Het’ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
Ci4alkyl, Cs scycloalkyl, hydroxy-Ci4alkyl-, C,4alkyloxyCi.4alkyl or polyhydroxy-C, satkyl-; Het® and Het’ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C,4alkyl, Cs.¢cycloalkyl, hydroxy- C4alkyl-, C,_4alkyloxyCialkyl or polyhydroxy-Ci.salkyl-; Het® and Het'® each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidiny! wherein said Het’ or Het! is optionally substituted C.4alkyl, Cs.scycloalkyl-Ci.salkyl- or amino-C;4alkyl-; 0 Het" represents a heterocycle selected from indolyl or & ; - Het!? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, : % + pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het!” is optionally Ll © substituted with one or where possible two or more substituents selected from : Se hydroxy, halo, amino, Cy4alkyl-, hydroxy-Ci.salkyl-, Ciaalkyl-oxy-Ciqalkyl-, So hydroxy-C; salkyl-oxy-C salkyl-, mono- or di(Cj.4alkyl)amino- or mono- or z ' di(C 14alkyl)amino-C4alkyl-; : Het" represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally a substituted with one or where possible two or more substituents selected from Ci4alkyl, Ca cycloalkyl, hydroxy-Ciallkyl-, Ci.4alkyloxyCi4alkyl or polyhydroxy-C,.alkyl-; Het! represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cy 4alkyl, Cs.ccycloalkyl, hydroxy-C;.4allkyl-, C,4alkyloxyCi.salkyl or polyhydroxy-C;.salkyl-; Het'® represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperaziny! or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cj4alkyl, Cs. ¢cycloalkyl, hydroxy-C, 4alkyl-, C4alkyloxyCi4alkyl or polyhydroxy-Ci.salkyl-; Het'® 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 C;4alkyl; and Het" represent a heterocycle selected from pyrrolidiny! or piperidinyl optionally substituted with one or where possible two or more substituents selected from
Ciaalkyl, Cs_¢cycloalkyl, hydroxy-Cj4alkyl-, C1.4alkyloxyCi alkyl or polyhydroxy-Ci.salkyl-; Het'® and Het'® each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperaziny} or piperidinyl optionally substituted with one or where possible two or more substituents selected from C,.4alkyl, Cs. scycloalkyl, hydroxy-C;-salkyl-, C).salkyloxyCi.salkyl or polyhydroxy-Ci.4alkyl-; Het®®, Het” and Het? each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperaziny! or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy,
C.salkyl, hydroxy-C.salkyl- or polyhydroxy-Ci.alkyl-; Het represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Ciualkyl, Cs.scycloalkyl, hydroxy-Ci4alkyl-, C14alkyloxyC.salkyl or polyhydroxy-C;.4alkyl-;
155. Art, Af, AP, Ar* and Ar each independently represent phenyl optionally substituted .% with cyano, Cy4alkylsulfonyl-, Cj_alkylsulfonylamino-, aminosulfonylamino-, . i hydroxy-C4alkyl, aminosulfonyl-, hydroxy-, Ci.salkyloxy- or Ci.4alkyl. TR
20.
2, A compound according to claim 1 wherein; To Z represents O, NH or S; Y represents -Cs galkyl-, -Cs.galkenyl-, -C1.salkyl-oxy-C; salkyl-, :
-Cy.salkyl-NR*-Cy salkyl-, -Cy.salkyl-NR'“-CO-C sallkyl-,
-Cy.salkyl-CO-NR *-C, salkyl-, -C1.2lkyl-CO-NH-, -C; galkyl-NH-CO-, -CO-NH-C; galkyl-, -NH-CO-C; ¢alkyl-, -CO-C,.7alkyl-, -Cy.7alkyl-CO-,
-C1.62lkyl-CO-C; galkyl-, -C1.5alkyl-NH-CO-CH,R '*-NH-; X" represents a direct bond, 0, -O-C; zalkyl-, CO, -CO- Cy.palkyl-, NR", NR!!-C; zalkyl-, -CH;-, -O-N=CH- or -C)alkyl-; X? represents a direct bond, O, -O-Cy.zalkyl-, CO, -CO- Cyzalkyl-, NR", NR'2-C; satkyl-, -CHz-, -O-N=CH- or -Ci.oalkyl-; R! represents hydrogen, cyano, halo, hydroxy, formyl, C;.salkoxy-, Ci.salkyl,
C1.¢alkoxy- substituted with halo, C14alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'®-carbonyl-, C4alkyloxycarbonyl-, Cj 4alkylcarbonyl-, aminocarbonyl-, mono-or di(C14alkyl)aminocarbonyl-, Het, formyl, C14alkyl-, Caalkynyl-, Csscycloalkyl-, Cscycloalkyloxy-, Cy.salkoxy-, Ar’, Ar'-oxy-, dihydroxyborane ,
C,.salkoxy- substituted with halo, C4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NRR®,
C.4alkylcarbonyl- wherein said C; 4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C4alkyl-oxy-; R? represents hydrogen, Cyalkyl or Cy 4alkyl substituted with one or more substituents selected from halo, Cy4alkyloxy-, amino-, mono-or di(Cisalkyl)amino-, C4alkyl-sulfonyl- or phenyl, R* represents hydrogen, hydroxy, Ar-oxy, Ar*-C,qalkyloxy-, Ci4alkyloxy-, C,4alkenyloxy- optionally substituted with Het'? or R* represents C;.salkyloxy : substituted with one or where possible two or more substituents selected from 15% Cyaalkyloxy-, hydroxy, halo, Het’, -NR'R®, -carbonyl- NR’R'® or Het’-carbonyl-; vd R® and RS are each independently selected from hydrogen or Cralkyl; os ~ w Rand R® are each independently selected from hydrogen, C;salkyl, Het®, 4 aminosulfonyi-, mono- or di (C;4alkyl)-aminosulfonyl, hydroxy-Ci.salkyl-, : .. : C1alkyl-oxy-C;4alkyl-, hydroxycarbonyl-Ci.salkyl-, Csscycloalkyl, -
20. . Het’-carbonyl-C; 4alkyl-, Het'-carbonyl-, polyhydroxy-Cialkyl-, Het'!-Cpaalkyl- © or AP -Cj4alkyl-; } R® and R'? are each independently selected from hydrogen, C;alkyl, C;.¢cycloatkyl, Het?, hydroxy-Csalkyl-, C1alkyloxyCyalkyl- or polyhydroxy-Ci.salkyl-; R!! represents hydrogen, Ci.salkyl, Het’, Het$-C; 4alkyl-, C;.4alkenylcarbonyl- optionally substituted with Het'-Cy4alkylaminocarbonyl-, Cy 4alkenylsulfonyl-, C14alkyloxyCjalkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or Ci4alkyloxy-; R' represents hydrogen, Cyalkyl, Ci.salkyl-oxy-carbonyl-, Het!?, Het'®-C\4alkyl-,
C,.salkenylcarbonyl- optionally substituted with Het'*-C, 4alkylaminocarbonyl-,
C,.salkenylsulfonyl-, Ci.alkyloxyCialkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C;qalkyloxy-; R? represents hydrogen, Cyqalkyl, Het'®, Het!*-C,4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C4alkyloxy-;
R' and R?* are each independently selected from hydrogen, Ci4atkyl, Het'>-C) 4alkyl- or Cy.salkyloxyCi.4alkyl-; R'S represents hydrogen or C;4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; Het! represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidiny]l wherein said Het! is optionally substituted with amino, C).4alkyl, hydroxy-Cj.4alkyl-, phenyl, phenyl-Cy4alkyl-, C1 4alkyl-oxy-C) 4alkyl- mono- or di(Cj4alkyl)amino- or amino-carbonyl-; Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholiny! or dithianyl wherein said Het’ is optionally substituted with one or where possible two or more substituents selected from .. . hydroxy, halo, amino, C;4alkyl-, hydroxy-Cj.4alkyl-, Ci.4alkyl-oxy-Ci4alkyl-.
+ . hydroxy-C.4alkyl-oxy-C;.4alkyl-, mono- or di(C;.4alkyl)amino-, mouo- or » he di(C;4alkyl)amino-C;4alkyl-, aminoC4alkyl-, mono- or : . RE di(C;4alkyl)amino-sulfonyl-, aminosulfonyl-; . . Het’, Het* and Het? each independently represent a heterocycle selected from : morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,
20 . oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidiny! wherein i said Het’, Het* or Het® is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, Cy4alkyl-,
Cs.¢cycloalkyl-C;.4alkyl-, aminosulfonyl-, mono- or di(C;.salkyl)aminosulfony! or amino-Cy4alkyl-; Het’ represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Ci4alkyl, Cs.¢cycloalkyl, hydroxy-C;.salkyl-, Ci4alkyloxyCi.salkyl or polyhydroxy-Cj.4alkyl-; Het’ and Het’ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C;4alkyl, Cs.scycloalkyl, hydroxy- C14alkyl-, Cy 4alkyloxyCi4alkyl or polyhydroxy-C;alkyl-; Het’ and Het!? each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het’ or Het'? is optionally substituted Cj 4alkyl, Cs.¢cycloalkyl-C; 4alkyl- or amino-C;.4alkyl-;
. ~~ CL=- Het! represents a heterocycle selected from indolyl or 7 Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het'? is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, Ci4alkyl-, hydroxy-C)4alkyl-, C;4alkyl-oxy-Ci4alkyl-, : hydroxy-C;.4alkyl-oxy-C;4alkyl-, mono- or di(C;4alkyl)amino- or mono- or di(C;_salkyl)amino-C;salkyl-; Het? represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from
C1.alkyl, Cs cycloalkyl, hydroxy-Ci4allkyl-, Ci4alkyloxyCi4alkyl or polyhydroxy-Cjsalkyl-; Het' represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or tn piperidinyl optionally substituted with one or where possible two or more oo x substituents selected from Ci4alkyl, Csecycloalkyl, hydroxy-Ci4alikyl-, : E = C14alkyloxyC;.salkyl or polyhydroxy-Ci4alkyl-; CT -+4_ Het" represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or Con
©. piperidinyl optionally substituted with one or where possible two or more i substituents selected from Cy4alkyl, Cs.scycloalkyl, hydroxy-C;.4alkyl-, C;aalkyloxyCj4alkyl or polyhydroxy-Ci.salkyl-; Het represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 5 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from Cj_salkyl; and Het!” represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C14alkyl, Csecycloalkyl, hydroxy-C4alkyl-, Ci1.4alkyloxyCy4alkyl or polyhydroxy-C;.4alkyl-; Het'® and Het! each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Ci4alkyl, Cs¢cycloalkyl, hydroxy-C).salkyl-, Ci salkyloxyCi.salkyl or polyhydroxy-C, salkyl-; Ar', AP, Ar, Ar’ and Ar’ each independently represent phenyl optionally substituted with cyano, C;4alkylsulfonyl-, Cy4alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C; 4alkyl, aminosulfonyl-, hydroxy-, Ci4alkyloxy- or Ci4alkyl.
3. A compound according to claims 1 or 2 wherein; Z represents NH;
Y represents -Cs galkyl-, -Ca.galkenyl-, -Cy.salkyl-oxy-C,.salkyl-,
-C1.5alkyl-NR *-C,.salkyl-, -Cy.salkyl-NR'*-CO-C.salkyl-, -Cysalkyl-NH-CO-, -NH-CO-C,alkyl-, -CO-C;alkyl-, -C1.7alkyl-CO-, C1-6alkyl-CO-C; alkyl,
-C.2alkyl-NH-CO-CR'*R"-NH-, -C; zalkyl-CO-NH-CR'*R"-CO-,
-C.2alkyl-CO-NR?-C; alkyl-CO-, -C1.,alky}-NR?'-CH,-CO-NH-C).3alkyl-, NR%-CO-C; salkyl-NH-, -C; salkyl-NH-CO-Het*-, C}.2alkyl-CO-Het*'-CO-, or © “Het®-CH,-CO-NH-C,salkyl-; X! represents O, -O-Cp.palkyl-, -0-N=CH-, NR"! or -NR"'-C.zalkyl-; X? represents a direct bond, -Ci.alkyl-, O, -O-Ci.aalkyl-, -O-N=CH-, NR? or NR'2-C, alkyl; R! represents hydrogen, cyano, halo or hydroxy; R? represents hydrogen, cyano, halo, hydroxy, hydrox ycarbonyl-, Calkyloxycarbonyl-, Het'S-carbonyl-, C4alkyl-, C26alkynyl-, Ar or Het'; +R represents hydrogen;
15 . R* represents hydrogen, hydroxy, Cyalkyloxy- or R* represents C; 4alkyloxy Ch substituted with one or where possible two or more substituents selected from Soe C,qalkyloxy- or Het’; R" represents hydrogen, Cy.alkyl- or Cy.salkyl-oxy-carbonyl~; : . R" represents hydrogen or Het'*-C; 4alkyl; } 26 © Rand R?’ represent hydrogen; ) R!® represents hydrogen or C, salkyl substituted with hydroxy; ’ RY represents hydrogen or Ci 4alkyl, in particular hydrogen or methyl, R'® represents hydrogen or C;.4alkyl optionally substituted with hydroxy or phenyl; R® represents hydrogen or C;salky}; R? represents hydrogen or Cy 4alkyl; R? represents hydrogen, C;4alkyl, Het?-C, salkylcarbonyl- or R* represents mono-or di(Cyalkyl)amino-Cy4alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or Cy 4alkyloxy; R* represents hydrogen or C_4alkyl optionally substituted with hydroxy or C;. salkyloxy; Het! represents thiazolyl optionally substituted with amino, C1.salkyl, hydroxy-C;. salkyl-, phenyl, phenyl-C alkyl, C;4alkyl-oxy-Cialkyl- mono- or di(Ci. 4alkyl)amino- or amino-carbonyl-; Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cy salkyl-;
Het represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het’ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cy 4alkyl-; Het'? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het'? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cy4alkyl-; ~ Het'® represents a heterocycle selected from piperidinyl or pyrrolidinyl; Het? represents pyrrolidinyl, 2-pyrrolidinonyl, piperidinyl or hydroxy-pyrrolidinyl, preferably pyrrolidinyl or hydroxy-pyrrolidinyl; Het?! represents pyrrolidinyl or hydroxy-pyrrolidinyl; Het? represents pyrrolidinyl, piperazinyl or piperidinyl.
4. A compound according to claims 1 or 2 wherein; ; Z represents NH; 3+ Y represents -Ca.oalkyl-, -Cyoalkenyl-, -Cy.salkyl-oxy-C.salkyl-, .- ye 3 -C 1.salkyl-NR-Cy salkyl-, -C;.salkyl-NH-CO-, -CO-C,.qalkyl-, -C,7alkyl-CO- or - Lh C1.6alkyl-CO-Cy.¢alkyl; EE x! represents O, -O-Cy.zalkyl-, -O-N=CH-, NR"! or -NR'!-Cyzalkyl-; hd
_. X? represents a direct bond, O, -O-Cy.zalkyl-, -O-N=CH-, NR"? of NR!*-C, alkyl; “
20 . R' represents hydrogen, cyano, halo or hydroxy, preferably halo; Ct R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Cs Cialkyloxycarbonyl-, Het'®-carbonyl-, Cz.¢alkynyl-, Ar or Het’; R? represents hydrogen; R* represents hydroxy, Cj.alkyloxy- or rR? represents Cj4alkyloxy substituted with one or where possible two or more substituents selected from C;salkyloxy- or Het’; R'2 represents hydrogen, Ci.salkyl- or Cyalkyl-oxy-carbonyl-; R" represents Het'*-C alkyl; Het! represents thiazolyl optionally substituted with amino, Cyalkyl, hydroxy-Ci. salkyl-, phenyl, phenyl-C; alkyl, C;4alkyl-oxy-C;4alkyl- mono- or di(C,. salkyl)amino- or amino-carbonyl-; Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or : pyrrolidinyl wherein said Het? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C; 4alkyl-; Het? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het’ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C;4alkyl-;
Het'? represents a heterocycle selected from morpholiny), piperazinyl, piperidinyl or pyrrolidinyl wherein said Het"? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cj4alkyl-; Het'® represents a heterocycle selected from piperidinyl or pyrrolidinyl.
5. A compound according to claim 1 wherein; Z represents NH, Y represents -Cs.galkyl-, -CO-C;_7alkyl- or -Cy.7alkyl-CO-; x! represents -NR!'., -O- or -O-CH;-; X° represents a direct bond, ~O- or -O-CHs-; R! represents halo; R? represents hydrogen, cyano, halo, hydroxy or Cysalkynyl-; R? represents hydrogen; - R* represents C;.qalkyloxy substituted with one or where possible two or more + substituents selected from C4alkyloxy- or Het>-; + i R'? represents Cy4alkyl or R!? represents C)4alkyl-oxy-carbonyl; . «= % Het? represents a heterocycle selected from morpholinyl or piperidinyl optionally : : substituted with Cy 4alkyl-; i Het’ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or oo ‘ pyrrolidinyl wherein said Het’ is optionally substituted with one or where possible . i two or more substituents selected from hydroxy, amino or C; 4alkyl-; Het'? represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het'? is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or Cy 4alkyl-.
6. A compound according to claim 1 wherein; Z represents NH; Y represents -Cs.oalkyl-, -C;.galkenyl-, -C3.7alkyl-CO-NH optionally substituted with amino, mono — or di(Cj_salkyl)amino or C;4alkyloxycarbonylamino-, -C37alkenyl-CO-NH- optionally substituted with amino, mono- or di(C,. salkyl)amino- or C;4alkyloxycarbonylamino-,
C,.salkyl-NR>-C, salkyl-, -C; salkyl-NR'*-CO-C.salkyl-, -C; salkyl-CO-NH-,
-Cy.5alkyl-CO NR¥-C, salkyl-, -Cy.salkyl-NH-CO-Het?’-,
-C.5alkyl-CO-Het*'-CO-, -Cy.5alkyl-NH-CO-CR'R'"-NH-, -C, alkyl-CO-NH-CR"*R"°-CO-, -C;.5alkyl-CO-NR*-C, salkyl-CO-, or -NR%-CO-C,.3alkyl-NH-; x! represents a direct bond, O or -0-Cj.alkyl-;
X? represents a direct bond, -CO-Ci.zalkyl-, NR'?, -NR'%-C,.palkyl-, -O-N=CH- or
—C.alkyl-; R! represents hydrogen or halo; R? represents hydrogen or halo; R represents hydrogen; R* represents hydrogen or C;4alkyloxy; R* represents hydrogen or C;.4alkyl; R™ represents hydrogen or Cy4alkyl; R represents hydrogen; RY represents hydrogen; R' and R! each independently represent hydrogen or Ci4alkyl; R® and R® each independently represent hydrogen or Cyalky! optionally substituted with phenyl! or hydroxy;
©. R™ and RY each independently represent hydrogen or Ci.4alkyl optionally substituted i with Cy4alkyloxy; : ~ 3 Het?®, Het*! and Het? each independently represent a heterocycle selected from the - te : Ba group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally a. : substituted with hydroxy. Toy
20.
7. A compound according to formula (I) wherein said compound is selected from the JE group consisting of; 4 6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17-bromo- 8,9,10,11,12,13 ,14,19-octahydro-20-methoxy-13-methyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclopentadecine, 17-bromo- 8,9,10,11,12,13,14,19-octahydro-20-methoxy-,, 4 6-ethanediylidenepyrimido[4,5-b[6,1,10,13]benzoxatriazacycloheptadecine-12,15- dione, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-13-(2- methylpropyl)-, 4 ,6-ethanediylidenepyrimido[4,5-b] [6,1,10,13]benzoxatriazacycloheptadecine-12,15- dione, 19-chloro-8,9,10,11,13,14,16,21-octahydro-22-methoxy-, 4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1- ¥]1[6,1,9,12]benzoxatriazacyclopentadecin-1 1(8H)-one, 19-chloro-18-fluoro- 9,10;11a,12,13,14,16,21-octahydro-22-methoxy-, 4 6-ethanediylidene-8H-pyrimido[4,5-b] [6,1,10,13]benzoxatriazacyclohexadecine, 18- chloro-9,10,11,12,13,14,15,20-octahydro-21-methoxy-14-methyl-, 4,6-ethanediylidenepyrimido[4,5-b][6,1,11,14]benzoxatriazacycloheptadecine, 19- chloro-8,9,10,1 1,12,13,14,15,16,21-decahydro-22-methoxy-15-methyl-,
4 6-ethanediylidenepyrimido[4,5-b} [6,1,9,12]benzoxatriazacyclopentadecine, 17- chloro-8,9,10,11,12,13,14, 19-octahydro-20-methoxy-13-methyl-, 12H-4,6-ethanediylidene-13,17-methanopyrimido[4,5- b][6,1,10,16]benzoxatriazacyclononadecin-12-one, 21-chloro- 8,9,10,11,13,14,15,16,18,23-decahydro-25-methoxy-, 4,6-ethanediylidene-12H-pyrimidof4,5-b](6,1,10,13]benzoxatriazacyclohexadecin-12- © one, 18-chloro-8,9,10,11,13,14,15,20-octahydro-21-methoxy-13,14-dimethyl-, 4 6-ethanediylidenepyrimido[4,5-5][6,1,11 ,14]benzoxatriazacycloheptadecin- 13(8H)- one, 19-chloro-15-ethyl-9,10,11,12,14,15,16,21-octahydro-22-methoxy-, or 4,6-ethanediylidenepyrimido{4,5-b][6,1,1 1,14]benzoxatriazacycloheptadecin-13(8 H)- one, 19-chloro-9,10,11,12,14,15,16,21-octahydro-22-methoxy-14,15-dimethyl-,
8. A compound according to any one of claims 1 to 6 wherein the X? substituent is at ¢ position 2’, the R! substituent is at position 4°, the R? substituent is at position 5°, v4 theR? substituent is at position 3 and the R* substituent at position 7 of the - . . + = structure of formula (I). : : X
9. A kinase inhibitor of formula (I). : :
10. A compound as claimed in any one of claims 1 to 7 for use as a medicine. .
11. Use of a compound as claimed in any one of claims 1 to 7 in the manufacture of a medicament for treating cell proliferative disorders such as atherosclerosis, restenosis and cancer.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective kinase inhibitory amount of a compound as described in any one of the claims 1 to 7.
13. A process for preparing a compound as claimed in claims 1 to 7, comprising a) coupling the 6-acetoxy-quinazolines of formula (II) with the suitable substituted anilines of formula (II) to furnish the intermediates of formula (IV), and deprotecting the intermediates of formula (IV) followed by ring closure under suitable conditions.
V. “ow v= x2 a R? ~° cl W 0 1 : or TT — Ra SL + NUN 1 = = N i” yp NR HN FE) le. SR a an NT aw) 2 Y XF 1 HO |X: ~F ya HN qt Xi Ring Closure HN Rr! TOT eC N pZ ? V = protective group T) b) Deprotecting the intermediates of formula (IV ®) followed by formation of the corresponding ether using the appropriate aminated alcohol under standard & conditions provides the intermediates of formula (XX VII). Next, deprotection . 5% followed by ring closure provides the target compounds of formula a. : v=0, v—0. v—0 Y2—X YX Sy : 2 Ne Pek 2 ech Y Y2 SOL YW A, HN SN noo Boe Pee CO R 17, 1 ~o Nv) Rg pov RAP pov V=—0. HO ~ Yo=% np NY,—Xo Y>—% BR Vv ~~ FN A, ee ETT N NY, ANT SN Psy, J 2 HN SN 1 Ry i HN Ry \ Ry
A". Pp! 17 J RY, J 0 NT (xxi RS # 0 N (XXIX) (o) Nx ) V = protective group such as for example, protective group such as for example, methyicarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl groups, or In case of solid phase chemistry V represents the resin to which the remainder of the molecule is being attached. RY represents Ar®, Ar*-Cy_qalkyl, Cy.4alkyl, C.salkenyl optionally substituted with Het"? or R'® represents C14alkyl substituted with one or where possible two or more substituents selected from Cy4alkyloxy, hydroxy, halo, Het2, NRTR®, NR®R®-carbony! or Het®-carbonyl, wherein Ar, Ar%, Het'2, Het?, R, R%, RS, RC and Het® are dsfined as for the compounds of formula (|) Y, and Y each independently represent a Cy.salkyl, CO-Gy.salkyl or CO-CHpR'S-NH-
14. An intermediate of formula (IIT)
vO ENR Rr! ty) the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein V represents hydrogen or a protective group preferably selected from the group consisting of methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl; Y represents -Cs.qalkyl-, -Cs.0alkenyl-, -C;.7alkyl-CO-NH- optionally substituted with amino, mono- or di(Cj4alkyl)amino or Cj4alkyloxycarbonylamino-, -Cs.jalkenyl- CO-NH- optionally substituted with amino, mono- or di(C;4alkyl)amino or C,4alkyloxycarbonylamino- ,
-Cy.salkyl-oxy-Ci.salkyl-, -Cy.salkyl-NR'*-C)_salkyl-, -C).salkyl-NR'*-CO-C;. salkyl-,
-C\.salkyl-CO-NR'5-C,.salkyl-, -C, salkyl-CO-NH-, -C,_¢alkyl-NH-CO-,
-C}.;alkyl-NH-CS-Het?-, -C).;alkyl-NH-CO-Het?-, C, ,alkyl-CO-Het*'-CO-, -Het?2-CH,-CO-NH-C, salkyl-, -CO-NH-C,_alkyl-, -NH-CO-Calkyl-, -CO-C_jalkyl-, -C,.7alkyl-CO-, -C,alkyl-CO-C,.salkyl-, -CO-Het®-, -C, 2alkyl-NH-CO-CR*R'’-NH-, -C,_,alkyl-CO-NH-CR*R"*-CO-,
-C.2alkyl-CO-NR?-C, ;alkyl-CO-, -C;_salkyl-NR?'-CH,-CO-NH-C,_salkyl-, or -NR?2-CO-C,.3alkyl-NH- ; )'G represents a direct bond, O, -O-Cj.zalkyl-, CO, -CO- C\.;alkyl-, NR'2, -NR'2-C}.,alkyl-, -CH,-, -O-N=CH- or -C).,alkyl-; R! represents halo, R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'®-carbonyl-, Ci 4alkyloxycarbonyl-, C;4alkylcarbonyl-, aminocarbonyl-, mono-or di(C,4alkyl)aminocarbonyl-, Het!, formyl, C, 4alkyl-, C;¢alkynyl-, Cs. scycloalkyl-, Ciscycloalkyloxy-, Cisalkoxy-, Ar’, Ar'-oxy-, dihydroxyborane ,
C,.¢alkoxy- substituted with halo, C,4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR? RS, C, 4alkylcarbonyl- wherein said C;4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or
C,.salkyl-oxy-; AMENDED SHEET
R® and R® are each independently selected from hydrogen or C; alkyl; R'2 represents hydrogen, Cy_salkyl, Cy4alkyl-oxy-carbonyl-, Het!3-C, salkyl-, phenyl-Cysalkyl-oxy-carbonyl-, Het'”, Czalkenylcarbonyl- optionally substituted with Het!’-C, salkylaminocarbonyl-, Cz salkenylsulfonyl-, C1alkyloxyCisalkyl- or R"? represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C;.salkyloxy-; 'R" represents hydrogen, Cy4alkyl, Het'?, Het'*-Cy 4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C;_salkyloxy-; R™and RY are each independently selected from hydrogen, Ci.salkyl, Het'*-C;.salkyl- or C;.4alkyloxyCi4alkyl-; R'® and R" each indepedently represents hydrogen or Cy.4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; <;R'® and R™ each indepedently represents hydrogen or C;4alkyl optionally substituted H with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, - : 4 aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; . R oo R® and R* each independently represents hydrogen or C;4alkyl optionally substituted + 3 a with hydroxy or C;.alkyloxy; Ce : R? represents hydrogen, Cy4alkyl, Het”®-C; salkylcarbonyl- or - rR? represents mono-or di(Cj4alkyl)amino-C,4alkyl-carbonyl- optionally - substituted with hydroxy, pyrimidinyl, dimethylamine or C,alkyloxy; : Het! represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het! is optionally substituted with amino, C;4alkyl, hydroxy-C; 4alkyl-, phenyl, phenyl-Ci.4alkyl-, C;4alkyl-oxy-Cj.4alkyl- mono- or di(C;4alkyl)amino- or amino-carbonyl-; Het'? represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C;4alkyl, Cs.gcycloalkyl, hydroxy-C.sallkyl-, Ci4alkyloxyCi alkyl or polyhydroxy-Cj.4alkyl-; Het“ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C,4alkyl, Cs ¢cycloalkyl, hydroxy-Cj.sallkyl-,
C;.4alkyloxyC;.salkyl or polyhydroxy-C;.4alkyl-; Het! represent a heterocycle selected from morpholinyl, pyrrolidiny), piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Csalkyl, Cs.scycloalkyl, hydroxy-Ci4allkyl-, C4alkyloxyCi4alkyl or polyhydroxy-Cialkyl-; : Het'® represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Ci4alkyl, C.¢cycloalkyl, hydroxy-Cialkyl-, C, salkyloxyCisalkyl or polyhydroxy-Cialkyl-; Het'® 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 C4alkyl; and Het' represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Ciaalkyl, C;.scycloalkyl, hydroxy-Ci4alkyl-, C, salkyloxyCi4alkyl or polyhydroxy-Cialkyl- Het'® and Het!’ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidiny! optionally substituted with one or where possible two or more substituents selected from C,4alkyl, Cs. cycloalkyl, hydroxy-Ci-alkyl-, C alkyloxyCi4alkyl or polyhydroxy-Cisalkyl-; Het?, Het? and Het? each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy, Ci «alkyl, hydroxy-Ci4alkyl- or polyhydroxy-Cisalkyl-; Ar, AP, Ar, Ar® and Ar each independently represent phenyl optionally substituted with cyano, Calkylsulfonyl-, C, salkylsulfonylamino-, aminosulfonylamino-, hydroxy-Cj4alkyl, aminosulfonyl-, hydroxy-, C,alkyloxy- or C4alkyl.
15. Use of an ifitermediate of formula (IIT) Oy XR INL HoN Rr! (III) the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein V represents hydrogen or a protective group preferably selected from the group consisting of methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl; Y represents -C3.qalkyl-, -Cs.alkenyl-, -Cs.qalkyl-CO-NH- optionally substituted with amino, mono- or di(C4alkyl)amino or C,4alkyloxycarbonylamino-, -Csalkenyl- CO-NH- optionally substituted with amino, mono- or di(C,4alkyl)amino or C, salkyloxycarbonylamino- , AMENDED SHEET
-C1.salkyl-oxy-Cy_salkyl-, -Cy.salkyl-NR'*-C|_salkyl-, -Cy_salkyl-NR '*-CO-C;. salkyl-,
-C1.5alkyl-CO-NR'*-C,_salkyl-, -C, ¢alkyl-CO-NH-, -C,_¢alkyl-NH-CO-, :
-C).;alkyl-NH-CS-Het?-, -C,_salkyl-NH-CO-Het?-, C,.,alkyl-CO-Het*'-CO-, -Het*-CH,-CO-NH-C)_salkyl-, -CO-NH-C, galkyl-, -NH-CO-C¢alkyl-, -CO-C;.alkyl-, -C,.7alkyl-CO-, -C,alkyl-CO-C, galkyl-, -CO-Het®-, -C, ,alkyl-NH-CO-CR'*R'7-NH-, -C|.,alkyl-CO-NH-CR'*R*-CO-,
-C;.,alkyl-CO-NR®-C,_;alkyl-CO-, -C;.,alkyl-NR*'-CH,-CO-NH-C; salkyl-, or -NR**-CO-C;.;alkyl-NH- ; xX? represents a direct bond, O, -O-C;.,alkyl-, CO, -CO- Ci.»alkyl-, NR", -NR "2-C.salkyl-, -CH;-, -O-N=CH- or -C, alkyl; R! represents hydrogen, cyano, halo, hydroxy, formyl, C;.salkoxy-, C.salkyl-, halo-phenyl-carbonylamino-,
C,.salkoxy- substituted with halo, C)4alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R? represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het'S-carbonyl-, C,4alkyloxycarbonyl-, C4alkylcarbonyl-, aminocarbonyl-, mono-or di(C,4alkyl)aminocarbonyl-, Het!, formyl, C,4alkyl-, Ca.¢alkynyl-, Cs. scycloalkyl-, Cs.¢cycloalkyloxy-, Cjealkoxy-, Ar’, Ar'-oxy-, dihydroxyborane ,
C,.salkoxy- substituted with halo, Ci4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR°R®, Calkylcarbonyl- wherein said C,4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or Ci4alkyl-oxy-; R’ and R® are each independently selected from hydrogen or C,4alkyl; R!2 represents hydrogen, Cialkyl, C;4alkyl-oxy-carbonyl-, Het!'®-C,4alkyl-, phenyl-C, salkyl-oxy-carbonyl-, Het!”, C,4alkenylcarbonyl- optionally substituted with Het'’-C_alkylaminocarbonyl-, C,4alkenylsulfonyl-, C,. salkyloxyCi4alkyl- or R'? represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C4alkyloxy-; R!? represents hydrogen, C4alkyl, Het'?, Het'*-C,4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C4alkyloxy-; R'* and R!® are each independently selected from hydrogen, C4alkyl, Het'S-Cy. salkyl- or C;4alkyloxyC,salkyl-; AMENDED SHEET
R'® and R'" each indepedently represents hydrogen or C,_alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
R'® and R" each indepedently represents hydrogen or C;4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
R% and R* each independently represents hydrogen or C;4alkyl optionally substituted with hydroxy or C;4alkyloxy;
R* represents hydrogen, C; alkyl, Het?-C4alkylcarbonyl- or rR represents mono-or di(C4alkyl)amino-C) 4alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C4alkyloxy;
Het! represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het! is optionally substituted with amino, C,4alkyl, hydroxy-C, 4alkyl-, phenyl, phenyl-C,4alkyl-, C)4alkyl-oxy-C;4alkyl- mono- or di(C4alkyl)amino- or amino-carbonyl-;
Het"? represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C,salkyl, Ciscycloalkyl, hydroxy-C4allkyl-, Ci4alkyloxyCialkyl or polyhydroxy-C,salkyl-;
Het" represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from Cj alkyl, Cs ¢cycloalkyl, hydroxy-Cj4allkyl-, C,alkyloxyC,4alkyl or polyhydroxy-Ci.salkyl-;
Het'’ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents seleeted from C)alkyl, Cs.¢cycloalkyl, hydroxy-Cjaalkyl-, Ci4alkyloxyCi4alkyl or polyhydroxy-C,salkyl-;
Het'® 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 C,4alkyl; and
Het!” represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C,4alkyl, Cs cycloalkyl, hydroxy-C4alkyl-, C.alkyloxyC, salkyl or polyhydroxy-Cj4alkyl-;
Het'® and Het"? each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C, alkyl, Cs.
AMENDED SHEET scycloalkyl, hydroxy-C,4alkyl-, Cj 4alkyloxyCi4alkyl or polyhydroxy-C;salkyl-; Het®, Het*' and Het? each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy, Ci4alkyl, hydroxy-C; 4alkyl- or polyhydroxy-C,4alkyl-; Ar! Ar?, AP, Ar* and Ar each independently represent phenyl optionally substituted with cyano, C;alkylsulfonyl-, C,4alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C;4alkyl, aminosulfonyl-, hydroxy-, Ci4alkyloxy- or C4alkyl, in the synthesis of a compound of formula (I).
16. A compound according to any one of claims 1 to 8, or 10, substantially as herein described with reference to and as illustrated in any of the examples.
17. A kinase inhibitor according to claim 9, substantially as herein described with reference to and as illustrated in any of the examples.
18. Use according to claim 11 or 15, substantially as herein described with reference to and as illustrated in any of the examples.
19. A composition according to claim 12, substantially as herein described with reference to and as illustrated in any of the examples.
20. A process according to claim 13, substantially as herein described with reference to and as illustrated in any of the examples.
21. An intermediate according to claims 14, substantially as herein described with reference to and as illustrated in any of the examples.
41. A substance or composition for use in a method of treatment according to any one of claims 28 to 34, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0305723 | 2003-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200509541B true ZA200509541B (en) | 2007-02-28 |
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ID=34956895
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200509541A ZA200509541B (en) | 2003-05-27 | 2005-11-24 | Macrocyclic quinazoline derivatives as antiproliferative agents |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1794996A (en) |
| ZA (1) | ZA200509541B (en) |
-
2004
- 2004-05-25 CN CN200480014512.8A patent/CN1794996A/en active Pending
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- 2005-11-24 ZA ZA200509541A patent/ZA200509541B/en unknown
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| Publication number | Publication date |
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| CN1794996A (en) | 2006-06-28 |
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