HK1095742B - 3-cyano-quinoline derivatives with antiproliferative activity - Google Patents

Description

3-cyanoquinoline derivatives having antiproliferative activity

The present invention relates to quinoline-derived macrocycles which have been found to possess antiproliferative activity, such as anti-cancer activity, and are therefore useful in methods of treatment of the human or animal body, for example in the manufacture of medicaments for hyperproliferative diseases such as atherosclerosis, restenosis and cancer. The invention also relates to a method for producing said quinoline derivatives, to pharmaceutical compositions containing them and to their use for producing medicaments for producing an anti-proliferative effect.

In particular, the compounds of the present invention were found to inhibit tyrosine kinases. Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to the phenolic hydroxyl group of tyrosine residues present in target proteins. Several oncogenes known to be involved in the transformation of cells into malignant cells encode tyrosine kinases including certain growth factor receptors such as EGF, FGF, IGF-1R, IR, PDGF and VEGF. This family of receptor tyrosine kinases, in particular the EGF family of receptor tyrosine kinases (hereinafter also referred to as EGFR receptors or EGF-type receptor tyrosine kinases), is commonly present in common human cancers, such as breast cancer; non-small cell lung cancer, including adenocarcinoma and squamous cell lung cancer; bladder cancer; esophageal cancer; gastrointestinal cancer such as colon cancer, rectal cancer or stomach cancer; prostate cancer; leukemia; and ovarian, bronchial or pancreatic cancer, which are examples of cell proliferation-related disorders of sputum.

Accordingly, selective inhibition of tyrosine kinases has been recognized as being of value in the treatment of diseases associated with cell proliferation. This view leads to Herceptin(Trastuzumab) and Gleevec^TMSupport for the development of (imatinib mesylate) they were the first examples of target-based anti-cancer drugs. Herceptin(Trastuzumab) targets against Her2/neu, Her2/neu is a receptor tyrosine kinase found up to 100-fold amplified in about 30% of invasive breast cancer patients. In clinical trials, Herceptin(Trastuzumab) has been demonstrated to have anti-tumor activity against breast Cancer (reviewed by L.K. Shawer et al in Smartdrugs: Tyrosine kinases inhibitors in Cancer therapy, 2002, Cancer Cell Vol.1, 117) and thus provides proof of principle for therapies targeting receptor Tyrosine kinases. Second example Gleevec^TM(Imatinib mesylate) targets against abelson tyrosine kinase (BcR-Ab1), an abelson tyrosine kinase present in almost all Chronic Myelogenous Leukemias (CML)Structurally active cytoplasmic tyrosine kinases neutralize between 15% and 30% of adult patients with acute lymphoblastic leukemia. In clinical trials, Gleevec^TM(imatinib mesylate) exhibited surprising efficacy and had few side effects, making it approved within 3 months of filing. The speed at which this drug passes clinical trials and regulatory scrutiny has become a case-by-case study of rapid drug development (Drucker B.J.&Lydon N.，″Lessons learned from thedevelopment of an Ab1 tyrosine kinase inhibitor for chronicmyelogenous leukaemia.″，2000，J.Clin.Invest.，105，3)。

Additional support derives from the demonstration that EGF receptor tyrosine kinase inhibitors specifically attenuate the growth of transplanted cancers such as human breast cancer or human squamous cell carcinoma in athymic nude mice (reviewed by t.r. burke jr., Drugs of the Future, 1992, 17, 119). As a result, considerable attention has been paid to the development of EGFR receptor-targeting drugs for the treatment of various cancers. For example, several antibodies that bind to the extracellular domain of EGFR are in clinical trials, including Erbitux^TM(also known as C225, Cetuximab), which was developed by Imclone Systems, is now in phase III clinical trials for the treatment of a variety of cancers. Furthermore, several promising orally active drugs are currently in clinical trials as potent and relatively specific EGFR tyrosine kinase inhibitors. Now called IRESSAAstraZeneca compound ZD1839, and now known as Tarceva, approved for the treatment of advanced non-small cell lung cancer^TM(erlotinib) OSI/Genentech/Roche compound OSI-774 has shown significant efficacy against several cancers in human clinical trials (Morin M.J. "From Oncogene to drug: maintenance of small molecule type cancer inhibitors as anti-tumor and anti-angiogenic agents, 2000, Oncogene 19, 6574).

In addition to the above, EGF receptor tyrosine kinase has been shown to be involved in non-malignant proliferative sputum diseases such as psoriasis (elder et al, Science, 1989, 243; 811). Therefore, inhibitors of EGF type receptor tyrosine kinases are expected to be useful in the treatment of non-malignant diseases of excessive cell proliferation such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.

Certain 4-anilino-3-cyanoquinolines are disclosed as being useful as inhibitors of tyrosine kinases, particularly EGF-type receptor tyrosine kinases, in U.S. patent 6,288,082 and U.S. patent 6,002,008 and international patent applications WO98/43960 and WO00/018761, as well as in j.med.chem., 2000, 43(17), 3244. Unexpectedly, it was found that the 3-cyanoquinoline derivatives of formula (I) of the present invention having different structures exhibit tyrosine kinase inhibitory activity.

It is therefore an object of the present invention to provide additional tyrosine kinase inhibitors useful in the manufacture of a medicament for the treatment of cell proliferation-related diseases.

The present invention relates to a compound represented by the following formula (I)

And the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

Z represents O, NH or S;

y represents-C_3-9Alkyl-, -C_3-9Alkenyl-, -C_1-5alkyl-oxy-C_1-5Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-5alkyl-CO-NR¹⁴-C_1-5Alkyl-, -C_1-6alkyl-CO-NH-, -C_1-6alkyl-NH-CO-, -CO-NH-C_1-6Alkyl-, -NH-CO-C_1-6Alkyl-, -CO-C_1-7Alkyl-, -C_1-7alkyl-CO-、C_1-6alkyl-CO-C_1-6Alkyl, -C_1-2alkyl-NH-CO-CH₂R¹⁵-NH-；

X¹Represents a direct bond, O, -O-C_1-2Alkyl-, CO-C_1-2Alkyl-, NR¹⁰、-NR¹⁰-C_1-2Alkyl-, NR¹⁶-CO-、NR¹⁶-CO-C_1-2Alkyl, -O-N ═ CH-or C_1-2An alkyl group;

X²represents a direct bond, O, -O-C_1-2Alkyl-, CO-, -CO-C_1-2Alkyl-, NR¹¹、NR¹¹-C_1-2Alkyl-, NR¹⁷-CO-、NR¹⁷-CO-C_1-2Alkyl, Het²⁰-C_1-2Alkyl, -O-N ═ CH-or C_1-2An alkyl group;

R¹represents hydrogen, cyano, halogen, hydroxy, formyl, C_1-6alkoxy-C_1-6Alkyl-, C substituted by halogen_1-6Alkoxy-, C substituted by one or, when possible, two or more substituents selected from hydroxy or halogen_1-4An alkyl group;

R²represents hydrogen, cyano, halogen, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C_1-4Alkyloxycarbonyl-, C_1-4Alkylcarbonyl-, aminocarbonyl-, mono-or di (C)_1-4Alkyl) aminocarbonyl-, Het¹Formyl, C_1-4Alkyl-, C_2-6Alkynyl-, C_3-6cycloalkyl-C_3-6Cycloalkyloxy-, C_1-6alkoxy-Ar⁵、Ar¹-oxy-, dihydroxyborane, C substituted by halogen_1-6Alkoxy-, by one or, when possible, by two or more radicals selected from halogen, hydroxy or NR⁴R⁵C substituted by a substituent of_1-4Alkyl radical, C_1-4Alkylcarbonyl-wherein said C_1-4Alkyl is optionally substituted by one or, when possible, two or more groups selected from hydroxy or C_1-4Alkyl-oxy-substituted;

R³represents hydrogen, hydroxy, Ar³-oxy, Ar⁴-C_1-4Alkyloxy-, C_1-4Alkyloxy-, optionally Het¹²Substituted C_2-4Alkenyloxy-; or R³Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy-, hydroxy, halo, Het²-、-NR⁶R⁷-carbonyl-NR⁸R⁹Or Het³C substituted by a substituent of-carbonyl-_1-4An alkyloxy group;

R⁴and R⁵Each independently selected from hydrogen or C_1-4An alkyl group;

R⁶and R⁷Each independently selected from hydrogen and C_1-4Alkyl, Het⁸Aminosulfonyl-, mono-or di (C)_1-4Alkyl) -aminosulfonyl, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-, hydroxycarbonyl-C_1-4Alkyl-, C_3-6Cycloalkyl, Het⁹-carbonyl-C_1-4Alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C_1-4Alkyl-, Het¹¹-C_1-4Alkyl-or Ar²-C_1-4Alkyl-;

R⁸and R⁹Each independently selected from hydrogen and C_1-4Alkyl radical, C_3-6Cycloalkyl, Het⁴hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl-, or polyhydroxy-C_1-4Alkyl-;

R¹⁰represents hydrogen, C_1-4Alkyl, Het⁵、Het⁶-C_1-4Alkyl-, optionally Het⁷-C_1-4Alkylaminocarbonyl-substituted C_2-4alkenylcarbonyl-C_2-4Alkenylsulfonyl-, C_1-4Alkyloxy C_1-4Alkyl-or optionally one or, when possible, two or more radicals selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹¹represents hydrogen, C_1-4Alkyl radical, C_1-4Alkyl-oxy-carbonyl-, Het¹⁷、Het¹⁸-C_1-4Alkyl-, optionally Het¹⁹-C_1-4Alkylaminocarbonyl-substituted C_2-4alkenylcarbonyl-C_2-4Alkenylsulfonyl-, C_1-4Alkyloxy C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹²represents hydrogen, C_1-4Alkyl, Het¹³、Het¹⁴-C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹³and R¹⁴Each independently selected from hydrogen and C_1-4Alkyl, Het¹⁵-C_1-4Alkyl-or C_1-4Alkyloxy C_1-4Alkyl-;

R¹⁵represents hydrogen or C optionally substituted by phenyl, indolyl, methylthio (methylsulfide), hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazolyl or guanidino_1-4An alkyl group;

R¹⁶and R¹⁷Each independently selected from hydrogen and C_1-4Alkyl, Het²¹-C_1-4Alkyl or C_1-4Alkyloxy C_1-4An alkyl group;

Het¹represents a compound selected from the group consisting of piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, and the like,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is¹Optionally substituted by amino, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substituted;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, or dithianyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, halogen, amino, C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-, hydroxy-C_1-4alkyl-oxy-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-, mono-or di (C)_1-4Alkyl) amino-C_1-4Alkyl-, amino-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-sulfonyl-, aminosulfonyl-substituents;

Het³、Het⁴and Het⁸Each independently represents a group selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, piperazinyl,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is³、Het⁴Or Het⁸Optionally one or, when possible, two or more radicals selected from hydroxy-, amino-, C_1-4Alkyl-, C_3-6cycloalkyl-C_1-4Alkyl-, aminosulfonyl-, mono-or di (C)_1-4Alkyl) aminosulfonyl or amino-C_1-4Alkyl-substituted;

Het⁵represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het⁶and Het⁷Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het⁹and Het¹⁰Each independently represents a group selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, piperazinyl,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is⁹Or Het¹⁰Optionally is covered with C_1-4Alkyl radical, C_3-6cycloalkyl-C_1-4Alkyl-or amino-C_1-4Alkyl-substitution;

Het¹¹represents a heterocycle selected from indolyl or of formula:

Het¹²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, or dithiacyclohexylyl, wherein said Het is¹²Optionally one or, when possible, two or more radicals selected from hydroxy, halogen, amino, C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-C₁-₄Alkyl-, hydroxy-C_1-4alkyl-oxy-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-or mono-or di (C)_1-4Alkyl) amino-C_1-4Alkyl-substituted;

Het¹³represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁴represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁵and Het²¹Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁶represents a heterocyclic ring selected from morpholinyl, pyrrolidinyl, piperazinyl, 1, 3, 2-dioxaborolan (dioxaborolane) or piperidinyl, wherein said heterocyclic ring is optionally substituted by oneOr more are selected from C_1-4Alkyl substituent substitution; and

Het¹⁷represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁸and Het¹⁹Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het²⁰represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl or pyrazolidinyl, wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted; in particular Het²⁰Represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl or pyrazolidinyl, wherein said heterocycle is optionally substituted by one or, when possible, by two or more groups selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted; and

Ar¹、Ar²、Ar³、Ar⁴and Ar⁵Each independently represents optionally cyano, C_1-4Alkylsulfonyl-, C_1-4Alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C_1-4Alkyl, aminosulfonyl-, hydroxyradical-C_1-4Alkyloxy-and C_1-4Alkyl-substituted phenyl.

As used in the foregoing definitions and hereinafter,

halogen generally means fluorine, chlorine, bromine and iodine;

-C_1-2alkyl means methyl or ethyl;

-C_1-3alkyl refers to straight and branched chain saturated hydrocarbon groups having 1 to 3 carbon atoms, such as, for example, methyl, ethyl, propyl, and the like;

-C_1-4alkyl means straight and branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2-dimethylethyl and the like;

-C_1-5alkyl means straight and branched chain saturated hydrocarbon groups having 1 to 5 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl, 2-dimethylpropyl, 2-dimethylethyl and the like;

-C_1-6alkyl means including C_1-5Alkyl groups and their higher homologues having 6 carbon atoms, such as, for example, hexyl, 1, 2-dimethylbutyl, 2-methylpentyl, and the like;

-C_1-7alkyl means including C_1-6Alkyl groups and their higher homologs having 7 carbon atoms, such as, for example, 1, 2, 3-dimethylbutyl, 1, 2-methylpentyl, and the like;

-C_3-9alkyl means straight and branched chain saturated hydrocarbon groups having 3 to 9 carbon atoms, such as propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like;

-C_2-4alkenyl means straight and branched chain hydrocarbon groups containing one double bond and having 2 to 4 carbon atoms, such as, for example, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, etc.;

-C_3-9alkenyl means straight-chain and branched hydrocarbon groups containing one double bond and having 3 to 9 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like;

-C_2-6alkynyl refers to straight and branched chain hydrocarbon groups having one triple bond and having 2 to 6 carbon atoms, such as, for example, 2-propynyl, 3-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, and the like;

-C_3-6cycloalkyl is generically referring to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

-C_1-4alkyloxy means a straight or branched chain saturated hydrocarbon group such as methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 2-methylpropoxy, etc.;

-C_1-6alkyloxy is meant to include C_1-4Alkyloxy and its higher homologues such as methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 2-methylpropoxy and the like;

-polyhydroxy-C_1-4Alkyl generally refers to C as defined above having two, three or, when possible, more hydroxy substituents_1-4Alkyl groups such as, for example, trifluoromethyl.

As used in the foregoing definitions and hereinafter, the term formyl refers to a group of formula-CH (═ O).

The heterocyclic rings mentioned in the above definitions and hereinafter are meant to include all possible isomeric forms thereof, e.g. pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1, 2, 4-triazolyl and 1, 3, 4-triazolyl;the diazolyl group includes 1, 2, 3-DiazolesBase, 1, 2, 4-Oxadiazolyl, 1, 2, 5-Oxadiazolyl and 1, 3, 4-A diazolyl group; the thiadiazolyl group includes 1, 2, 3-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 1, 2, 5-thiadiazolyl group and 1, 3, 4-thiadiazolyl group; pyranyl includes 2H-pyranyl and 4H-pyranyl.

In addition, the heterocyclic rings mentioned in the above definitions and hereinafter may suitably be attached to the remainder of the molecule of formula (I) via any ring carbon or heteroatom. Thus, for example, when the heterocycle is imidazolyl, it can be 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 a triazolyl group, it may be a1, 2, 4-triazol-1-yl group, a1, 2, 4-triazol-3-yl group, a1, 2, 4-triazol-5-yl group, a1, 3, 4-triazol-1-yl group and a1, 3, 4-triazol-2-yl group; when it is a benzothiazolyl group, it may be a 2-benzothiazolyl group, a 4-benzothiazolyl group, a 5-benzothiazolyl group, a 6-benzothiazolyl group, or a 7-benzothiazolyl group.

Pharmaceutically acceptable addition salts as described above include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt forms are conveniently obtained by treating the base form with the appropriate acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

Pharmaceutically acceptable addition salts as described above include the therapeutically active non-toxic base addition salt forms which the compounds of formula (1) are able to form. Examples of such base addition salt forms are, for example, the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, N' -dibenzylethylenediamine, N-methyl-D-glucamine, hydrabamine, amino acids such as arginine, lysine.

Conversely, the salt form may be converted to the free acid or base form by treatment with an appropriate base or acid.

The term addition salt as used hereinbefore also includes solvates which the compounds of formula (I) and salts thereof are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term stereochemically isomeric forms as used above defines the different isomeric forms and configurations which the compounds of formula (I) may possess. Unless otherwise specified or indicated, the chemical names of compounds denote a mixture of all possible stereochemically and conformationally isomeric forms, said mixture 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 and in admixture with 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 form. Such forms, although not represented in the above formula, are intended to be included within the scope of the present invention.

N-oxide forms of the compounds of formula (I) include those compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide.

One group of preferred compounds consists of those compounds of formula (I) wherein one or more of the following limitations apply:

z represents NH;

y represents-C_3-9Alkyl-, -C_2-9Alkenyl-, -C_1-5alkyl-oxy-C_1-5Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-, -CO-C_1-7Alkyl-, -C_1-7alkyl-CO-or C_1-6alkyl-CO-C_1-6An alkyl group;

X¹represents O, -O-C_1-2Alkyl-, -O-N ═ CH-, NR¹⁰or-NR¹⁰-C_1-2Alkyl-; in a specific embodiment, X¹represents-O-or-O-CH₂-；

X²Represents a direct bond, O, -O-C_1-2Alkyl-, -O-N ═ CH-, C_1-2Alkyl, NR¹¹Or NR¹¹-C_1-2Alkyl-; in a specific embodiment, X²Represents a direct bond, -O-N ═ CH-, -NR-¹¹-C_1-2Alkyl-, -NR¹¹-CH₂-、-C_1-2Alkyl-, -O-C_1-2Alkyl, -O-or-O-CH₂-；

R¹Represents hydrogen, cyano, halogen or hydroxy, preferably halogen;

R²represents hydrogen, cyano, halogen, hydroxy, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-, C_2-6Alkynyl-, Ar⁵Or Het¹(ii) a In another embodiment, R²Represents hydrogen, cyano, halogen, hydroxy, C_2-6Alkynyl-or Het¹；

R³Represents hydrogen, hydroxy, C_1-4Alkyloxy-, Ar⁴-C_1-4An alkyloxy group; or R³Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy-or Het²C substituted by a substituent of (A)_1-4An alkyloxy group;

R¹⁰represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

Het¹represents an optionally substituted amino group, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substituted thiazolyl;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl substituent substitution; in another embodiment, Het²Represents a heterocycle selected from morpholinyl or piperidinyl, optionally substituted by C_1-4Alkyl-substituted, preferably by methyl;

Het¹⁴represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is¹⁴Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl substituent substitution;

Het¹⁶represents a heterocycle selected from piperidinyl, morpholinyl or pyrrolidinyl;

Ar⁴represents optionally cyano, hydroxy-, C_1-4Alkyloxy or C_1-4Alkyl-substituted phenyl;

Ar⁵represents optionally cyano, hydroxy, C_1-4Alkyloxy or C_1-4Alkyl-substituted phenyl.

Another group of compounds consists of those compounds of formula (I) wherein one or more of the following limitations apply:

z represents NH;

y represents-C_3-9Alkyl-, -C_1-5Alkyl radical-NR¹²-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-or-CO-NH-C_1-6Alkyl-;

X¹represents-O-;

X²represents a direct bond, -NR¹¹-C_1-2Alkyl-, -NR¹¹-CH₂-、-C_1-2Alkyl, -O-C_1-2Alkyl, -O-or-O-CH₂-；

R¹Represents hydrogen or halogen;

R²represents hydrogen, cyano, halogen, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-or Ar⁵；

R³Represents hydrogen, hydroxy, C_1-4Alkyloxy-, Ar⁴-C_1-4An alkyloxy group; or R³Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy-or Het⁷C substituted by a substituent of (A)_1-4An alkyloxy group;

R¹⁰represents hydrogen;

R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted; in another embodiment, Het²Represents a heterocycle selected from morpholinyl or piperidinyl, optionally substituted by C_1-4Alkyl-substituted, preferably by methyl;

Het¹⁴represents morpholinyl;

Het¹⁶represents a heterocycle selected from morpholinyl or pyrrolidinyl;

Ar⁴represents a phenyl group;

Ar⁵represents phenyl optionally substituted by cyano.

Another group of compounds consists of those compounds of formula (I) wherein one or more of the following limitations apply:

z represents NH;

y represents-C_3-9Alkyl-, -C_2-9Alkenyl-, -C_1-5alkyl-oxy-C_1-5Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-, -CO-C_1-7Alkyl-, -C_1-7alkyl-CO-or C_1-6alkyl-CO-C_1-6An alkyl group;

X¹represents O, -O-C_1-2Alkyl-, -O-N ═ CH-, NR¹⁶-CO、-NR¹⁶-CO-C_1-2Alkyl-, NR¹⁰or-NR¹⁰-C_1-2Alkyl-; in a specific embodiment, X¹represents-O-, -O-CH₂-、NR¹⁰or-NR¹⁰-C_1-2Alkyl-;

X²represents a direct bond, O, -O-C_1-2Alkyl-, -O-N ═ CH-, Het²⁰-C_1-2Alkyl radical, C_1-2Alkyl, NR¹⁷-CO、-NR¹⁷-CO-C_1-2Alkyl-, NR¹¹Or NR¹¹-C_1-2Alkyl-; in a specific embodiment, X²Represents a direct bond, -O-N ═ CH-, -NR-¹¹-C_1-2Alkyl-, -NR¹¹-CH₂-、Het²⁰-C_1-2Alkyl, NR¹⁷-CO、-NR¹⁷-CO-C_1-2Alkyl radical-C_1-2Alkyl-, -O-C_1-2Alkyl, -O-or-O-CH₂-；

R¹Represents hydrogen, cyano, halogen or hydroxy, preferably halogen;

R²represents hydrogen, cyano, halogen, hydroxy, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-, C_2-6Alkynyl-, Ar⁵Or Het¹(ii) a In another embodiment, R²Represents hydrogen, cyano, halogen, hydroxy, C_2-6Alkynyl-or Het¹；

R³Represents hydrogen, hydroxy, C_1-4Alkyloxy-, Ar⁴-C_1-4An alkyloxy group; or R³Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy-or Het²C substituted by a substituent of (A)_1-4An alkyloxy group;

R¹⁰represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

R¹⁶represents hydrogen, C_1-4Alkyl-, Het²¹-C_1-4Alkyl or C_1-4alkyl-oxy-C_1-4An alkyl group; in particular, R¹⁶Represents hydrogen or C_1-4An alkyl group;

R¹⁷represents hydrogen, C_1-4Alkyl-, Het²¹-C_1-4Alkyl or C_1-4alkyl-oxy-C_1-4An alkyl group; in particular R¹⁶Represents hydrogen or C_1-4An alkyl group;

Het¹represents an optionally substituted amino group, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substitutedA substituted thiazolyl group;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted; in another embodiment, Het²Represents a heterocycle selected from morpholinyl or piperidinyl, optionally substituted by C_1-4Alkyl-substituted, preferably by methyl;

Het¹⁴represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is¹⁴Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted;

Het¹⁶represents a heterocycle selected from piperidinyl, morpholinyl or pyrrolidinyl;

Het²⁰represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl or piperidinyl;

Het²¹represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is²¹Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted;

Ar⁴represents optionally cyano, hydroxy-, C_1-4Alkyloxy or C_1-4Alkyl-substituted phenyl;

Ar⁵represents optionally cyano, hydroxy, C_1-4Alkyloxy or C_1-4Alkyl-substituted phenyl.

Another group of compounds consists of those compounds of formula (I) wherein one or more of the following limitations apply:

z represents NH;

y represents-C_3-9Alkyl, -C_1-5alkyl-NR¹²-C_1-5Alkyl, aryl, heteroaryl, and heteroaryl,-C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-5alkyl-CO-NR¹⁴-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-or-CO-NH-C_1-6Alkyl-; in particular, Y represents-C_3-9Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-or-CO-NH-C_1-6Alkyl-;

X¹represents a direct bond, NR¹⁰、-NR¹⁰-C_1-2Alkyl-, -NR¹⁰-CH₂-、-C_1-2Alkyl-, -O-C_1-2Alkyl, -O-or-O-CH₂-；

X²represents-O-, NR¹¹、NR¹⁷-CO、NR¹⁷-CO-C_1-2Alkyl or Het²⁰-C_1-2An alkyl group;

R¹represents hydrogen or halogen;

R²represents hydrogen, cyano, halogen, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-or Ar⁵；

R³Represents hydrogen, hydroxy, C_1-4Alkyloxy-, Ar⁴-C_1-4An alkyloxy group; or R³Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy-or Het²C substituted by a substituent of (A)_1-4An alkyloxy group;

R¹⁰represents hydrogen;

R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

R¹³represents hydrogen;

R¹⁷represents hydrogen;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted; in another embodiment, Het²Represents a heterocycle selected from morpholinyl or piperidinyl, optionally substituted by C_1-4Alkyl-substituted, preferably by methyl;

Het¹⁴represents morpholinyl;

Het¹⁶represents a heterocycle selected from morpholinyl or pyrrolidinyl;

Het²⁰represents pyrrolidinyl or piperidinyl;

Ar⁴represents a phenyl group;

Ar⁵represents phenyl optionally substituted by cyano.

Other specific groups of compounds are:

in which-X¹-those compounds of formula (I) which represent-O-;

in which-X¹-represents-NR¹⁰-, in particular-NH-;

in which-X²-represents-NR¹⁷-CO-C_1-2Alkyl-, especially-NH-CO-C_1-2Alkyl-those of formula (I);

in which-X²-represents-NR¹¹-C_1-2Alkyl-, especially-NH-C_1-2Alkyl-those of formula (I);

wherein-Y-represents-C_1-5alkyl-NR¹³-CO-C_1-5alkyl-or-C_1-5alkyl-CO-NR¹⁴-C_1-5Alkyl-, especially-C_1-5alkyl-NH-CO-C_1-5Alkyl-those of formula (I);

-wherein R is¹Those compounds of formula (I) which are fluorine, chlorine or bromine;

-wherein R is²Those compounds of formula (I) which are fluorine, chlorine or bromine;

-wherein R is¹And R²Those compounds of formula (I) which represent halogen, in particular wherein R¹Represents fluorine and R²Those compounds of formula (I) which represent chlorine;

-wherein R is Het¹In particular those of formula (I) wherein the thiazolyl is optionally substituted by methyl;

-wherein R is²Is C_2-6Alkynyl-, particularly ethynyl, of those of formula (I);

-wherein R is²Is Ar⁵In particular phenyl optionally substituted by cyano, are those of formula (I);

-wherein R is³Those compounds of formula (I) which represent a methoxy group and wherein the methoxy group is in the 7-position of the structure of formula (I);

-wherein R is³Is selected from C_1-4Alkyloxy-or Het²C substituted by one substituent of (A)_1-4Those compounds of formula (I) which are alkyloxy, in particular propyloxy substituted by morpholinyl;

-wherein R is¹¹Is hydrogen or C_1-4Alkyl-, especially methyl or wherein R¹¹Is C_1-4Alkyl-oxy-carbonyl-, especially tert-butyl-oxy-carbonyl-, of those compounds of formula (I);

-wherein Het²Represents an optional quilt C_1-4Alkyl-substituted morpholinyl, preferably morpholinyl, which is linked to the remainder of the compound of formula (I) via a nitrogen atom;

-wherein Het³Represents an optional quilt C_1-4Alkyl-substituted morpholinyl, preferably linked via the nitrogen atom toMorpholinyl of the remainder of the compounds of formula (I);

-wherein Het¹²Represents an optional quilt C_1-4Alkyl-substituted morpholinyl, preferably morpholinyl which is attached to the remainder of the compound of formula (I) via a nitrogen atom.

In another embodiment of the invention, R¹The substituent is at the 4' -position of the structure of formula (I), R²The substituent is at the 5' -position of the structure of formula (I), R³The substituent is at the 7-position of the structure of formula (I).

The compounds of the present invention can be prepared by any of several standard synthetic procedures commonly employed by those skilled in the art of organic chemistry and described, for example, in the following references: "Heterocyclic Compounds", Vol.24 (part 4) page 261-304, Fusedplastics, Wiley-Interscience; chem. pharm. Bull., Vol 41(2)362-368 (1993); chem.soc., Perkin trans.1, 2001, 130-.

Y₁And Y₂Is represented by C_1-5Alkyl or CO-C_1-5Alkyl radical

X₃And X₄Represents an optionally protected functional group, such as, for example, a primary, secondary or tertiary amine, a hydroxyl group or a halogen (Cl, Br or I), which, when reacted, is in each case bound to Y to which they are bound₁And Y₂The substituents together form a divalent Y group as defined in formula (I).

As further exemplified in the experimental part of the specification, wherein X¹The compound of formula (I) representing-O-is generally prepared starting from 6-acetoxy-4-amino-3-cyanoquinoline of formula (II), which can be prepared from the known 5-acetoxy-4-alkoxy-2-nitrobenzoic acid (scheme 2).

The coupling of quinolines of formula (II) with appropriately substituted anilines (III) to give the intermediate compounds (IV), which can be prepared according to reaction schemes 3-7.

Intermediates of formula (IV) were deprotected as described in t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis, third edition, 1998, followed by ring closure under Mitsunobu conditions to give the target compound (I) (scheme 1).

Scheme 1

A protecting group such as, for example, methylcarbonyl, tert-butyl, methyl, ethyl, benzyl or trialkylsilyl

R¹⁸Represents Ar³、Ar⁴-C_1-4Alkyl radical, C_1-4Alkyl, optionally substituted with Het¹²Substituted C_2-6An alkenyl group; or R¹⁸Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy, hydroxy, halogen, Het²、NR⁶R⁷、NR⁸R⁹-carbonyl or Het³C substituted by a substituent of a carbonyl group_1-4Alkyl radical, wherein Ar³、Ar⁴、Het¹²、Het²、R⁶、R⁷、R⁸、R⁹And Het³See the definition for compounds of formula (I).

6-acetoxy-4-chloro-3-cyano-quinoline (II) can be produced according to scheme 2. In this synthesis scheme, the 2-amino-benzoate derivative (VII) can be prepared by esterification of 5-acetoxy-4-methoxy-2-nitrobenzoic acid (V) with, for example, dimethyl sulfate in the presence of a base such as potassium carbonate, followed by reduction of the nitro group with, for example, iron/acetic acid.

The compound (VII) thus obtained is then converted into a quinoline ring of formula (IX) according to the method described, for example with 1, 1-dimethoxytrimethylamine (DMFDMA) in Dimethylformamide (DMF), followed by electrophilic substitution to introduce a 3-cyano substituent.

Then, by chlorinating agent such as SOCl in DMF₂The 3-cyano-quinoline derivative thus obtained is chlorinated to obtain a quinoline derivative of the formula (II).

Scheme 2

R¹⁸Represents Ar³、Ar⁴-C_1-4Alkyl radical, C_1-4Alkyl, optionally substituted with Het¹²Substituted C_2-6An alkenyl group; or R¹⁸Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy, hydroxy, halogen, Het²、NR⁶R⁷、NR⁸R⁹-carbonyl or Het³C substituted by a substituent of a carbonyl group_1-4Alkyl radical, wherein Ar³、Ar⁴、Het¹²、Het²、R⁶、R⁷、R⁸、R⁹And Het³See the definition for compounds of formula (1).

For X in²Those compounds of formula (III) which represent-O-^a) The appropriately substituted anilines of (A) are generally prepared under basic conditions in a reaction-inert solvent (e.g. using Dimethylacetamide (DMA) in K₂CO₃In the presence of) from commercially available nitrophenols (X) and alpha, omega-protected halohydrins (XI). The resulting nitro-phenyl derivative (XII) is then reduced, e.g. with iron/acetic acid, according to standard conditions to give formula (III)^a) Substituted anilines of (a) are shown in scheme 3.

Scheme 3

X represents halogen, such as, for example, Cl, Br, I and F

V represents a protecting group such as, for example, methylcarbonyl

For X in²represents-NR¹¹-and-NR¹¹-C_1-2Those of alkyl-, formula (III)^b) Are generally prepared from commercially available 2-nitro-benzaldehydes (XIII) and amine-substituted alcohols (XIV) by reductive amination under standard conditions, for example using NaBH in ethanol as solvent₄And titanium (IV) isopropoxide, to give, in a first step, a nitrobenzylamine of the formula (XV).

The free primary alcohol is then esterified with acetic anhydride, for example in the presence of pyridine, using methods known in the art.

The intermediate of formula (XVI) thus obtained is subsequently reduced according to standard conditions, for example using iron/acetic acid, to give formula (III)^b) Substituted anilines of (a) and (b) are shown in scheme 4.

Scheme 4

V represents a protecting group such as, for example, methylcarbonyl.

For X²Those compounds of formula (III) which represent-O-N ═ CH-^c) The appropriately substituted anilines of (a) are generally prepared according to reaction scheme 5.

In a first step, the known 2-nitro-benzaldehyde (XIII) is converted into the corresponding oxime (XVII) using, for example, a condensation reaction with hydroxylamine as known in the art.

The oxime of the formula XVII is then reacted with a haloalkyl acetate under basic conditions, for example in DMSOK of₂CO₃Subsequent reduction of the nitro group using, for example, iron/acetic acid, gives the formula (III)^c) An appropriately substituted aniline of (a).

Scheme 5

X represents halogen, such as, for example, Cl, Br, I or F

For X in²Denotes a direct bond and Y denotes C_1-6Those compounds of alkyl-NH-CO-, formula (III)^d) The appropriately substituted anilines of (a) are generally prepared according to reaction scheme 6.

In a first step, the known 2-nitrobenzoic acid (XX) is amidated under conditions known in the art to give an intermediate of formula (XXII), for example using the addition of a hydroxylated amine of formula (XXI) dropwise to (XX) in the presence of 1, 1' -carbonylbis-1H-imidazole in CH₂Cl₂In the mixture of (1).

The free primary alcohol is then protected using methods known in the art, such as esterification with acetic anhydride in the presence of pyridine.

The intermediate of formula (XXIII) thus obtained is subsequently reduced, for example using iron/acetic acid, according to standard conditions to give formula (III)^d) Substituted anilines of (a).

Scheme 6

V represents a protecting group such as, for example, methylcarbonyl.

For X in²Those compounds representing a direct bond, formula (III)^e) Is generally prepared according to reaction scheme 7And (4) preparing.

In a first step, the known 2-nitro-benzaldehyde (XIII) is olefinated under conditions known in the art to give an intermediate of formula (XXV), for example with a suitable phosphorus of formula (XXIV)Wittig (Wittig) reaction of salts.

Reduction of the intermediate of formula (XXVI) after esterification of the free carboxylic acid under standard conditions, for example using ethanol under acidic conditions, gives the desired formula (III)^e) Substituted anilines of (a).

Scheme 7

Y₃Is represented by C_1-7An alkyl group.

Or, wherein Y represents-C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-2alkyl-NH-CO-CH₂R¹⁵-NH-or-C_1-5alkyl-CO-NR¹⁴-C_1-5Alkyl-those of formula (I'^b) The compounds of (a) were prepared by the following synthetic scheme. As described above, formula (IV)^b) An intermediate of (1). Deprotection under standard conditions and subsequent formation of the corresponding ether using the appropriate aminated alcohol affords intermediates of formula (XXVIII). Deprotection followed by ring closure affords formula (I'^b) The target compound of (1).

Scheme 8

A protecting group such as, for example, methylcarbonyl, t-butyl, methyl, ethyl, benzyloxycarbonyl, or trialkylsilyl, or, in the case of solid phase chemistry, a resin linking the remainder of the molecule,

R¹⁸represents Ar³、Ar⁴-C_1-4Alkyl radical, C_1-4Alkyl, optionally substituted with Het¹²Substituted C_2-6An alkenyl group; or R¹⁸Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy, hydroxy, halogen, Het²、NR⁶R⁷、NR⁸R⁹-carbonyl or Het³C substituted by a substituent of a carbonyl group_1-4Alkyl radical, wherein Ar³、Ar⁴、Het¹²、Het²、R⁶、R⁷、R⁸、R⁹，Het³See the definition for compounds of formula (I),

Y₁and Y₂Each independently represents C_1-5Alkyl, CO-C_1-5Alkyl or CO-CH₂R¹⁵-NH-。

Any one or more of the following additional steps may be performed in any order, as necessary or desired:

(i) removing any remaining protecting groups;

(ii) converting a compound of formula (I) or a protected form thereof to another compound of formula (I) or a protected form thereof;

(iii) converting a compound of formula (I) or a protected form thereof to an N-oxide, salt, quaternary amine or solvate of a compound of formula (I) or a protected form thereof;

(iv) converting the N-oxide, salt, quaternary amine or solvate of the compound of formula (I) or a protected form thereof to a compound of formula (I) or a protected form thereof;

(v) converting a compound of formula (I) or a protected form of an N-oxide, salt, quaternary amine or solvate thereof to another N-oxide, pharmaceutically acceptable addition salt, quaternary amine or solvate of a compound of formula (I) or a protected form thereof;

(vi) when the compound of formula (I) is obtained as a mixture of enantiomers of (S) of (R), the mixture is resolved to obtain the desired enantiomer.

The compounds of formula (I), the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof may be converted into additional compounds of the present invention using methods known in the art.

It will be appreciated by those skilled in the art that in the above process, the functional groups of the intermediate compound may need to be blocked by protecting groups.

Functional groups desirably protected include hydroxyl, amino, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino groups include tert-butoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include C_1-6Alkyl esters or benzyl esters.

The protection and deprotection of the functional groups may be performed before or after the reaction step.

Alternatively, the N-atom in the compound of formula (I) may be replaced by CH in a suitable solvent such as, for example, acetone, tetrahydrofuran or dimethylformamide by methods known in the art₃I is methylated.

The compounds of formula (I) may also be converted to each other according to functional group conversion methods known in the art, some examples of which are mentioned below.

The compounds of formula (I) may also be converted to the corresponding N-oxides according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can be generally carried out by reacting the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaaziridine or with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g., sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids such as, for example, peroxybenzoic acid and halogen-substituted peroxybenzoic acids, such as 3-chloroperoxybenzoic acid, peroxy alkanoic acids, such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are for example water; lower alkanols such as ethanol and the like; hydrocarbons such as toluene; ketones such as 2-butanone; halogenated hydrocarbons such as dichloromethane; and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by methods known in the art. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatographic techniques such as countercurrent distribution, liquid chromatography and the like.

Some of the compounds of formula (I) and some of the intermediates in the present invention may contain asymmetric carbon atoms. Pure stereochemically isomeric forms of said compounds and of said intermediates may be obtained by using methods known in the art. For example, diastereomers may be separated by physical means such as selective crystallization or chromatographic techniques such as countercurrent distribution, liquid chromatography, and the like. The racemic mixture can be converted into a mixture of diastereomeric salts or compounds by first converting the racemic mixture with an appropriate resolving agent such as, for example, a chiral acid; the diastereomeric salt or mixture of compounds is then physically separated by, for example, selective crystallization or chromatographic techniques such as liquid chromatography; and finally converting said separated diastereomeric salt or compound into the corresponding enantiomer to obtain the enantiomer. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reaction proceeds in a stereospecific manner.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, particularly using a chiral stationary phase.

Some of the intermediates and starting materials used in the foregoing reaction methods are known compounds and are commercially available or can be prepared according to methods known in the art. However, in the synthesis of macrocyclic kinase inhibitors such as, for example, compounds of formula (I), the present invention additionally provides:

a) intermediates of formula (III)

And pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein

Y represents-C_3-9Alkyl-, -C_3-9Alkenyl-, -C_1-5alkyl-oxy-C_1-5Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-5alkyl-NR¹³-CO-C_1-5Alkyl-, -C_1-5alkyl-CO-NR¹⁴-C_1-5Alkyl-, -C_1-6alkyl-CO-NH-, -C_1-6alkyl-NH-CO-, -C_1-7alkyl-CO-, C_1-6alkyl-CO-C_1-6An alkyl group;

X²represents a direct bond, O, -O-C_1-2Alkyl-, CO-C_1-2Alkyl-, NR¹¹、-NR¹¹-C_1-2Alkyl-, -CH₂-, -O-N ═ CH-or C_1-2An alkyl group;

R¹represents hydrogen, cyano, halogen, hydroxy, formyl, C_1-6alkoxy-C_1-6Alkyl-, C substituted by halogen_1-6Alkoxy-, C substituted by one or, when possible, two or more substituents selected from hydroxy or halogen_1-4An alkyl group; and

R²represents hydrogen, cyano, halogen, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C_1-4Alkyloxycarbonyl-, C_1-4Alkylcarbonyl-, aminocarbonyl-, mono-or di (C)_1-4Alkyl) aminocarbonyl-, Het¹Formyl, C_1-4Alkyl-, C_2-6Alkynyl-, C_3-6cycloalkyl-C_3-6Cycloalkyl radicalsOxy-, C_1-6alkoxy-Ar⁵、Ar¹-oxy-, dihydroxyborane, C substituted by halogen_1-6Alkoxy-, by one or, when possible, by two or more radicals selected from halogen, hydroxy or NR⁴R⁵C substituted by a substituent of_1-4Alkyl radical, C_1-4Alkylcarbonyl-wherein said C_1-4Alkyl is optionally substituted by one or, when possible, two or more groups selected from hydroxy or C_1-4Alkyl-oxy-substituted;

R⁴and R⁵Each independently selected from hydrogen or C_1-4An alkyl group;

R¹¹represents hydrogen, C_1-4Alkyl radical, C_1-4Alkyl-oxy-carbonyl-, Het¹⁷、Het¹⁸-C_1-4Alkyl-, optionally Het¹⁹-C_1-4Alkylaminocarbonyl-substituted C_2-4alkenylcarbonyl-C_2-4Alkenylsulfonyl-, C_1-4Alkyloxy C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹²represents hydrogen, C_1-4Alkyl, Het¹³、Het¹⁴-C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹³and R¹⁴Each independently selected from hydrogen and C_1-4Alkyl, Het¹⁵-C_1-4Alkyl-or C_1-4Alkyloxy C_1-4Alkyl-;

Het¹represents a compound selected from the group consisting of piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, and the like,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is¹Optionally substituted by amino, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substituted;

Het¹³represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁴represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said Het is¹⁴Optionally one or, when possible, two or more radicals selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁵represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said Het is¹⁵Optionally one or, when possible, two or more radicals selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁶represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1, 3, 2-oxaborolidine or piperidinyl, wherein said heterocycle is optionally substituted by one or more groups selected from C_1-4Alkyl substituent substitution; and

Het¹⁷represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁸and Het¹⁹Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said Het is¹⁸And Het¹⁹Optionally one or, when possible, two or more radicals selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Ar¹、Ar²、Ar³、Ar⁴and Ar⁵Each independently represents optionally cyano, C_1-4Alkylsulfonyl-, C_1-4Alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C_1-4Alkyl, aminosulfonyl-, hydroxy-, C_1-4Alkyloxy-or C_1-4Alkyl-substituted phenyl.

In particular intermediates of formula (III) wherein one or more of the following limitations apply:

i) y represents-C_3-9Alkyl-, -C_1-5alkyl-oxy-C_1-5Alkyl-, -C_1-5alkyl-NR¹²-C_1-5Alkyl-, -C_1-6alkyl-NH-CO-;

ii)X²represents a direct bond, O, -O-C_1-2Alkyl-, NR¹¹、-NR¹¹-C_1-2Alkyl-, -CH₂-, -O-N-CH-or C_1-2An alkyl group;

iii)R¹represents hydrogen, cyano, halogen or hydroxy, preferably halogen;

iv)R²represents hydrogen or cyanogenRadical, halogen, hydroxy, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-, C_1-4Alkyl-, C_2-6Alkynyl-, Ar⁵Or Het¹(ii) a In another embodiment, R²Represents hydrogen, cyano, halogen, hydroxy, C_2-6Alkynyl-or Het¹(ii) a In particular R²Represents hydrogen, cyano, halogen, hydroxy, or Ar⁵；

v)R¹¹Represents hydrogen, C_1-4Alkyl, or C_1-4An alkyloxycarbonyl group;

vi)R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

vii)Het¹represents an optionally substituted amino group, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substituted thiazolyl;

viii)Het¹⁶represents a heterocycle selected from piperidinyl or pyrrolidinyl.

b) Intermediates of formula (XXX)

And pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein

Y₁And Y₂Each independently represents C_1-5Alkyl, CO-C_1-5Alkyl or CO-CH₂R¹⁵-NH-；

X¹Represents a direct bond, O, -O-C_1-2Alkyl-, CO-C_1-2Alkyl-, NR¹⁰、-NR¹⁰-C_1-2Alkyl-, -CH₂-, -O-N ═ CH-or-C_1-2Alkyl-;

X²represents a direct bond, O, -O-C_1-2Alkyl-, CO-C_1-2Alkyl-, NR¹¹、-NR¹¹-C_1-2Alkyl-, -CH₂-, -O-N-CH-or C_1-2An alkyl group;

R¹represents hydrogen, cyano, halogen, hydroxy, formyl, C_1-6alkoxy-C_1-6Alkyl-, C substituted by halogen_1-6Alkoxy-, C substituted by one or, when possible, two or more substituents selected from hydroxy or halogen_1-4An alkyl group; and

R²represents hydrogen, cyano, halogen, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C_1-4Alkyloxycarbonyl-, C_1-4Alkylcarbonyl-, aminocarbonyl-, mono-or di (C)_1-4Alkyl) aminocarbonyl-, Het¹Formyl, C_1-4Alkyl-, C_2-6Alkynyl-, C_3-6cycloalkyl-C_3-6Cycloalkyloxy-, C_1-6alkoxy-Ar⁵、Ar¹-oxy-, dihydroxyborane, C substituted by halogen_1-6Alkoxy-, by one or, when possible, by two or more radicals selected from halogen, hydroxy or NR⁴R⁵C substituted by a substituent of_1-4Alkyl radical, C_1-4Alkylcarbonyl-wherein said C_1-4Alkyl is optionally substituted by one or, when possible, two or more groups selected from hydroxy or C_1-4Alkyl-oxy-substituted;

R⁴and R⁵Each independently selected from hydrogen or C_1-4An alkyl group;

R⁶and R⁷Each independently selected from hydrogen and C_1-4Alkyl, Het⁸Aminosulfonyl-, mono-or di (C)_1-4Alkyl) -aminosulfonyl, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-, hydroxycarbonyl-C_1-4Alkyl-, C_3-6Cycloalkyl, Het⁹-carbonyl-C_1-4Alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C_1-4Alkyl-, Het¹¹-C_1-4Alkyl-or Ar²-C_1-4Alkyl-;

R⁸and R⁹Each independently selected from hydrogen and C_1-4Alkyl radical, C_3-6Cycloalkyl, Het⁴hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl-or polyhydroxy-C_1-4Alkyl-;

R¹⁰represents hydrogen, C_1-4Alkyl radical, C_1-4Alkyl-oxy-carbonyl-, Het¹⁷、Het¹⁸-C_1-4Alkyl-, optionally Het¹⁹-C_1-4Alkylaminocarbonyl-substituted C_2-4alkenylcarbonyl-C_2-4Alkenylsulfonyl-, C_1-4Alkyloxy C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹¹represents hydrogen, C_1-4Alkyl, Het¹³、Het¹⁴-C_1-4Alkyl-, or optionally one or, when possible, two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

R¹⁸represents Ar³、Ar⁴-C_1-4Alkyl radical, C_1-4Alkyl, optionally substituted with Het¹²Substituted C_2-6An alkenyl group; or R¹⁸Denotes a group consisting of one or, when possible, two or more of C_1-4Alkyloxy, hydroxy, halogen, Het²、NR⁶R⁷、NR⁸R⁹-carbonyl or Het³C substituted by a substituent of a carbonyl group_1-4An alkyl group;

R¹⁵represents hydrogen, or C optionally substituted by phenyl, indolyl, methylthio, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazolyl or guanidino_1-4An alkyl group;

Het¹represents a compound selected from the group consisting of piperidyl, morpholinyl, piperazinyl, furyl, pyrazolyl, dioxolanyl, thiazolyl, and the like,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is¹Optionally substituted by amino, C_1-4Alkyl, hydroxy-C_1-4Alkyl-, phenyl-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-mono-or di (C)_1-4Alkyl) amino-or amino-carbonyl-substituted;

Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, or dithiacyclohexylyl, wherein said Het is²Optionally one or, when possible, two or more radicals selected from hydroxy, halogen, amino, C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-G_1-4Alkyl-, hydroxy-C_1-4alkyl-oxy-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-, mono-or di (C)_1-4Alkyl) amino-C_1-4Alkyl-, amino-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-sulfonyl-, aminosulfonyl-substituents;

Het³、Het⁴and Het⁸Each independently represents a group selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, piperazinyl,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is³、Het⁴Or Het⁸Optionally one or, when possible, two or more radicals selected from hydroxy-, amino-, C_1-4Alkyl-, C_3-6cycloalkyl-C_1-4Alkyl-, aminosulfonyl-, mono-or di (C)_1-4Alkyl) aminosulfonyl or amino-C_1-4Alkyl-substituted;

Het⁹and Het¹⁰Each independently represents a group selected from furyl, piperidyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, piperazinyl,Azolyl, imidazolyl, isoAzolyl group,Heterocycles of oxadiazolyl, pyridinyl or pyrrolidinyl, wherein said Het is⁹Or Het¹⁰Optionally is covered with C_1-4Alkyl radical, C_3-6cycloalkyl-C_1-4Alkyl-or amino-C_1-4Alkyl-substitution;

Het¹¹represents a heterocycle selected from indolyl or of formula:

Het¹²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithiacyclohexylyl, wherein said Het is¹²Optionally one or, when possible, two or more radicals selected from hydroxy, halogen, amino, C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, C_1-4alkyl-oxy-C_1-4Alkyl-, hydroxy-C_1-4alkyl-oxy-C_1-4Alkyl-, mono-or di (C)_1-4Alkyl) amino-or mono-or di (C)_1-4Alkyl) amino-C_1-4Alkyl-substituted;

Het¹³represents a heterocycle selected from pyrrolidinyl or piperidinyl, wherein said Het is¹³Optionally one or, when possible, two or more radicals selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁴represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁶represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1, 3, 2-dioxaborolane or piperidinyl, wherein said heterocycle is optionally substituted by one or more substituents selected from C_1-4Alkyl substituent substitution; and

Het¹⁷represents a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted by one or, when possible, by two or more substituents selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁸and Het¹⁹Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said Het is¹⁸And Het¹⁹Optionally one or, when possible, two or more radicals selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Ar¹、Ar³、Ar⁴and Ar⁵Each independently represents optionally cyano, C_1-4Alkylsulfonyl-, C_1-4Alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C_1-4Alkyl, aminosulfonyl-, hydroxy-, C_1-4Alkyloxy-or C_1-4Alkyl-substituted phenyl.

In particular those of formula (XXX) wherein one or more of the following limitations apply:

i)X¹represents-O-;

ii)X²represents a direct bond, -NR¹¹-C_1-2Alkyl-, -NR¹¹-CH₂-、-C_1-2Alkyl-, -O-C_1-2Alkyl, -O-or-O-CH₂-；

iii)R¹Represents hydrogen or halogen;

iv)R²represents hydrogen, cyano, halogen, hydroxycarbonyl-, C_1-4Alkyloxycarbonyl-, Het¹⁶-carbonyl-or Ar⁵；

v)R¹⁸Represents hydrogen, C_1-4Alkyl-, Ar⁴-C_1-4An alkyl group; or R¹⁸Denotes a group consisting of one or, when possible, two or more selected from C_1-4Alkyloxy-or Het²C substituted by a substituent of (A)_1-4An alkyl group;

vi)R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-;

vii)R¹²represents Het¹⁴-C_1-4Alkyl, especially morpholinyl-C_1-4An alkyl group;

viii)Het²represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl,wherein said Het²Optionally one or, when possible, two or more radicals selected from hydroxy, amino or C_1-4Alkyl-substituted;

in another embodiment, Het²Represents a heterocycle selected from morpholinyl or piperidinyl, optionally substituted by C_1-4Alkyl-substituted, preferably by methyl;

ix)Het¹⁴represents morpholinyl;

x)Het¹⁶represents a heterocycle selected from morpholinyl or pyrrolidinyl;

xi)Ar⁴represents a phenyl group;

xii)Ar⁵represents phenyl optionally substituted by cyano.

It is also an object of the present invention to provide the use of intermediates of formula (III) or (XXX) in the synthesis of compounds of formula (I).

The compounds of the present invention are useful because they have pharmacological properties. They are therefore useful as medicaments.

As described in the experimental section below, the compounds of the invention have shown growth inhibitory effect and antitumor activity in an enzymatic assay of the receptor tyrosine kinase EGFR in vitro. In an alternative assay, compounds were tested for growth inhibition on ovarian cancer cell line SKOV3 using cytotoxicity assays known in the art, such as LIVE/dead (molecular probes) or MTT.

The present invention therefore provides compounds of formula (I) and pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, for use in therapy. More particularly, for the treatment or prevention of cell proliferation mediated diseases. The compounds of formula (I) and the pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof may hereinafter be referred to as the compounds of the present invention.

Diseases in which the compounds of the invention may be particularly useful are atherosclerosis, restenosis, cancer, and diabetic complications such as retinopathy.

In view of the utility of the compounds of the present invention, there is provided a method of treating an animal, such as a mammal (including a human) suffering from a cell proliferative disease, such as atherosclerosis, restenosis, and cancer, which comprises administering an effective amount of a compound of the present invention.

The methods comprise systemically or locally administering to an animal, including a human, an effective amount of a compound of the invention.

Due to the high selectivity of the compounds of formula (I) as defined above as EGFR inhibitors, they may also be used to label or identify the kinase domain within receptor tyrosine kinases receptors. To this end, the compounds of the invention may be labeled, in particular by partial or complete replacement of the original atom with a radioisotope of one or more atoms in the molecule. Examples of labeled compounds of interest are those having at least one halogen that is a radioisotope of iodine, bromine, or fluorine; or has at least one¹¹Those of a C-atom or a tritium atom.

A particular group consisting of¹Those compounds of formula (I) which are radioactive halogen atoms. In principle, any compound of formula (I) containing a halogen atom is intended to be radiolabelled with a suitable isotope instead of the halogen atom. Suitable halogen radioisotopes for this purpose are radioiodines, e.g.¹²²I、¹²³I、¹²⁵I、¹³¹I; the radioactive bromine is, for example,⁷⁵Br、⁷⁶Br、⁷⁷br and⁸²br; and radioactive fluorine such as¹⁸F. The introduction of the radioactive halogen atom may be carried out by an appropriate exchange reaction, or by using any of the above-mentioned methods for preparing the halogen derivative of formula (I).

Another interesting form of radiolabel is by¹¹C-atoms instead of carbon atoms or tritium atoms instead of hydrogen atoms.

Thus, the radioisotope-labeled compound of formula (I) can be used in a method of specifically labeling a receptor site in a biological material. The method comprises the following steps: (a) radiolabelling a compound of formula (I), (b) administering such a radiolabelled compound to a biological material, followed by (c) detecting radiation from the radiolabelled compound.

The term biomaterial includes any type of material of biological origin. More particularly, the term refers to tissue samples, plasma or body fluids, and also to animals, in particular to warm-blooded animals or parts of animals such as organs.

When used for in vivo analysis, a radioisotope-labeled compound is administered to an animal in a suitable composition and the position of the radioisotope-labeled compound is detected using an imaging technique such as, for example, Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET). In this way, the distribution of specific receptor sites throughout the body can be detected and the organ containing the receptor sites can be visualized by the imaging techniques described above. Methods of imaging an organ by administering a radioisotope labelled compound of formula (I) and detecting radiation from the radioactive compound also form part of the invention.

In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of any of the above cell proliferative diseases or indications.

The amount of a compound of the invention (also referred to herein as an active ingredient) required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, the particular condition or disease being treated. Suitable daily dosages are from 0.01mg/kg body weight to 300mg/kg body weight, in particular from 10mg/kg body weight to 100mg/kg body weight. The method of treatment further comprises administering the active ingredient according to a one to four intake regimen per day.

Although it is possible to administer the active ingredient separately, it is preferred to provide it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The Pharmaceutical compositions of the invention may be prepared by any method known in the art of pharmacy, for example using the methods described, for example, in Remington's Pharmaceutical sciences (18 th edition, Mack Pubblishing Company, 1990, see especially Part 8: Pharmaceutical preparations and the human Manufacture) of Gennaro et al. A therapeutically effective amount of a particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably suitable for systemic administration such as oral, transdermal or parenteral administration; or unit dosage forms for topical administration, such as by inhalation, nasal spray, eye drops, or by cream, gel, shampoo, and the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water (including at least a major portion of sterile water), and may also include other ingredients, for example, to aid solubility. For example, injectable solutions may be prepared in which the carrier comprises saline solution, dextrose solution, or a mixture of saline and dextrose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally in combination with minor proportions of suitable additives of any nature, which additives do not cause any significant deleterious effect on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions may be administered in a variety of ways, such as a transdermal patch, as drops (spot-on), or as an ointment.

It is particularly advantageous to formulate the above-described pharmaceutical compositions in unit dosage form for ease of dosage administration and uniformity. Unit dosage form as used herein the specification and claims refer to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient intended to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, as well as segregated multiples thereof. Experimental part

The following terms "ADDP" is defined as 1, 1' - (azodicarbonyl) bispiperidine, "BuLi" is defined as butyllithium, "DCM" is defined as dichloromethane, "DIPE" is defined as diisopropyl ether, "DMF" is defined as N, N-dimethylformamide, "MeOH" is defined as methanol, "THF" is defined as tetrahydrofuran, "iPrOH" is defined as isopropanol, "t-BuOT" is defined as 2-methyl-2-butanol, "AcOEt" is defined as ethyl acetate, "TFA" is defined as trifluoroacetic acid, "DIPEA" is defined as diisopropylethylamine, and "HBTU" is defined as (1-) hexafluorophosphate 1- [ bis (dimethylamino) methylene ] bispiperidine]- [ 3-OXO (1H-benzotriazole)]，″(n-Bu)₄NI "is defined as tetrabutylammonium iodide," NMP "as 1-methyl-2-pyrrolidone," Et₃N "is defined as N, N-diethylethylamine.

Example 01-general description of the Synthesis of Compounds of formula 12

Scheme 9

As used in the foregoing scheme 9, R¹And R²Each independently represents hydrogen or C_1-4An alkyl group; or R¹And R²Together form a heterocycle selected from pyrrolidinyl, imidazolinyl, piperidinyl, morpholinyl, pyrazolidinyl, or piperazinyl; n represents 0, 1, 2 or 3.

Reductive amination

To a solution of 1(1 eq) and 2(1 eq) of 1, 2-dichloroethane (3mL/mmol) was added MgSO₄(1.5 eq.) and the mixture was stirred at room temperature for 90 minutes. To the resulting mixture is added NaBH (OAc)₃(1.1 equiv.) and added in three portions (one per hour) and the resulting mixture stirred at room temperature for an additional 2 hours. The reaction mixture was poured over Na₂CO₃And extracted with dichloromethane (3 ×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (SiO)₂AcOEt/hexane mixture) to afford pure 3.

Reduction of nitro groups

To a solution of 3(1 eq) in methanol (5mL/mmol) was added Pt/C (10% w/w) and the resulting mixture was placed in H₂Stir overnight (14 hours) at room temperature under atmosphere (balloon). The mixture was filtered through a short pad of celite and concentrated to dryness. In some cases, purification by flash chromatography is required to provide pure aniline of type 4.

Nucleophilic substitution

To a stirred suspension of chlorocyanoquinoline 5(1.05 eq) in iPrOH or t-BuOH (11mL/mmol) was added 4(1 eq). The mixture is at reflux temperature under N₂The reaction is carried out for 6 to 8 hours. The reaction mixture was evaporated to dryness and the resulting residue was purified by flash chromatography (SiO)₂AcOEt/hexane mixture) to give pure 6.

Deacetylation

Dissolve Compound 6 in MeOH/NH₃7N (8 mL/mmol). To this solution was added iPrOH (2mL/mmol) and the reaction mixture was stirred at room temperature for 30-120 min (TLC monitoring). The mixture was concentrated to dryness and the resulting product was used in the next step without further purification.

Alkylation reaction

To a stirred solution of 7 in DMF (5mL/mmol) was added Cs₂CO₃(3 equiv.) followed by addition of alkylating agent (2.5 equiv.). The reaction mixture was stirred at room temperature overnight. If necessary, add another 3 equivalents of Cs₂CO₃And 2.5 equivalents of alkylating agent and the reaction mixture was further stirred at room temperature until the reaction was completely complete (TLC monitoring). The reaction mixture was partitioned between brine and AcOEt and the layers were separated. The organic layer was washed with MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography (AcOEt/n-hexane) to afford pure 9.

Cleavage of Boc group

Cold (0 ℃) CH of 9₂Cl₂To the solution (3mL/mmol) was added TFA (2mL/mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 1-2 hours. Adding NaHCO to the reaction mixture₃The solution was saturated until a basic pH was reached. CH for the mixture₂Cl₂And (2x) extracting. The organic layer was washed with MgSO₄Dried, filtered and concentrated to dryness. The free amine obtained was of sufficient purity to be used in the next step without further purification.

Saponification of the ester group

To 10 in MeOH/H₂Adding LiOH & H into solution in O (10: 1)₂O (5 equivalents) and the reaction mixture was stirred at room temperature for up to 2 hours. The solvent was evaporated under vacuum and the residue was dissolved in DMF and filtered through a sintered glass funnel. DMF was removed and the product was used directly in the following reaction.

Cyclization reaction

A solution of 11(0.25mmol, 1 equiv.) and DIPEA (6 equiv.) in DMF (10mL) was added dropwise to a solution of HBTU (3 equiv.) in DMF (100mL/mmol of 11). The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the product was purified by reverse phase HPLC.

By the above synthesis method, the following compounds were obtained:

7-chloro-8-fluoro-21-methoxy-13-oxo-10, 11, 12, 13, 14, 15, 16, 17-octahydro-5H-1, 19- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 13] benzoxatriazacyclohexadecyne-4-carbonitrile (Compound 1.1)

20-chloro-19-fluoro-23-methoxy-12-oxo-9, 10, 11, 12, 12a, 13, 14, 15, 17, 22-decahydro-8H-4, 6- (dimethylene) pyrido [4, 3-b ] pyrrolo [2, 1-1] [6, 1, 10, 13] benzoxatriazacyclohexadecyne-1-carbonitrile (Compound 1.2)

7-chloro-8-fluoro-21-methoxy-11-methyl-13-oxo-10, 11, 12, 13, 14, 15, 16, 17-octahydro-5H-1, 19- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 13] benzoxatriazacyclohexadecyne-4-carbonitrile (Compound 1.3)

17-chloro-16-fluoro-20-methoxy-13-methyl-11-oxo-8, 9, 10, 11, 12, 13, 14, 19-octahydro-4, 6- (dimethylene) pyrido [4, 3-b ] [6, 1, 9, 12] benzoxatriazacyclopentadecyne-4-carbonitrile (Compound 1.4)

7-chloro-8-fluoro-12-isobutyl-21-methoxy-13-oxo-10, 11, 12, 13, 14, 15, 16, 17-octahydro-5H-1, 19- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 13] benzoxatriazacyclohexadecyne-4-carbonitrile (Compound 1.5)

Example 02 general description of the Synthesis of Compounds of formula 13

Scheme 10

As used in the above illustration 10; x represents halogen, in particular chlorine, fluorine or bromine; n represents 0, 1, 2 or 3; m represents 0, 1, 2 or 3.

Amide formation

To stirred 1(1 equivalent) of CH₂Cl₂To the solution (5mL/mmol) was added diisopropylcarbodiimide (1.05 eq). The reaction mixture was stirred at room temperature for 30 minutes, then amine 2(1.05 eq) was added and stirring was continued for another 30 minutes. The reaction mixture was then washed with 1N citric acid and CH₂Cl₂Are distributed among the devices. The layers were separated and the organic layer was washed with MgSO₄Drying, filtration and evaporation gave 3 with sufficient purity for the next step.

Reduction of nitro groups

To a solution of 3(1 eq) in MeOH (5mL/mmol) was added Pt/C (10% w/w) and the resulting mixture was taken up in H₂Stir overnight (14 hours) at room temperature under atmosphere (balloon). The mixture was filtered through a short pad of celite and concentrated to dryness. In some cases, purification by flash chromatography is required to provide pure aniline of type 4.

Nucleophilic substitution

To a stirred suspension of chlorocyanoquinoline 5(1.05 eq) in iPrOH (11mL/mmol) was added 4(1 eq) and a few drops of concentrated HCl. The mixture is at reflux temperature under N₂The reaction is carried out for 6 to 8 hours. The reaction mixture was evaporated to dryness and the resulting residue was purified by flash chromatography (SiO)₂AcOEt/hexane mixture) to give pure 6.

Cleavage of Boc group

To cold (0 ℃) CH of 6₂Cl₂To the solution (3mL/mmol) was added TFA (2mL/mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 1-2 hours. Adding NaHCO to the reaction mixture₃The solution was saturated until a basic pH was reached. CH for the mixture₂Cl₂And (2x) extracting. The combined organic layers were washed with MgSO₄Drying and passing throughFiltered and concentrated to dryness. The free amine obtained was of sufficient purity to be used in the next step without further purification.

Sulfonylation reaction

To cold (0 ℃ C.) 7(1 eq.) CH₂Cl₂Et was added to the solution (2mL/mmol)₃N (1.5 equiv.) and DMAP (10% mol). O-nitrobenzenesulfonyl chloride (1.1 equiv.) in CH is added dropwise₂Cl₂Solution (1mL/mmol of 7). The reaction mixture was stirred at 0 ℃ and allowed to warm to room temperature overnight. 1N HCl was added until an acidic pH was reached and the layers separated. The organic layer was washed with MgSO₄Dried, filtered and evaporated. The resulting residue was purified by flash chromatography (AcOEt/hexane) to afford pure 9.

Deacetylation

Dissolve Compound 9 in MeOH-NH₃7N (8 mL/mmol). To this solution was added iPrOH (2mL/mmol) and the reaction mixture was stirred at room temperature for 30-120 min (TLC monitoring). The mixture was concentrated to dryness and the resulting product was used in the next step without further purification.

Alkylation reaction

To a stirred solution of 10 in DMF (5mL/mmol) was added Cs₂CO₃(3 equiv.) the alkylating agent (2.5 equiv.) is then added. The reaction mixture was stirred at room temperature overnight. If necessary, add another 3 equivalents of Cs₂CO₃And 2.5 equivalents of alkylating agent and the reaction mixture was further stirred at room temperature until the reaction was completely complete (TLC monitoring). The reaction mixture was partitioned between brine and AcOEt and the layers were separated. The organic layer was washed with MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography (AcOEt/n-hexane) to afford pure 11.

Cyclization reaction

11(1 equiv.) of MeCN (60mL/mmol) solution was added dropwise to Cs at room temperature₂CO₃(5 eq.) and (n-Bu)₄NI (2 equiv.) in a mixture of MeCN (30 mL/mmol). Will be reversedThe mixture was stirred at 65 ℃ overnight. On completion of the reaction (LC monitoring), H was added₂And O. The resulting precipitate was collected by filtration and purified as H₂And (4) O washing. The product was dried under vacuum at 65 ℃. The solid material was boiled in iPrOH. The solid material was filtered and dried.

Desulfonation reaction

Mixing 12(1 equivalent), thiophenol (1.2 equivalents) and Cs₂CO₃A mixture of (3 equivalents) in DMF (45mL/mmol of 12) was stirred at room temperature for 2 hours. Subjecting the reaction mixture to ice-H₂Quenching with CH₂Cl₂Extraction with MeOH (90: 10). Separating the organic layer with MgSO 2₄Dried, filtered and evaporated. The product was purified by reverse phase HPLC.

By the above synthesis method, the following compounds were obtained:

7-bromo-23-methoxy-12-oxo-10, 11, 12, 13, 14, 15, 16, 17, 18, 19-decahydro-5H-1, 21- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 13] benzoxatriazacyclo-octadecane-4-carbonitrile (Compound 1.6)

7-chloro-23-methoxy-11-oxo-10, 11, 12, 13, 14, 15, 16, 17, 18, 19-decahydro-5H-1, 21- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 14] benzoxatriazacyclo-octadecane-4-carbonitrile (Compound 2.1)

7-Nitrogen-24-methoxy-12-oxo-5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-dodecahydro-1, 22- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 14] Benzoxatriazacyclononacarbne-4-carbonitrile (Compound 2.2)

7-chloro-23-methoxy-12-oxo-10, 11, 12, 13, 14, 15, 16, 17, 18, 19-decahydro-5H-1, 21- (dimethylene) pyrido [4, 3-b ] [6, 1, 10, 13] benzoxatriazacyclo-octadecane-4-carbonitrile (Compound 2.4)

Example 03-general description of the Synthesis of Compounds of formula 8

Scheme 11

22-methoxy-14-oxo-11, 12, 13, 14, 15, 16, 17, 18-octahydro-5H-1, 20- (dimethylene) pyrido [3, 4-m ] [1, 10, 6, 15] benzodiazepine heptadecyne-4-carbonitrile (Compound 2.3)

Nucleophilic substitution

To a stirred suspension of chlorocyanoquinoline 2(1.05 eq) in iPrOH (11mL/mmol) was added 1(1 eq) followed by Et₃N (1 equivalent). In N₂The mixture was then heated to reflux for 6 hours. The reaction mixture was evaporated to dryness and the resulting residue was purified by flash chromatography (SiO)₂AcOEt/hexane mixture) to give pure 3.

Deacetylation

Dissolve Compound 3 in MeOH/NH₃7N (8 mL/mmol). To this solution was added iPrOH (2mL/mmol) and the reaction mixture was stirred at room temperature for 30-120 min (TLC monitoring). The mixture was concentrated to dryness and the resulting product was used in the next step without further purification.

Alkylation reaction

To a stirred solution of 4 in DMF (5mL/mmol) was added Cs₂CO₃(3 equiv.) the alkylating agent (2.5 equiv.) is then added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between brine and AcOEt and the layers were separated. The organic layer was washed with MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography (AcOEt/n-hexane) to afford pure 5.

Cleavage of Boc group

Cold (0 ℃) CH of 5₂Cl₂To the solution (3mL/mmol) was added TFA (2mL/mmol) dropwise. Will obtainThe mixture was warmed to room temperature and stirred for 1-2 hours. Adding NaHCO to the reaction mixture₃The solution was saturated until a basic pH was reached. CH for the mixture₂Cl₂And (2x) extracting. The combined organic layers were washed with MgSO₄Dried, filtered and concentrated to dryness. The free amine obtained was of sufficient purity to be used in the next step without further purification.

Saponification of the ester group

MeOH/H to 6₂Adding LiOH & H into O (10: 1) solution₂O (5 equivalents) and the reaction mixture was stirred at room temperature for up to 2 hours. The solvent was evaporated under vacuum and the residue was dissolved in DMF and filtered through a sintered glass funnel. DMF was removed and the product was used directly in the following reaction.

Cyclization reaction

A solution of 7(0.25mmol, 1 equiv.) and DIPEA (6 equiv.) in DMF (10mL) was added dropwise to a solution of HBTU (3 equiv.) in DMF (100mL/mmol of 7). The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the product was purified by reverse phase HPLC.

Example 04-general description of the Synthesis of Compounds of formula 6

Scheme 12

17-chloro-16-fluoro-20-methoxy-8, 9, 10, 11, 12, 13, 14, 19-octahydro-4, 6- (dimethylene) pyrido [4, 3-b ] [6, 1, 12] benzodioxadiazepin-1-carbonitrile (Compound 2.5)

Nucleophilic substitution

To a stirred solution of chlorocyanoquinoline 2(1.05 eq.) in t-BuOH/DMF 12: 1(11mL/mmol) was added 1. In N₂The mixture was then warmed to 80 ℃ for 6 hours. The reaction mixture is evaporated to dryness and the residue obtained isThe residue was stirred in MeCN for 1 hour. The solid precipitate was collected by filtration, washed with MeCN and dried to give pure 3 in 63% yield.

Chlorination reaction

Methylsulfonamide (9.4mL) was added to a solution of 3(12.50mmol) in 50mL of NMP at room temperature. The reaction mixture was then stirred at 90 ℃ for 1 hour. The reaction mixture was then poured into 300mL of H₂In O, the aqueous layer was extracted with AcOEt (3X 100 mL). Combined organic layers with H₂O wash (2X 100mL), finally dry the organic layer, filter and concentrate under reduced pressure. The resulting residue was purified by column chromatography to give pure 4 in 90% yield.

Cyclization reaction

The compound 4(5.0mmol) and K₂CO₃(5 eq.) in a preheated sealed reactor at 83mL DMA/H₂Stirring in O (1: 1) at 150 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give 5.

Removal of CBz groups

To a solution of 5(1 eq) in MeOH (5mL/mmol) was added Pt/C (10% w/w) and the resulting mixture was taken up in H₂Stir at room temperature overnight (14 hours) under an atmosphere (balloon). The mixture was filtered through a short pad of celite and concentrated to dryness. The residue was purified by reverse phase HPLC to give pure 6.

Example 05-general description of the Synthesis of Compounds of formula 10

Scheme 13

7-chloro-8-fluoro-21-methoxy-11-methyl-10, 11, 12, 13, 14, 15, 16, 17-octahydro-5H-1, 19- (dimethylene) pyrido [4, 3-b ] [6, 1, 13] benzoxadiazacyclohexadecyne-4-carbonitrile (Compound 2.6)

Reductive amination

To a solution of 1(1 eq) and 2(1 eq) in 1, 2-dichloroethane (3mL/mmol) was added MgSO₄(1.5 eq.) and the mixture was stirred at room temperature for 90 minutes. To the resulting mixture is added NaBH (OAc)₃(1.1 eq), added in three portions (one per hour) and the resulting mixture stirred at room temperature for an additional 2 hours. The reaction mixture was poured over Na₂CO₃Using CH in combination with saturated solution₂Cl₂And (3x) extracting. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (SiO)₂AcOEt/hexane mixture)) to give pure 3.

Reduction of nitro groups

5 equivalents of 0.5M NH were added at room temperature₄H of Cl₂The O solution was added to a 0.1M solution of nitro derivative 3(1 eq) in toluene. Iron powder (5 equivalents) was added with vigorous stirring. The reaction mixture was stirred at reflux temperature for 1 hour, then cooled to room temperature, filtered through a pad of celite and the organic layer was separated, over MgSO₄Dried and evaporated under reduced pressure. Aniline 4 was quantitatively obtained, which was sufficiently pure to be used in the next step without further purification.

Nucleophilic substitution

To a stirred suspension of chlorocyanoquinoline 5(1.05 eq) in iPrOH (11mL/mmol) was added 4(1 eq). The mixture is at reflux temperature under N₂The reaction is carried out for 6 to 8 hours. The reaction mixture was evaporated to dryness and the resulting residue was purified by flash chromatography (SiO)₂AcOEt/hexane mixture) to give pure 6.

Deacetylation

Dissolve Compound 6 in MeOH/NH₃7N (8 mL/mmol). To this solution was added iPrOH (2mL/mmol) and the reaction mixture was stirred at room temperature for 30-120 min (TLC monitoring). Concentrating the mixture to dryness andthe resulting product was used in the next step without further purification.

Alkylation reaction

To a stirred solution of 7 in DMF (5mL/mmol) was added Cs₂CO₃(3 equiv.) the alkylating agent (2.5 equiv.) is then added. The reaction mixture was stirred at room temperature overnight.

Closed-loop metathesis

To 8(1 equivalent) in anhydrous CH₂Cl₂(100mL/mmol) was added to the solution of second generation Grubbs catalyst (20% mol). In N₂The resulting mixture was refluxed under atmosphere for 4 hours with stirring. Thereafter, additional catalyst (20% mole) was added and the mixture was stirred for an additional 2 hours at which time the reaction was substantially complete. The solvent was removed under reduced pressure and the resulting crude product was purified by flash chromatography (AcOEt/hexanes) to give pure product 9.

Hydrogenation of double bonds

To a solution of 9(1 eq) in MeOH (5mL/mmol) was added Pt/C (10% w/w) and the resulting mixture was taken up in H₂Stir overnight (14 hours) at room temperature under atmosphere (balloon). The mixture was filtered through a short pad of celite and concentrated to dryness. The residue was purified by reverse phase HPLC to give pure 10.

A. Preparation of intermediates

Example A1

a) Preparation of 5- [ [ (4-bromo-2-nitrophenyl) methyl ] amino ] -1-pentanol (intermediate 1)

A solution of 4-bromo-2-nitrobenzaldehyde (0.013mol), 5-amino-1-pentanol (0.013mol) and titanium tetrakis (isopropoxide) (0.014mol) in ethanol (15ml) was stirred at room temperature for 1 hour, then the reaction mixture was heated to 50 ℃ and stirred for 30 minutes. The mixture was cooled to room temperature and sodium borohydride (0.013mol) was added in portions. The reaction mixture was stirred overnight and then poured into ice water (50 ml). The resulting mixture was stirred for 20 minutes, and the precipitate formed was filtered off (to give filtrate (I)) Washed with water and stirred in DCM (to dissolve the product and remove Ti salts therefrom). The mixture was filtered and the filtrate was dried (MgSO₄) And filtered, and finally the solvent is evaporated to dryness. The filtrate (I) was evaporated until ethanol was removed and the aqueous concentrate was extracted 2 times with DCM. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent to dryness gave 3.8g (93%) of intermediate 1.

b) Preparation of [ (4-bromo-2-nitrophenyl) methyl ] (5-hydroxypentyl) -carbamic acid 1, 1-dimethylethyl ester (intermediate 2)

A solution of intermediate 1(0.0032mol) in DCM (20ml) was stirred at room temperature and a solution of bis (1, 1-dimethylethyl) dicarbonate (0.0032mol) in DCM (5ml) was added dropwise. The reaction mixture was stirred at room temperature for l hours and washed with water 2 times. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent to dryness gave intermediate 2.

c) Preparation of [5- (acetoxy) pentyl ] [ (4-bromo-2-nitrophenyl) methyl ] -carbamic acid 1, 1-dimethylethyl ester (intermediate 3)

A solution of intermediate 2(0.0032mol) and pyridine (0.032mol) in acetic anhydride (15ml) was stirred at room temperature for 16 h, then the solvent was evaporated under reduced pressure and co-evaporated with toluene. The residue was used directly in the next reaction step to give 1.47g (100%) of intermediate 3.

d) Preparation of [5- (acetoxy) pentyl ] [ (2-amino-4-bromo-phenyl) -methyl ] -carbamic acid 1, 1-dimethylethyl ester (intermediate 4)

A mixture of intermediate 3(0.0033mol) in THF (50ml) was hydrogenated with Pt/C5% (0.5g) as a catalyst in the presence of a thiophene solution (0.5 ml). In absorption of H₂After (3 equivalents), the catalyst was filtered off and the filtrate was evaporated to give intermediate 4.

Example A2

a) Preparation of 2-amino-4-methoxy-5- (phenylmethoxy) -benzoic acid methyl ester (intermediate 5)

A mixture of 4-methoxy-2-nitro-5- (phenylmethoxy) -benzoic acid methyl ester (0.166mol) and triethylamine (0.198mol) in THF (400ml) was hydrogenated in the presence of a solution of thiophene in DIPE (4ml) using Pt/C (5g) as the catalyst. After absorption of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was treated with DIPE (300ml) and stirred for 3 hours, then the resulting precipitate was filtered off and dried in a vacuum oven to yield 45.9g (96%) of intermediate 5.

b) Preparation of 4-hydroxy-7-methoxy-6- (phenyl-methoxy) -3-quinolinecarbonitrile (intermediate 6)

A mixture of intermediate 5(0.029mol) and 1, 1-dimethoxytrimethylamine (0.058mol) in DMF (30ml) was stirred and refluxed for 2.5 h, then the solvent was evaporated and co-evaporated with toluene (2 ×) to give residue (I). A solution of n-BuLi (2.5M in hexane, 0.058mol) in THF (40ml) was stirred and cooled to-75 deg.C and acetonitrile (0.058mol) was added dropwise over 30 minutes. After 15 minutes, a solution of the residue (I) in THF (40ml) was added dropwise and the reaction was quenched with acetic acid (0.058mol) at-75 ℃ and the mixture was allowed to warm to room temperature and diluted with water (50 ml). The organic solvent (THF) was evaporated and the aqueous concentrate was diluted with isopropanol (10 ml). The mixture was stirred for 1 hour, then the resulting precipitate was filtered and air dried to give 4.4g of intermediate 6. The filtrate was evaporated and the residue was treated with water, and DCM/MeOH (90/10). The resulting mixture was stirred for 15 minutes and the resulting solid was collected and air dried to yield 1.8g of intermediate 6. The total yield is as follows: 6.2g (70.4%).

c) Preparation of 4, 6-dihydroxy-7-methoxy-3-quinolinecarbonitrile (intermediate 7)

A mixture of intermediate 6(0.016mol) in triethylamine (3ml) and THF was hydrogenated over Pd/C (1.0g) as a catalyst. In absorption of H₂After (1 eq) the catalyst was filtered off and the filtrate was evaporated, yielding 2.8g of intermediate 7 (used directly in the next reaction step).

d) Preparation of 6- (acetoxy) -4-hydroxy-7-methoxy-3-quinolinecarbonitrile (intermediate 8)

A mixture of intermediate 7(0.011mol) pyridine (0.016mol) in acetic anhydride (30ml) was heated on an oil bath at 95 ℃ for 1 hour, then the reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated, then the residue was treated with DIPE (30ml) and the mixture was stirred for 2 hours. The resulting precipitate was collected and dried to yield 2.58g (90.8%) of intermediate 8.

e) Preparation of 6- (acetoxy) -4-chloro-7-methoxy-3-quinolinecarbonitrile (intermediate 9)

A mixture of intermediate 8(0.01mol) and DMF (3 drops) in thionyl chloride (25ml) was heated for 2 hours on an oil bath at 80 ℃ and the solvent was evaporated. The residue was treated with DIPE and the mixture was stirred for 1 hour. The resulting solid was filtered and air dried. The residue (2.7g) was dissolved in DCM and NaHCO₃And (4) washing with the solution. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 2.5g of intermediate 9.

f) Preparation of [ [2- [ [6- (acetoxy) -3-cyano-7-methoxy-4-quinolinyl ] amino ] -4-bromophenyl ] methyl ] [5- (acetoxy) pentyl ] -carbamic acid 1, 1-dimethylethyl ester (intermediate 10)

A mixture of intermediate 9(0.0018mol) and intermediate 4(0.0018mol) in isopropanol (20ml) was heated overnight in an oil bath at 65 ℃ and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 99.7/0.3). One fraction was collected and the column was re-eluted with DCM/MeOH/THF (90/5/5). The other fraction was collected and further purified by column chromatography on silica gel (eluent: DCM/MeOH gradient). The product fractions were collected and the solvent was evaporated, yielding 0.61g (50.6%) of intermediate 10.

g) Preparation of 1, 1-dimethylethyl [ [ 4-bromo-2- [ (3-cyano-6-hydroxy-7-methoxy-4-quinolyl) amino ] phenyl ] methyl ] (5-hydroxypentyl) -carbamate (intermediate 11)

A stirred solution of intermediate 10(0.000896mol) in MeOH (20ml) was treated with an aqueous solution of potassium carbonate (0.0018mol) (5 ml). Mixing the reactionThe mixture was stirred at room temperature overnight and then neutralized with acetic acid until pH7. The solvent was evaporated. The residue was diluted with DCM and washed with water. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.38g (73.1%) of intermediate 11, m.p. 114.3-136.2 ℃.

B. Preparation of the Compounds

Example B1

a) Preparation of 1, 1-dimethylethyl 17-bromo-1-cyano-9, 10, 11, 12, 14, 19-hexahydro-20-methoxy-4, 6-dimethylenepyrido [4, 3-b ] [6, 1, 12] benzoxadiazacyclopentadecyne-13 (8H) -carboxylate (Compound 1)

A mixture of intermediate 11(0.000649mol) and ADDP (0.00094mol) in thfp.a. (40ml) was treated with tributylphosphine (0.00094mol) for one hour, then additional ADDP (0.00094mol) and tributylphosphine (0.00094mol) were added. After 16 hours, the solvent was partially evaporated and the resulting concentrate was filtered and the filtrate was evaporated. The residue was dissolved in THF p.a. (40ml), then ADDP (2 eq) followed by tributylphosphine (2 eq). The resulting mixture was purified by reverse phase high performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 0.0955g (26.0%) of compound 1.

b) Preparation of 17-bromo-8, 9, 10, 11, 12, 13, 14, 19-octahydro-20-methoxy-4, 6-dimethylenepyrido [4, 3-b ] [6, 1, 12] benzoxadiazacyclopentadecyne-1-carbonitrile monohydrochloride (Compound 2)

A solution of Compound 1(0.00012mol) in MeOH (5ml) was treated with HCl/isopropanol (6N) (1ml) and the reaction mixture was stirred over the weekend. The resulting precipitate was collected and dried in a vacuum oven to give 0.0197g of compound 2, isolated as the monohydrochloride salt.

C. Pharmacological examples

Example c.1: in vitro EGFR inhibition

In vitro EGFR inhibition was evaluated using Flash Plate technology or glass fiber filtration technology as described by Davies, s.p. et al, Biochem j. (2000), 351, pages 95-105. The Flash Plate technology is generally edited by B.A. Brown et al at High through hputscreening (1997), page 317-: devlin, John p., publisher: dekker, New York, n.y.

In the Flash Plate EGFR kinase reaction assay, a kinase substrate consisting of biotinylated poly (L-glutamic acid-L-tyrosine) (poly (GT) biotin) is subjected to³³P) in the presence of radiolabeled ATP is incubated with the protein. The substrate was subsequently measured by trapping and quantifying the binding of the biotinylated and radiolabeled substrates using a streptavidin-coated Flash Plate (Perkinelmer Life Sciences) ((S))³³P) phosphorylation, expressed as the amount of light energy emitted.

Detailed Description

The EGFR kinase reaction was performed in 96-well microtiter plates FlashPlate (Perkin Elmer Life sciences) at 30 ℃ for 60 minutes. For each test compound, 1.10 was performed^-6M to 1.10^-10Full dose response of M. IRESSAAnd Tarceva^TM(erlotinib) was used as reference compound. A reaction volume of 100. mu.l contained 54.5mM Tris HCl (pH 8.0), 10mM MgCl₂、100μM Na₃VO₄5.0. mu.M unlabeled ATP, 1mM DTT, 0.009% BSA, 0.8. mu. Ci AT³³P, 0.35. mu.g/well of poly (GT) biotin, and 0.5. mu.g/well of EGFR-kinase domain.

The reaction was stopped by aspirating the reaction mixture and washing the plate 3x with 200 μ l wash/stop buffer (PBS +100 mMEDTA). After the last wash step, 200 μ l of wash/stop buffer was added to each well and phosphorylation was determined by counting in a microtiter plate scintillation counter (30 sec/well) ((S))³³P) amount of poly (GT) biotin.

In the EGFR kinase reaction test of the glass fiber filtration technology, poly (L-glutamic acid-Kinase substrates consisting of L-tyrosine (poly (GT) biotin) are described in³³P) in the presence of radiolabeled ATP is incubated with the protein. Subsequent measurement of the substrate (³³P) phosphorylation, expressed as radioactivity bound to the glass fiber filter.

Detailed Description

The EGFR kinase reaction was performed in 96 well microtiter plates at 25 ℃ for 10 minutes. For each compound tested, 1.10 was performed^-6M to 1.10^-10Full dose response of M. IRESSAAnd Tarceva^TM(erlotinib) was used as reference compound. A reaction volume of 25. mu.l contained 60mM TrisHCl (pH7.5), 3mM MgCl₂、3mM MnCl₂、3μM Na₃VO₄50. mu.g/ml PEG20000, 5.0. mu.M unlabeled ATP, 1mM DTT, 0.1. mu. Ci AT³³P, poly (GT) at 62.5 ng/well and EGFR-kinase domain at 0.5. mu.g/well.

The reaction was stopped by adding 5. mu.l of a 3% phosphoric acid solution. 10 μ l of the reaction mixture was then spotted on a Filtermat A filter (Wallac) and washed 3 times (5 minutes each) in 75mM phosphoric acid and once in methanol (5 minutes), then dried and quantified on typhoon (Amersham) using a LEphosphorage storage screen.

Example c.2: serum deficient proliferation assay on ovarian carcinoma SKOV3 cells

Ovarian cancer cell line (SKOV3) was used in epidermal growth factor-stimulated cell proliferation assays to evaluate the inhibitory effect of compounds on EGF in whole cells.

In a first step, SKOV3 cells were cultured in the presence of 10% FCS serum for 24 hours. In a second step, the cells were incubated in the absence of serum (37 ℃ C. and 5% (v/v) CO)₂) Incubated with test compounds and subsequently stimulated with a final concentration of 100ng/ml of EGF for 72 hours. Finally, the effect of the compounds on EGF stimulation was evaluated in a standard MTT cell survival assay.

The following table provides pIC50 values for the compounds of the invention obtained using the kinase assay described above.

Compound numbering	FlashPlate(C2)：IC50，nM	SKOV3 cell (C3): IC50, μ M
			2	8.3	6.8

D. Composition examples

The following formulations serve to illustrate typical pharmaceutical compositions suitable for systemic administration to animal and human subjects in accordance with the present invention.

The "active ingredient" (a.i.) used in these examples refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example d.1: film coated tablet

Preparation of the tablet core

A mixture of a.i. (100g), lactose (570g) and starch (200g) was mixed thoroughly. Then wetted with a solution of sodium lauryl sulfate (5g) and polyvinylpyrrolidone (10g) in about 200ml of water. The wet powder mixture was sieved, dried and sieved again. Then microcrystalline cellulose (100g) and hydrogenated vegetable oil (15g) were added thereto. The entire mass was mixed well and compressed into tablets to give 10,000 tablets each containing 10mg of active ingredient.

Coating film

To a solution of methylcellulose (10g) in denatured ethanol (75ml) was added CH of ethylcellulose (5g)₂Cl₂(150ml) solution. Then adding CH₂Cl₂(75ml) and 1, 2, 3-propanetriol (2.5 ml). Polyethylene glycol (10g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the former solution, and then magnesium octadecanoate (2.5g), polyvinylpyrrolidone (5g) and concentrated pigment suspension (30ml) were added thereto and the whole was mixed well. The tablet cores are coated with the mixture thus obtained in a coating apparatus.

Claims (7)

1. A compound represented by the following formula (I)

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

Z represents NH;

y represents-C_3-9Alkyl-;

X¹represents O;

X²represents NR¹¹-C_1-2Alkyl-;

R¹represents hydrogen or halogen;

R²represents hydrogen or halogen;

R³is represented by C_1-4Alkyloxy-;

R¹¹represents hydrogen, C_1-4Alkyl radical, C_1-4Alkyl-oxy-carbonyl-, Het¹⁷、Het¹⁸-C_1-4Alkyl-, optionally Het¹⁹-C_1-4Alkylaminocarbonyl-substituted C_2-4alkenylcarbonyl-C_2-4Alkenylsulfonyl-, C_1-4Alkyloxy C_1-4Alkyl-, or optionally substituted by one or two or more groups selected from hydrogen, hydroxy, amino or C_1-4Phenyl substituted with a substituent of alkyloxy-;

Het¹⁷represents a heterocycle selected from pyrrolidinyl or piperidinyl, wherein said Het is¹⁷Optionally one or two or more selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted;

Het¹⁸and Het¹⁹Each independently represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl, wherein said Het is¹⁸And Het¹⁹Optionally one or two or more selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy-C_1-4Alkyl-, C_1-4Alkyloxy C_1-4Alkyl or polyhydroxy-C_1-4Alkyl-substituted.

2. The compound of claim 1, wherein

Z represents NH;

y represents-C_3-9Alkyl-;

X¹represents O;

X²represents NR¹¹-C_1-2Alkyl-;

R¹represents hydrogen or halogen;

R²represents hydrogen or halogen;

R³is represented by C_1-4Alkyloxy-;

R¹¹represents hydrogen, C_1-4Alkyl-or C_1-4Alkyl-oxy-carbonyl-.

3. The compound of claim 1 or 2, wherein R¹The substituent is at the 4' -position of the structure of formula (I), R²The substituent is at the 5' -position of the structure of formula (I), R³The substituent is at the 7-position of the structure of formula (I).

4. A compound according to claim 1 or 2 for use as a medicament.

5. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of a cell proliferative disorder selected from atherosclerosis, restenosis and cancer.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective kinase-inhibiting amount of a compound according to any one of claims 1 to 3.

7. A process for preparing a compound as claimed in claims 1 to 3, which comprises:

a) coupling a known 6-acetoxy-4-chloro-3-cyano-quinoline of formula (II) with an appropriate substituted aniline of formula (III) to give an intermediate of formula (IV), and deprotecting the intermediate of formula (IV) and subsequent ring closure under appropriate conditions

V ═ a protecting group selected from methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl;

R¹⁸represents C alkyl_1-4A group;

Y，X²，R¹，R²as defined in claim 1;

b) formula (IV)^b) Deprotection of the intermediate of (XXVIII) and subsequent formation of the corresponding ether under standard conditions using the appropriate aminated alcohol gives the intermediate of formula (XXVIII); deprotection followed by ring closure affords formula (I'^b) Target compound of (2)

V ═ a protecting group selected from methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl, or, in the case of solid phase chemistry, a resin linking the rest of the molecule,

R¹⁸is represented by C_1-4An alkyl group, a carboxyl group,

Y₁and Y₂Each independently represents C_1-5Alkyl, CO-C_1-5An alkyl group.

X₂，R₁And R₂As defined in claim 1.