HU230095B1 - Substituted 3-cyanoquinolines with inhibitory activity against protein tyrosine kinases - Google Patents

Description

PROTEIN TYROSINE KINASE INHIBITING SUBSTITUTED

3-CYANOQUINOLINES

The invention relates to certain substituted 3-cyanoquinoline compounds and their pharmaceutically acceptable salts. The compounds of the invention inhibit the activity of certain growth factor receptor protein tyrosine kinases (PTKs) and other protein kinases, thereby inhibiting the abnormal growth of certain cell types. The compounds of the invention are therefore useful in the treatment of diseases resulting from dysregulation of the above PTKs. The compounds of the invention are anticancer agents and are useful in the treatment of cancer in mammals. In addition, the compounds of the invention are useful in the treatment of polycystic kidney disease in mammals. The invention also relates to a process for preparing the above 3-cyanoquinolines, their use in the treatment of cancer and polycystic kidney disease, and to pharmaceutical compositions containing the above compounds.

Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue on a protein substrate. It is well known that protein tyrosine kinases play a role in normal cell growth. Many growth factor receptors function as protein tyrosine kinases and signal through them. The interaction of growth factors with these receptors is a necessary event in the normal regulation of cell growth. However, under certain circumstances, as a result of mutation or overexpression, these receptors become deregulated; the result is uncontrolled cell proliferation, which can lead to tumorigenesis and ultimately to the disease known as cancer [Wilks A. F., Adv. Cancer Res. 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita V. T. eds. J. B. Lippincott Co., Phila., 3 (1993). Growth factor receptor kinases and their proto-oncogenes that are targets of the compounds of the invention include epidermal growth factor receptor kinase (EGFR kinase, the product of the erbB oncogene protein), and the product produced by the erbB-2 (also known as novel or HER2) oncogene. Since the phosphorylation event is a necessary signal for the initiation of cell division, and since overexpressed or mutant kinases are associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, may be of therapeutic value in the treatment of cancer or other diseases characterized by uncontrolled or abnormal cell division. For example, overexpression of the erbB-2 oncogene receptor kinase product has been associated with human breast and ovarian cancers [Slamon D. J. et al., Science 244: 707 (1989) and Science 235, 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermal tumors [Reiss M. et al., Cancer Res. 51, 6254 (1991)], breast tumors [Macias A. et al., Anticancer Res. 7, 459 (1987)], and tumors of other major organs [Gullick W. J., Brit. Med. Bull. 47, 87 (1991)]. Because of the important role of deregulated receptor kinases in cancer pathogenesis, many studies have recently addressed the development of specific PTK inhibitors as potential anticancer therapeutics [for some recent literature reviews, see Burke T. R., Drugs Future 17, 119 (1992) and Chang C. J, Geahlen R. L., J. Nat. Prod. 55, 1529 (1992)]. The compounds of the invention inhibit the kinase activity of EGF-R and are therefore useful in the treatment of certain pathological conditions, such as cancer, which result, at least in part, from the deregulation of the above receptor. The compounds of the invention are also useful in the treatment of certain precancerous conditions94153-6405K SL/me

They can also be used to treat and prevent conditions such as the growth of colon polyps, which result, at least in part, from the deregulation of the above receptor.

It is known that the deregulation of EGF receptors is one of the factors in the growth of epithelial cysts in the disease known as polycystic kidney disease [Du J., Wilson P. D., Amer. J. Physiol. 269(2 Pt 1), 487 (1995); Nauta J. et al., Pediatric Research 37(6), 755 (1995); Gattone V. H. et al., Developmental. Biology, 169(2). 504 (1995); Wilson P. D. et al., Eur. J. Cell. Biol. 61(1), 131 (1993)]. The compounds of the invention, which inhibit the catalytic function of EGF receptors, can therefore also be used in the treatment of the above disease.

The mitogen-activated protein kinase (MAPK) pathway is a major pathway in the cellular signaling cascade from growth factors to the nucleus. The pathway involves kinases at two levels: the MAP kinase kinases (MAPKKs) and their substrates, the MAP kinases (MAPKs). There are different isoforms within the MAP kinase family (for a review, see Rony Seger and Edwin G. Krebs, FASEB, Vol. 9, 726, June 1995). The compounds of the invention are able to inhibit the activity of two of the above kinases: the activity of a MAP kinase kinase, MEK, and its MAP kinase substrate, ERK. MEK is activated by phosphorylation of two serine residues by upstream kinases (e.g., by members of the raf family). Upon activation, MEK catalyzes the phosphorylation of one threonine and one tyrosine residue of ERK. Activated ERK then phosphorylates and activates transcription factors in the nucleus, such as fost and junt, or other cellular targets with PXT/SP sequences. ERK, a p42 MAPK, has been shown to be essential for cell proliferation and differentiation. Overexpression and/or overactivation of Mek or ERK have been shown to be associated with various human tumors [e.g., Vimala S. Sivaraman, Hsien-yu Wang, Gerard J. Nuovo, and Craig C. Maibon, J. Clin. Invest. Vol. 99 (April 7, 1997)]. It has also been shown that inhibition of MEK prevents the activation of ERK and the subsequent activation of ERK substrates in the cell, resulting in inhibition of cell growth stimulation and reversal of the phenotype of ras-transformed cells [David T. Dudley, Long Pang, Stuart J. Decker, Alexander J. Bridges and Alan R. Saltiel, PNAS, vol. 92, 7686 (August 1995)]. Since, as will be shown below, the compounds of the invention are capable of inhibiting the combined action of MEK and ERK, they may be useful in the treatment of various diseases, such as cancer, characterized by uncontrolled cell proliferation and which are, at least in part, dependent on the MAPK pathway.

Epithelial cell kinase (ECK) is a receptor protein tyrosine kinase (RPTK) that belongs to the EPH (erythropoietin-producing hepatoma) family. Although it was originally identified as a tyrosine kinase specifically of epithelial origin, ECK has subsequently been shown to be expressed in vascular epithelial cells, smooth muscle cells, and fibroblasts. ECK is a type I transmembrane glycoprotein with an extracellular ligand-binding domain consisting of a cysteine-rich region followed by three type III fibronectin repeat units. The intracellular domain of ECK contains a tyrosine kinase catalytic domain that initiates a signal-amplifying cascade that mediates ECK function. ECK binds to and is subsequently activated by its counter-receptor, Eph-related kinase ligand (LERK)-1, which is readily induced by proinflammatory cytokines, such as IL-1 or TNF, in a manner independent of origin. Soluble LERK-1 has been shown to stimulate angiogenesis, in part by stimulating ECK, in a murine model of corneal angiogenesis. Tumor cells of various origins, unlike their normal counterparts, constitutively express LERK-1, and

- 3 this expression can be further regulated by hypoxia and proinflammatory cytokines. Most of the above tumor cells also express ECK at higher concentrations than their normal counterparts, thus providing the opportunity for autocrine stimulation through the ECK:LERK-1 interaction. Increased expression of both ECK and LERK-1 is associated with the transformation of melanomas from a non-invasive horizontal growth phase to highly invasive, vertically growing metastatic melanomas. In summary, the ECK:LERK-1 interaction likely promotes tumor growth through its pro-tumor and angiogenic effects. Thus, inhibition of ECK tyrosine kinase activity, which induces and mediates the signaling cascade by binding to and crosslinking with LERK-1, may be therapeutically useful in the treatment of cancer, inflammatory diseases, and hyperproliferative diseases. As will be shown below, the compounds of the invention inhibit the activity of ECK tyrosine kinase and are therefore useful in the treatment of the above-mentioned disorders.

The growth of most solid tumors depends on angiogenesis, which involves the activation, proliferation, and migration of vascular endothelial cells, followed by their differentiation into capillary tubes. Angiogenesis of tumors allows them to access oxygen and nutrients from the blood and provides them with adequate perfusion. Therefore, inhibition of angiogenesis is a very important therapeutic strategy not only in cancer but also in many chronic diseases such as rheumatoid arthritis, psoriasis, diabetic retinopathy, age-related macular degeneration, etc. Tumor cells produce a variety of angiogenic molecules. One of the angiogenic factors is vascular endothelial growth factor (VEGF). VEGF, a homodimeric disulfide-bonded molecule belonging to the PDGF family, is an endothelial cell-specific mitogen and is known to greatly increase the permeability of the vascular endothelium in affected tissues. VEGF is also a survival factor for endothelial cells that prevents senescence. Almost all nucleated tissues in the body have the ability to express VEGF in response to various stimuli, including hypoxia, glucose deprivation, advanced glycation end products, inflammatory cytokines, etc. VEGF exerts its growth-promoting angiogenic effects primarily through the signaling receptor kinase insert domain-containing receptor (KDR). KDR expression is low in most endothelial cells; however, activation by angiogenic agents results in significant upregulation of KDR in endothelial cells. Most vascularized blood vessels express KDR in high concentrations. KDR is a receptor protein tyrosine kinase with an extracellular VEGF-binding domain consisting of 7 immunoglobulin-like domains and a cytoplasmic domain containing a catalytic tyrosine kinase domain interrupted by a kinase insert region. Binding of VEGF induces dimerization of KDR, which results in its autophosphorylation and initiation of a signaling cascade. The tyrosine kinase activity of KDR is essential for its functional effects as a VEGF receptor. Inhibition of KDR-mediated functional effects by inhibiting the catalytic activity of KDR is considered an important therapeutic strategy in the treatment of angiogenic pathological conditions, including cancer. As will be shown below, the compounds of the invention inhibit the tyrosine kinase activity of KDR and are therefore useful in the treatment of the above-mentioned pathological conditions.

In addition to the above uses, the compounds of the invention can also be used to prepare other compounds of the invention.

The compounds of the invention are substituted 3-cyanoquinolines. In the specification, the quinoline ring system is numbered as shown in formula (A) and the quinazoline ring system is numbered as shown in formula (B).

3-cyanoquinolines have not been reported to exhibit biological activity as protein tyrosine kinase inhibitors. 3-cyanoquinolines with a 4-(2-methylanilino)-substituent exhibit gastric (Η ⁺ /Κ.*)ATPase inhibitory activity at high concentrations [Ife RJ et al., J. Med. Chem. 35(18),

3413 (1992)].

Quinolines which do not have a 3-cyano substituent and, unlike the compounds of the invention, are not substituted at the 4-position are also known and have been reported to inhibit protein tyrosine kinases [Gazit A. et al., J. Med. Chem. 39(11), 2170 (1996)]. A group of quinolines which contain a 3-pyridyl substituent and are unsubstituted at the 4-position have been reported as platelet-derived growth factor receptor kinase inhibitors [Dolle R. E. et al., J. Med. Chem. 372, 2627 (1994) and Maguire M. P. et al., J. Med. Chem. 372, 129 (1994)]. Patent publications WO 96/09294 and WO 98/13350 disclose protein tyrosine kinase inhibitors, such as 4-anilinoquinolines, which may be substituted with various substituents at positions 5-8, but must have a hydrogen or fluorine atom at position 3. US 5,480,883 discloses quinoline derivatives with protein tyrosine kinase inhibitory activity, but these derivatives do not have the specific combination of substituents, including the 3-cyano group, that are present in the compounds of the invention. Patent publications WO 98/02434 and WO 98/02438 disclose quinoline derivatives with tyrosine kinase inhibitory activity, but these quinolines also do not contain the important 3-cyano substituent.

In addition to quinolines, certain quinazoline derivatives, which are similar in some respects to the compounds of the invention, are known to inhibit protein tyrosine kinases. EP 520722 discloses 4-anilinoquinazolines which contain simple substituents such as chlorine, trifluoromethyl or nitro groups at the 5-8 position. EP 566226 discloses similar compounds, but the substituents at the 5-8 position are much more varied. WO 96/09294 discloses compounds which contain similar substituents at the 5-8 position, the substituent at the 4-position consisting of certain polycyclic ring systems. Some simple substituted quinazoline derivatives are also described in WO 95/24190, WO 95/21613 and WO 95/15758. Similar quinazoline derivatives are described in EP 602851 and WO 95/23141, in which the aryl group attached at the 4-position may be substituted with various heterocyclic ring structures. EP 635498 describes quinazoline derivatives which may contain, inter alia, alkenoylamino and alkinoylamino groups at the 6-position and a halogen atom at the 7-position. WO 95/19774 describes compounds in which one or more of the carbon atoms at positions 5-8 are substituted with heteroatoms, thereby giving various bicyclic systems, where the left-hand ring is a 5- or 6-membered heterocyclic ring, and in addition, a number of substituents can be attached to the left-hand ring. EP 682027-A1 describes certain pyrrolopyrimidine inhibitors of PTK. WO 95/19970 describes compounds in which the left-hand aromatic ring of the quinazoline backbone is substituted with various heterocyclic rings, resulting in tricyclic inhibitors. EP 635507 describes quinazolines which contain an additional, optionally substituted, 5- or 6-membered heterocyclic ring fused at the 5- and 6-positions.

In addition to the above-mentioned patents, 4-anilinoquinazolines are described in several publications: Fry, D. W. et al., Science 265, 1093 (1994), Rewcastle G. W. et al., J. Med. Chem. 38, 3482 (1995) and Bridges A. J. et al., J. Med. Chem. 39, 267 (1996). However, none of the above publications disclose 3-cyanoquinolines as PTK inhibitors.

The invention relates to compounds of general formula (1) - in the formula

X is (A) a bicyclic aryl or bicyclic heteroaryl ring system of 8-12 carbon atoms, wherein the bicyclic heteroaryl ring contains 1-4 heteroatoms selected from N, O, and S, with the proviso that the bicyclic heteroaryl ring does not contain an O-O, S-S, or S-O bond, and wherein the bicyclic aryl or bicyclic heteroaryl ring is optionally halogen, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl group, C2-7 carboalkoxy group, C2-7 carboalkyl group, phenoxy group, phenyl group, thiophenoxy group, benzoyl group, benzyl group, amino group, C1-6 alkylamino group, C2-12 dialkylamino group, phenylamino group, benzylamino group, C1-6 alkanoylamino group, C3-8 alkenoylamino group, C3-8 alkynylamino group, C2-7 carboxyalkyl group, C3-8 carboalkoxyalkyl group, C1-5 aminoalkyl group, C2-9 N-alkylaminoalkyl group, C3-10 N,N-dialkylaminoalkyl group, C2-9 N-alkylaminoalkoxy group, C3-10 N,N-dialkylaminoalkoxy group, mercapto group and benzoylamino group may be mono-, di-, tri- or tetrasubstituted with a substituent; or

X is a group of the general formula (B) -A-T-L, wherein

A is a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring is optionally halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl, C2-7 carboalkoxy, C2-7 carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, C1-6 alkylamino, C2-12 dialkylamino, phenylamino, may be mono- or disubstituted with a substituent selected from benzylamino group, C1-6 alkanoylamino group, C3-8 alkenoylamino group, C3-8 alkynylamino group, C2-7 carboxyalkyl group, C3-8 carboalkoxyalkyl group, C1-5 aminoalkyl group, C2-9 N-alkylaminoalkyl group, C3-10 N,N-dialkylaminoalkyl group, C2-9 N-alkylaminoalkoxy group, C3-10 N,N-dialkylaminoalkoxy group, mercapto group, methylmercapto group and benzoylamino group;

T is attached to a carbon atom of A and is -NH(CH ₂ ) _m -, -O(CH ₂ ) _m -, -S(CH ₂ ) _m -, -NR(CH ₂ ), _n -, -(CH ₂ ) _ra -, -(CH ₂ ) _in NH-, -(CH ₂ ), _n O-, -(CH,) _m S-, or -(CH ₂ ) _m NR-;

L is an unsubstituted phenyl ring, or a phenyl ring optionally substituted with a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an azido group, a C1-6 hydroxyalkyl group, a halomethyl group, a C2-7 alkoxymethyl group, a C2-7 alkanoyloxymethyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a hydroxyl group, a trifluoromethyl group, a cyano group, a nitro group, a carboxyl group, a C2-7 carboalkoxy group, a C2-7 carboalkyl group, a phenoxy group, a phenyl group, a thiophenoxy group, a benzoyl group, a benzyl group, an amino group, a C1-6 alkylamino group, a C2-12 dialkylamino group, a phenylamino group, a benzylamino group, a C1-6 is mono-, di- or trisubstituted with a substituent selected from alkanoylamino, C3-8 alkenoylamino, C3-8 alkynylamino, C2-7 carboxyalkyl, C3-8 carboalkoxyalkyl, C1-5 aminoalkyl, C2-9 N-alkylaminoalkyl, C3-10 N,N-dialkylaminoalkyl, C2-9 N-alkylaminoalkoxy, C3-10 N,N-dialkylaminoalkoxy, mercapto and benzoylamino; with the proviso that L can only be an unsubstituted phenyl group if m > 0 and T is other than -CH ₂ NH- or -CH ₂ O-; or

L is a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain O-O, S-S or S-O bonds, and wherein the heteroaryl ring is optionally halogen, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl, C2-7 carboalkoxy, C2-7 carboalkyl, phenoxy, phenyl, thiophenoxy group, benzoyl group, benzyl group, amino group, C1-6 alkylamino group, C2-12 dialkylamino group, phenylamino group, benzylamino group, C1-6 alkanoylamino group, C3-8 alkenoylamino group, C3-8 alkynylamino group, C2-7 carboxyalkyl group, C3-8 carboalkoxyalkyl group, C1-5 aminoalkyl group, C2-9 N-alkylaminoalkyl group, C3-10

- may be mono- or disubstituted with a substituent selected from 7 N,N-dialkylaminoalkyl groups, C2-9 N-alkylaminoalkoxy groups, C3-10 N,N-dialkylaminoalkoxy groups, mercapto groups and benzoylamino groups;

Z is -NH-, -O-, -S- or -NR-;

R is a C1-6 alkyl group or a C2-7 carboalkyl group;

G1, _G2 , R1 and R4 are independently hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkenyloxy, C2-6 alkynyloxy, hydroxymethyl, halomethyl, C1-6 alkanoyloxy, C3-8 alkenoyloxy, C3-8 alkinoyloxy, C2-7 alkanoyloxymethyl, C4-9 alkenoyloxymethyl, C4-9 alkinoyloxymethyl, C2-7 alkoxymethyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido group, C2-6 alkenylsulfonamido group, C2-6 alkynylsulfonamido group, hydroxyl group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, carboxyl group, C2-7 carboalkoxy group, C2-7 carboalkyl group, phenoxy group, phenyl group, thiophenoxy group, benzyl group, amino group, hydroxylamino group, C1-4 alkoxyamino group, C1-6 alkylamino group, C2-12 dialkylamino group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, C4-12 N-alkyl-N-alkenylamino group, C6-12 N,N-dialkenylamino group, phenylamino group, benzylamino group, group of general formula (a), (b), (c), (d) or (e); or R1 and R4 are as defined above and G or _G2 or both are a group of the general formula _R2 -NH-; or if any of the substituents _{Rb G2} , _G3 or R4 are located on adjacent carbon atoms, they may together form a divalent group of the general formula -O-CXRJrO-;

Y is a divalent group selected from -(CH ₂ ) _a -, -O- and -NR ₆ -;

R ₇ is -NR 1 R 2 , -OR 2 -J, -N(R ₁ ) ₃ * or -NR 1 R 2 ;

M is >NR<„ -O-, >N-(C(R ₆ ) ₂ ) _P NR ₆ R ₆ or >N-(C(R _Ó ) ₂ ) _P -OR _Í ;

W is >NR ₆ , -O- or a bond;

Seven is morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran or a heterocycle of general formula (f);

where H is optionally mono- or disubstituted on a carbon or nitrogen atom with an R^ group, optionally mono- or disubstituted on a carbon atom with a hydroxyl group, a group of the general formula -N(RJ ₂ or -ORo ), optionally mono- or disubstituted on a carbon atom with a monovalent group of the general formula -(C(R ₆ )2) _s OR6 or -(C(R ₆ ) ₂ ) _S N(R ₆ ) ₂ , or optionally mono- or disubstituted on a saturated carbon atom with a divalent group of the general formula -O- or -O(C(R6) ₂ ) _S O-;

K, represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6

- C8 alkynyl group, C1-C6 cycloalkyl group, C2-C7 carboalkyl group, C2-C7 carboxyalkyl group, phenyl group or optionally substituted with one or more substituents selected from halogen atom, C1-C6 alkoxy group, trifluoromethyl group, amino group, C1-C3 alkylamino group, C2-C6 dialkylamino group, nitro group, cyano group, azido group, halomethyl group, C2-C7 alkoxymethyl group, C2-C7 alkanoyloxymethyl group, C1-C6 alkylthio group, hydroxyl group, carboxyl group, C2-C7 carboalkoxy group, phenoxy group, phenyl group, thiophenoxy group, benzoyl group, benzyl group, phenylamino group, benzylamino group, C1-C6 alkanoylamino group and C1-C6 alkyl group phenyl group; with the proviso that the alkenyl or alkynyl residue is attached to a nitrogen or oxygen atom through a saturated carbon atom;

_R2 is a group of formula (g), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q), (r), (s), (t), (x), (y), (v), (w), (z), (aa), (bb), (cc), (dd), (ee) or (ff);

R ₃ is independently selected from hydrogen, C 1-6 alkyl, carboxyl, C 1-6 carboalkoxy, phenyl, C 2-7 carboalkyl, (gg), (hh), (ii), (jj) or (kk);

R ₅ is independently hydrogen, C 1-6 alkyl, carboxyl, C 1-6 carboalkoxy, phenyl, C 2-7 carboalkyl, a group of formula (gg), (hh), (ii), (jj) or (kk);

R ₈ and R q independently represent a group of the general formula -(CjR/JjjrNR/,!^ or -(QR^jrORfi;

J is independently hydrogen, chlorine, fluorine or bromine;

Q is C1-6 alkyl or hydrogen;

the value of a is 0 or 1;

g has a value of 1-6;

k value is 0-4;

n has a value of 0-1;

m is 0-3;

p-value is 2-4;

q has a value of 0-4;

r has a value of 1-4;

s has a value of 1-6;

u is 0-4 and v is 0-4, where the sum of u and v is 2-4 and pharmaceutically acceptable salts thereof are formed, with the proviso that when R0 is a C2-7 alkenyl group or a C2-7 alkynyl group, such alkenyl or alkynyl residue is attached to a nitrogen or oxygen atom through a saturated carbon atom;

and ^with the further proviso that when Y is -NR6- and _R7 is -NR6R*, -N(R6) ₃₊ or -NR6OR6), then g is 2-6;

- 9 if M is -O- and R ₇ is -OR<„ then p is 1-4;

if Y is -NRí-, then k is 2-4; if Y is -O- and M or W is -O-, then k is

1-4;

if W is not bonded to the Het group through a nitrogen atom, then q is 2-4; and if W is bonded to the Het group through a nitrogen atom and Y is -O- or -NR^-, then k is 2-4.

Pharmaceutically acceptable salts include salts derived from organic and inorganic acids, such as acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, malonic acid, gluconic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, and similar known acceptable acids.

Preferred bicyclic aryl or bicyclic heteroaryl ring systems include naphthalene, 1,2,3,4-tetrahydronaphthalene, indane, 1-χο-indane, 1,2,3,4-tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-1,3-dihydroisobenzofuran, benzothiaphene, 1,1-dioxobenzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, phthalimide, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyridine, pyrido[3,4-b]pyrazine-, pyrido[3,2-c]pyridazine-, pyrido[3,4-b]pyridine-, 1Hpyrazolo[3,4-d]pyrimidine-, 1,4-benzodioxane-, pteridine-, 2(1H)-quinolone-, 1(2H)-isoquinolone-, 2-oxo-2,3dihydro-benzthiazole-, 1,2-methylenedioxybenzene-, 2-oxindole-, 1,4-benzisoxazine-, benzothiazole-, quinoxaline-, quinoline-N-oxide-, isoquinoline-N-oxide-, quinoxaline-N-oxide-, quinazoline-N-oxide-, benzoazine-, phthalazine-, 1,4dioxo-1,2,3,4-tetrahydrophthalazine-, 2-oxo-1,2-dihydroquinoline-, 2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine, 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine or cinnoline ring.

When L is a 5- or 6-membered heteroaryl ring, preferred heteroaryl rings include pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole and 1,2,4-triazole rings.

One or both rings of a bicyclic aryl or bicyclic heteroaryl group may be fully unsaturated, partially saturated or fully saturated. The presence of an oxo substituent in a bicyclic aryl or bicyclic heteroaryl radical is understood to mean that one of the carbon atoms represents a carbonyl group. The presence of a thio substituent in a bicyclic aryl or bicyclic heteroaryl radical is understood to mean that one of the carbon atoms represents a thiocarbonyl group.

When L is a 5- or 6-membered heteroaryl ring, it may be fully unsaturated, partially saturated or fully saturated. The heteroaryl ring may be attached to A through a carbon or nitrogen atom. The presence of an oxo substituent in the heteroaryl ring is understood to mean that one of the carbon atoms represents a carbonyl group. The presence of a thio substituent in the heteroaryl ring is understood to mean that one of the carbon atoms represents a thiocarbonyl group.

The alkyl moiety in the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, carboalkoxy, carboalkyl, carboxyalkyl, carboalkoxyalkyl, alkanoylamino, N-alkylcarbamoyl, Ν,Ν-dialkylcarbamoyl, N-alkylaminoalkoxy, Ν,Ν-dialkylaminoalkoxy group substituents may be straight or branched. The alkenyl moiety in the alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido group substituents may be straight or branched and may contain one or more unsaturations and may exist in all possible configurational isomeric forms. The alkynyl moiety of the alkynyl, alkynyloxymethyl, alkynylsulfonamido, alkynyloxy group substituents may be straight or branched and may contain one or more unsaturations. The carboxyl group is a -CO ₂ H

- means a group of formula 10. A carboalkoxy group of 2-7 carbon atoms means a group of the general formula -CO ₂ R, where R is an alkyl group of 1-6 carbon atoms. A carboxyalkyl group means a group of the general formula HO ₂ C-R'-, where R' is a divalent alkyl group of 1-6 carbon atoms. A carboalkoxyalkyl group means a group of the general formula RO ₂ C-R', where R' is a divalent alkyl group, and R and R' together contain 2-7 carbon atoms. A carboalkyl group means a group of the general formula -COR, where R is an alkyl group of 1-6 carbon atoms. An alkanoyloxy group means a group of the general formula -OCOR, where R is an alkyl group of 1-6 carbon atoms. An alkanoyloxymethyl group means a group of the general formula RCO ₂ CH ₂ -, where R is an alkyl group of 1-6 carbon atoms. The alkoxymethyl group represents a group of the general formula ROCH ₂ -, where R represents an alkyl group of 1-6 carbon atoms. The alkylsulfinyl group represents a group of the general formula RSO-, where R represents an alkyl group of 1-6 carbon atoms. The alkylsulfonyl group represents a group of the general formula RSO ₂ , where R represents an alkyl group of 1-6 carbon atoms. The alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido groups can be defined by the general formula RSO ₂ NH-, where R represents an alkyl group of 1-6 carbon atoms, an alkenyl group of 2-6 carbon atoms or an alkynyl group of 2-6 carbon atoms. The N-alkylcarbamoyl group represents a group of the general formula RNHCO-, where R represents an alkyl group of 1-6 carbon atoms. The Ν,Ν-dialkylcarbamoyl group represents a group of the general formula RR'NCO-, where R represents an alkyl group having 1-6 carbon atoms, R' represents an alkyl group having 1-6 carbon atoms and R' and R are the same or different. In the case where X is substituted, it is preferred that it is mono-, di- or trisubstituted, most preferably monosubstituted. It is preferred that at least one of the substituents R1 and R4 represents a hydrogen atom, and more preferably both represent a hydrogen atom. It is also preferred that X represents a phenyl ring, Z represents -NH- and n = 0.

Het means a heterocycle as defined above, which may be optionally mono- or disubstituted on its carbon or nitrogen atom by a group, optionally mono- or disubstituted on its carbon atom by a group of the general formula -N/R^ or -OR^, optionally mono- or disubstituted on its carbon atom by a group of the general formula -(C(R ₆ ) ₂ ) _S OR ₆ or -(C(R ₆ ) ₂ ) _S N(R ₆ ) ₂ , and optionally mono- or disubstituted on its saturated carbon atom by a group of the general formula -O- or -Ο(ϋ(» ₂ ) ₅ Ο- (carbonyl or ketal group); in certain cases, when Het is substituted with a -O- (carbonyl) group, the carbonyl group may also be hydrate. When q = 0, the W group may be attached to the heterocyclic ring via a carbon atom, or when Het means a nitrogen-containing heterocycle which also contains a saturated carbon-nitrogen bond, such heterocycle may also be attached to the carbon atom through a nitrogen atom if W represents a bond. When q = 0 and Het means a nitrogen-containing heterocycle which also contains an unsaturated carbon-nitrogen bond, this nitrogen atom of the heterocycle may be attached to the carbon atom if W represents a bond, and the resulting heterocycle may carry a positive charge. When substituted with a group Het, such substituent may be attached to a ring carbon atom, or in the case of a nitrogen-containing heterocycle which also contains a saturated carbon-nitrogen bond, such nitrogen may also be substituted with R ₆ , or in the case of a nitrogen-containing heterocycle which also contains an unsaturated carbon-nitrogen bond, such nitrogen may also be substituted with R 6, in which case the heterocycle carries a positive charge. Preferred heterocycles include pyridine, 2,6-disubstituted morpholine, 2,5-disubstituted thiomorpholine, 2-substituted imidazole, substituted thiazole, thiazolidine, N-substituted imidazole, N-substituted 1,4 piperazine, N-substituted piperidine, dioxane, 1,3-dioxolane, and N-substituted pyrrolidine.

The compounds of the invention may contain one or more asymmetric carbon atoms; such

- In 11 cases, the compounds of the invention include individual diastereomers, racemates, and individual R and S enantiomers thereof. Some of the compounds of the invention may contain one or more double bonds; in such cases, the compounds of the invention include all possible configurational isomers, as well as mixtures of such isomers.

The compounds of general formula (1) and their salts can be prepared by

a) a compound of general formula (99) - wherein R _h G _h G ₂ , R4, Z, n and X are as defined above, is reacted with a dehydrating agent to convert the aminocarbonyl group to a cyano group, or

b) reacting a compound of the general formula A1-NH- _A2 or a salt thereof with a compound of the general formula _QA3 , where Q is a leaving group and A1, _A2 and _A3 are such that A1- _NA2 - _A3 forms a compound conforming to the general formula (1); or

c) reacting a compound of the general formula A4-OH or a salt thereof with a compound of the general formula _QA5 , where Q is as defined above and A4 and _A5 are such that A4-O-A5 forms a compound conforming to the general formula (1); or

d) the compound of general formula (1) is converted into an acid addition salt by reacting it with an acid.

The preparation of the compounds and intermediates of the invention of formula (5) is illustrated in Scheme 1, where Z, X, n, R1, _G2 , G1 and are as defined above. According to the process described in Scheme 1, a quinoline-3-carboxylic acid ester of formula (2) is hydrolyzed with a base to give a carboxylic acid of formula (3). The carboxylic acid of formula (3) is converted to an acyl imidazole by heating with carbonyldiimidazole in an inert solvent, such as dimethylformamide (DMF), followed by the addition of ammonia to give the amide of formula (4). Dehydration of the amide functional group with a dehydrating agent, such as trifluoroacetic anhydride in pyridine, phosphorus pentoxide in an inert solvent, or the like, gives the 3-cyano quinolines of formula (5) of the invention. In the case where any of the intermediates contain an asymmetric carbon atom, they can be used as racemates or as pure R or S enantiomers, in which case the compounds of the invention can be obtained in racemic form or in optically active R or S form. The quinoline-3-carboxylic acid esters of formula (2), quinoline-3-carboxylic acids of formula (3) and quinoline-3-carboxylic acid amides of formula (4) required for the preparation of the compounds of the invention are either known or can be prepared by known methods based on the teachings of the following references: Sarges, Reinhard; Gallagher, Andrea; Chambers, Timothy J.; Yeh, Li An: J. Med. Chem. 36, 2828 (1993); Savini, Luisa; Massarelli, Paola; Pellerano, Cesare; Bruni, Giancarlo: Farmaco 46(6), 805 (1993); Ife, Robert J.; Brown, Thomas H.; Keeling, David J.; Leach, Colin: J. Med. Chem. 35, 3413 (1992); Hanifin, J. William; Capuzzi, Rosemary; Cohen, Elliott: J. Med. Chem. 12(5), 1096 (1969); Marecki, Paul E.; Bambury, Ronald E.: J. Pharm. Sci. 73(8), 1141 (1984); Pellerano, C.; Savini, L.; Massarelli, P.; Bruni, G.; Fiashi, AI: Farmaco 45(3), 269 (1990); Marecki, Paul E.; Bambury, Ronald E.: J. Pharm. Sci. 73(8), 114 (1984); Patent Publication No. WO 89/08105; US Patents Nos. 4,343,804 and 3,470,186.

The preparation of the compounds of formula (12) according to the invention is illustrated in Scheme 2, where X, Z, n, R _h G ₂ , G, and are as defined above. The substituted aniline of formula (6) is heated with the reagent of formula (7) with or without a solvent to give the intermediate of formula (8) as a mixture of isomers. Thermolysis of compound of formula (8) in a high boiling solvent, such as diphenyl ether at 200-350°C affords 3-cyanoquinolines of formula (9); these are

- 12 intermediates also exist in the form of the 4-hydroxyquinoline tautomer. In the case where R ₄ is hydrogen, the intermediates of formula (9) may be formed as a mixture of two regioisomers. These isomers can be separated by known methods, for example by fractional crystallization or chromatography. The separated isomers can then be separately converted into the compounds of the invention. Alternatively, the isomers can be separated at a later stage of the synthesis. The compound of formula (9) is heated with a chlorinating agent, for example phosphorus oxychloride or phosphorus pentachloride, with or without a solvent, to give 4-chloro-3-cyanoquinolines of formula (10). The compound of formula (10) is reacted with a nucleophilamine of formula (11), aniline, mercaptan, thiophenol, phenol or alcohol to give the 3-cyanoquinoline intermediates of formula (12); this condensation can be accelerated by heating the reaction mixture or by using basic catalysts such as trialkylamines, sodium hydride in an inert solvent, sodium or potassium alkoxides in alcoholic solvents and the like. In cases where the substituents contain an asymmetric carbon atom, the intermediates can be used as racemates or as pure R or S enantiomers, in which case the compounds of the invention are obtained in racemic form or in R or S optical isomer form, respectively. In cases where the substituents contain more than one asymmetric carbon atom, diastereoisomers may be present; these can be separated by known methods, for example by fractional crystallization or chromatographic procedures. In cases where the residues R _{1 ;} G ₂ , G] and R 4 contain primary or secondary amino groups, it may be necessary to first protect the amino groups before reaction with the reagent of general formula (7). Suitable protecting groups include, but are not limited to, the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The former protecting group can be removed from the final products of general formula (12) by treatment with an acid, for example trifluoroacetic acid, while the latter protecting group can be removed by catalytic hydrogenation. In cases where R _{1 ;} G ₂ , G! and R 4 are residues containing hydroxyl groups, it may be necessary to protect the hydroxyl groups before reaction with the reagent of general formula (7). Suitable protecting groups include, but are not limited to, tert-butyldimethylsilyl, tetrahydropyranyl or benzyl. The first two protecting groups can be removed from the final products of formula (12) by treatment with an acid, such as acetic acid or hydrochloric acid, while the latter protecting group can be removed by catalytic hydrogenation.

Intermediates (15) [which are identical to intermediates (9) shown in Scheme 2] can also be prepared by the process of Scheme 3. Substituted aniline (13) is heated with dimethylformamide dimethyl acetal, with or without a solvent, to give intermediate (14). Intermediate (14) is reacted with the lithium anion of acetonitrile, prepared using a base such as n-butyl lithium or the like, in an inert solvent to give 3-cyanoquinolines (15) or their 3-cyano-4-hydroxyquinoline tautomers, which can be converted into compounds of the invention. In cases where the R _h G ₂ , Gi and R 1 substituents contain primary or secondary amino groups, it may be necessary to first use these amino groups in protected form. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ). The latter protecting group can be removed from the final product of formula (15) by treatment with an acid, such as trifluoroacetic acid, while the latter protecting group can be removed by catalytic hydrogenation. In the case where R _b G ₂ , Gi and R 4 contain residual hydroxyl groups, these hydroxyl groups should optionally be used in protected form first. Suitable protecting groups include, but are not limited to, tert-butyldimethylsilyl, tetrahydropyranyl or benzyl. The first two protecting groups can be removed from the final product of formula (15) by treatment with an acid, such as acetic acid or hydrochloric acid, while the latter protecting group can be removed by catalytic hydrogenation.

The compounds of the invention of general formula (24) can be prepared by the process illustrated in Scheme 4. In the formulas of the scheme, R _b G ₂ , R 4 , Z, n and X are as defined, R ₁₀ is a C 1-6 alkyl group (preferably isobutyl group), R ₂ ' is a group of general formula (11), (mm), (nn), (00), (pp), (qq), (rr), (ss), (tt), (uu), (vv), (xx), (yy) or (zz), where R ₆ , R ₃ , R ₅ , J, s, r, u and v are as defined above. According to the process illustrated in Reaction Scheme 4, a 4-fluoro3-cyano-6-nitroquinoline of formula (16) is reacted with an amine or aniline of formula (17) in an inert solvent such as tetrahydrofuran, butanol or methoxyethanol by heating to give a compound of formula (20) where Z is -NH-. A compound of formula (16) is reacted with a mercaptan or thiophenol of formula (18) in an inert solvent in the presence of a base such as sodium hydride to give compounds of formula (20) where Z is -S-. A compound of formula (16) is reacted with an alcohol or phenol of formula (19) in an inert solvent in the presence of a base such as sodium hydride to give compounds of formula (20) where Z is -O-. Compound (20) can be reduced to 6-amino-3-cyanoquinoline (21) using a reducing agent such as sodium bisulfite in a two-phase system consisting of tetrahydrofuran and water in the presence of a small amount of a phase transfer catalyst, or using iron in a protic solvent containing acetic acid or ammonium chloride at reflux. Compound (21) can be acylated with an acid chloride of formula (22) or a mixed anhydride of formula (23) (prepared from the corresponding carboxylic acid) in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine or N-methylmorpholine to give the compound of formula (24) of the invention. In the case where the compound of formula (22) or (23) contains an asymmetric carbon atom, it can be used as a racemate or as one of the R or S enantiomers, in which case the compound of the invention is obtained in the racemic or R or S optically active form. In the case where R ₂ ' contains primary or secondary amino groups, the amino groups must first be protected before forming the acid anhydride or acid chloride. Suitable protecting groups include, but are not limited to, the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The former protecting group can be removed from the final product of formula (24) by treatment with an acid, such as trifluoroacetic acid, while the latter protecting group can be removed by catalytic hydrogenation. In the case where R ₂ ' contains hydroxyl groups, the hydroxyl groups must first be protected before forming the anhydride or acid chloride. Suitable protecting groups include, but are not limited to, tert-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final product of formula (24) by treatment with an acid, such as acetic acid or hydrochloric acid, while the latter protecting group can be removed by catalytic hydrogenation. In the case where X in the intermediates of formula (17), (18) or (19) contains a primary or secondary amino group or a hydroxyl group, these groups must be optionally protected before reaction with the compound of formula (16). The above-mentioned amine or alcohol protecting groups can be used and can be removed from the product of formula (24) as described above.

The intermediates of formula (25) can be converted to compounds of the invention of formula (26) (Scheme 4a) in a manner similar to the procedures described in Scheme 4.

Certain amines are required for the preparation of the compounds of the invention. Some representatives of the above amines are summarized in List A, where R 0 , p and r have the meanings given above. These amines are commercially available and are known from the literature, or can be prepared by methods known to those skilled in the art. In some cases, these amines contain asymmetric carbon atoms and can be used as racemates or resolved and used as pure R or S enantiomers, in which case the compounds of the invention are obtained in racemic or optically active form, respectively. In the reaction schemes below and throughout the specification, these amines and other similar amines are designated by the general formula (R') ₂ NH, which may represent primary or secondary amines.

Certain alcohols are required for the preparation of the compounds of the invention. Some representatives of the above alcohols are summarized in List B, where R', p and r have the meanings given above. These alcohols are commercially available and are known from the literature, or can be prepared by methods known to those skilled in the art. In some cases, these alcohols contain asymmetric carbon atoms and can be used as racemates, or they can be resolved and used as pure R or S enantiomers, in which case the compounds of the invention are obtained in racemic or optically active form, respectively. In the following reaction schemes and in the description, these alcohols and other similar alcohols are designated by the general formula R'OH, which formula can represent primary or secondary amines.

Some of the compounds of the present invention are prepared by using mixed anhydrides of formula (31), (34) and (38); these can be prepared by the processes of Schemes 5-6, where R', R10, X, Z, n and s are as defined above and J' is a halogen atom, i.e. chlorine, bromine or iodine, or a tosylate (p-toluenesulfonate) or mesylate (methanesulfonate) group. The compound of formula (27) is reacted with an amine listed in List A under heating in an inert solvent, such as tetrahydrofuran or N,N-dimethylformamide, or potassium or cesium carbonate is used in acetone. The reaction temperature and duration of heating depend on the reactivity of the compound of formula (27); longer reaction times and higher temperatures are required when s is greater than 1. Compound (28) is treated with an alkyl lithium reagent and quenched under an atmosphere of anhydrous carbon dioxide to give carboxylic acids (29). These can be converted to mixed anhydrides (31) using a reagent such as isobutyl chloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of the invention as shown in Scheme 4. Reaction of compound (27) with an alcohol listed in List B can be carried out using sodium hydride or other non-nucleophilic base such as potassium or cesium carbonate in an inert solvent such as tetrahydrofuran, acetone or N,N-dimethylformamide. In some cases, the alcohol listed in List B can also be the solvent for the reaction. Treatment of compound (32) with an alkyl lithium reagent followed by quenching in an atmosphere of anhydrous carbon dioxide affords carboxylic acids (33). These can be converted to mixed anhydrides (34) using various reagents, such as isobutyl chloroformate, in an inert solvent, such as tetrahydrofuran,

- 15 in the presence of a base, such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of the invention as illustrated in Scheme 4.

As illustrated in Reaction Scheme 6, where R _b Gi, R4, R*, R10, X, Z, n and s are as defined above, alcohols of formula (35) can be protected with a tert-butyldimethylsilyl protecting group by reaction with the appropriate silyl chloride in methylene chloride in the presence of triethylamine and 4-(N,N-dimethylamino)pyridine (DMAP). The resulting protected alcohol of formula (36) can be converted into an acetylenic Grignard reagent, which in turn, when kept under an anhydrous carbon dioxide atmosphere, gives the carboxylic acid of formula (37). The resulting compounds can be converted as described above into mixed anhydrides of formula (38) which can be reacted with 6-amino-3-cyanoquinoline of formula (39) to give compounds of formula (40). In the final step of the reaction sequence, the silyl protecting group is removed by treatment with acid in a protic solvent mixture to give compounds of general formula (41).

The compounds of the invention can also be prepared by the process illustrated in Scheme 7, where R _b G2, R4, R0, R10, X, Z, n and s are as defined above, and J' is a halogen atom, such as chlorine, bromine or iodine, or a tosylate or mesylate group. The compound of general formula (42) is treated with an alkyl lithium reagent at low temperature, followed by quenching with an anhydrous carbon dioxide atmosphere to give the carboxylic acids of general formula (43). These can be converted to the mixed anhydrides of general formula (44) using appropriate reagents, such as isobutyl chloroformate, in an inert solvent, such as tetrahydrofuran, in the presence of a base, such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of the invention by reacting with a 6-amino-3-cyanoquinoline of general formula (45) as illustrated in the Schemes. Compound (46) of formula (47) is reacted with an alcohol of formula (46) of formula (47)

Using the methods described above, compounds of formula (45b) can be converted to compounds of formula (47b) or (48b) [Scheme 7a]. Other carboxylic acid chlorides and anhydrides required for the preparation of certain compounds of the invention can be prepared by the methods of Scheme 8, where R ₆ , R ₃ , R ₁₀ , X, Z, J', n and s are as defined above and Q' is a C 1-6 alkyl group. Esters of formula (49), (53) or (57) can be hydrolyzed to the corresponding carboxylic acids of formula (50), (54) or (58) using a base such as barium hydroxide. These acids can be converted to the corresponding carboxylic acid chlorides of formula (51) or (56) using oxalyl chloride and a catalytic amount of N,N-dimethylformamide in an inert solvent, or to the corresponding mixed anhydrides of formula (55) or (59) using isobutyl chloroformate and an organic base such as N-methylmorpholine. The leaving group in the compounds of formula (52) can be replaced by the amines listed in List A or the alcohols listed in List B, as described above.

- 16 procedures are used to obtain intermediates of formula (57) and (53), respectively. Carboxylic acid chlorides of formula (51) and (56) and anhydrides of formula (55) and (59) can be converted to compounds of the invention by the procedures shown in the reaction schemes.

The analogous carboxylic acid chlorides and anhydrides listed in List C can also be prepared by the methods illustrated in Scheme 8, wherein R ₆ , R j , p and s are as defined above, G is a group of the general formula -C(=O)=C1 or -C(=O)-OC(=O)-OR| ₀ , and A is -N(R') ₂ , -OR' or J', where -N(R') ₂ is derived from the amines listed in List A, -OR' is derived from the alcohols listed in List B, and J' is a leaving group as defined above. Using the above carboxylic acid chlorides and anhydrides, the methods illustrated in the above Schemes, and the detailed teachings set forth in the Examples below, the compounds of the invention can be prepared.

The compounds of the invention of general formula (62)-(63) can be prepared by the process according to reaction scheme 9, where R _b G ₂ , R», R«, R ₃ , Rio, X, Z, J', n and s are as defined above. The carboxylic acid chlorides of general formula (60) are reacted with 6-amino-3-cyanoquinolines of general formula (61) using an organic base in an inert solvent to obtain the compounds of general formula (62). The compounds of general formula (62) are reacted with an alcohol listed in list B using sodium hydride or other non-nucleophilic base, such as potassium or cesium carbonate, in an inert solvent, such as tetrahydrofuran, acetone or N,N-dimethylformamide to obtain the compounds of general formula (63). In some cases, the alcohol listed in list B can also serve as the solvent for the reaction. The compound of formula (62) is reacted with an amine listed in List A to give the compounds of formula (64) of the invention, the above reaction being carried out by heating in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide. The temperature and duration of heating depend on the reactivity of the compound of formula (62), with longer reaction times and higher temperatures being required when s is greater than 1. In addition, the carboxylic acid chlorides and mixed anhydrides listed in List C can also be used to prepare the analogous compounds of the invention using the above process.

Using the above methods, compounds of general formula (61b) can be converted to compounds of general formula (63b) or (64b) via intermediates of general formula (62b) [Scheme 9a],

The compound of general formula (62) or (62b) is reacted with a heterocycle HET containing nitrogen and an unsaturated carbon-nitrogen bond in an inert solvent under reflux to give the compounds of general formula (64c) or (64d) of the invention, where the compound carries a positive charge [Reaction Scheme 9b). The anion AJ ^r can be replaced by any other pharmaceutically acceptable anion using a suitable ion exchange resin.

Some compounds of the invention can be prepared by the process of Scheme 10, where R _h G ₂ , R ₃ , R 4 , R ₆ , R | ₀ , X, Z, J', n and r are as defined above. Alcohols of formula (65) containing an acetylenic bond can be coupled with halides, mesylates or tosylates of formula (66) using a base such as sodium hydride in an inert solvent such as tetrahydrofuran. The resulting acetylenic compound of formula (67) is then treated with an alkyl lithium reagent at low temperature. The reaction mixture is maintained under a carbon dioxide atmosphere to give carboxylic acids of formula (68). These, in turn, can be reacted with 6-amino-3-cyanoquinolines of formula (69) via mixed anhydrides.

- 17 give the compounds of formula (70) according to the invention. Alternatively, the intermediate of formula (67) can be prepared starting from the alcohol of formula (71) by first treating with a base, such as sodium hydride, in an inert solvent, such as tetrahydrofuran, followed by the addition of an acetylene compound of formula (72) containing a suitable leaving group. Similarly, the alcohols of formula (R^)2N-(C(R^)2) _r -OH can be reacted with compounds of formula (72) and the methods of reaction scheme 10 can be used to prepare the compounds of formula (70a) and (70b), respectively.

Using the methods described above, compounds of formula (69b) can be converted to compounds of formula (70c) of the invention [Scheme 10a].

Compounds of formula (76) and (77) of the invention can be prepared by the process of reaction scheme all., where R _b R ₃ , R 4 , R 1 , and n are as defined above, and the amines of formula HN(R) 2 are selected from the amines shown in list A'. Compounds of formula (73) and (74) are refluxed in a solvent, for example ethanol, to give intermediate (75), which is reacted with an amine in ethanol, under reflux, to give compound (76) of the invention as the reaction product. Intermediate (75) is treated with excess sodium alkoxide in an inert solvent or in a solvent from which the alkoxide is derived to give compound (77) of the invention.

In a similar manner, compound (74b) can be converted to compound (76b) or (77b) [Scheme 11a].

The compounds of the invention of formula (83) can be prepared by the process of Scheme 12, where R ₍ , G2, R4, R0, _R3 , R10, X, Z, n and r are as defined above. According to the above process, the mercaptocarboxylic acid of formula (78) is reacted with the compound of formula (79) to give the compound of formula (80). Alternatively, the compound of formula (80) can also be prepared from the mercaptan of formula _R3SH using the mercaptoacid of formula (78), triethylamine and 2,2'-dipyridyl disulfide. After the formation of the mixed anhydride of formula (81), condensation with 6-amino-3-cyanoquinoline of formula (82) gives the compound of the invention.

Using procedures similar to those described above, compound (82b) can be converted to compound (83b) [Scheme 12a].

The compounds of the invention of formula (86)-(88) can be prepared according to Scheme 13, wherein Rj, _G2 , Ri, R4, Rj, J', X, Z and n are as defined above, Q' is an alkyl group containing 1-6 hydrogen atoms, an alkoxy group containing 1-6 hydrogen atoms, a hydroxyl group or a hydrogen atom. Alkylation of the compound of formula (84) with a 6-amino-3-cyanoquinoline of formula (85) can be carried out by heating in an inert solvent, such as N,N-dimethylformamide, using a base such as potassium carbonate, to give the compound of formula (86) as the reaction product. When Q' is an alkoxy group, the ester group can be hydrolyzed to an acid using a base such as sodium hydroxide in methanol. In a similar manner, the compounds of the invention of formula (87) and (88) can be prepared using the intermediates of formula (89) and (90), respectively.

Using similar procedures, compound (85b) can be converted to compounds (86b) - (88b) [Scheme 13a].

The compounds of the invention of formula (93) can be prepared by the process of Scheme 14, where R _b G ₂ , R 1 , R 4 , R 5 , X , Z and n are as defined above. The reagent of formula (91) is reacted with 6-amino-3-cyanoquinoline of formula (92) using an excess of an organic base, such as triethylamine, in an inert solvent, such as tetrahydrofuran, to give the compound of formula (93) of the invention.

The compounds of the invention of formula (96) can be prepared by the process of Scheme 15, where R _b G _b R _b R4, R ₅ , R 6 , W, Het, X, Z, k and n are as defined above. The phenol of formula (94) and an alcohol of formula (95) are reacted in an inert solvent under Mitsunobu reaction conditions. Alternatively, the Mitsunobu reaction can be applied to the compound of formula (97) to give the compound of formula (98). This compound can be converted to the compound of formula (96) by the process of Scheme 4. The introduction of the heterocycle at the 6-position can be carried out using the appropriate compound, where G1 is a hydroxyl group and _G2 is located at the 7-position.

Certain functional group transformations can be used to prepare the compounds of the invention, which can be used to prepare both the various 3-cyanoquinoline intermediates and the final products of the invention. These modifications involve the R, _{G, G,} or R substituents in the 3-cyanoquinolines shown in the above reaction schemes. Some of the above functional group transformations are described below.

In the case where one or more of R _b G _b G ₂ and R 4 is a nitro group, it can be converted to a corresponding amino group by reduction using a reducing agent such as iron/acetic acid, or by catalytic hydrogenation. In the case where one or more of R _b G _b G ₂ and R 4 is an amino group, it can be converted to a corresponding C 2-12 dialkylamino group by alkylation with at least two equivalents of a C 1-6 alkyl halide, heating in an inert solvent, or by reductive alkylation using a C 1-6 aldehyde and a reducing agent such as sodium cyanoborohydride. In the case where one or more of the substituents R _b G _b G ₂ and R 4 are methoxy, this can be converted to a corresponding hydroxyl group by reaction with a demethylating agent, for example boron tribromide, in an inert solvent, or by heating with pyridinium chloride, in a solvent or without a solvent. In the case where one or more of the substituents R _b G _b G ₂ and R 4 are amino, it can be converted to a corresponding C 2-6 alkylsulfonamido, alkenylsulfonamido or alkynylsulfonamido group by reaction with an alkylsulfonyl chloride, alkenylsulfonyl chloride or alkynylsulfonyl chloride in an inert solvent using a basic catalyst, for example triethylamine or pyridine. In the case where one or more of the substituents R _b G _b G ₂ and R 4 is an amino group, it can be converted to the corresponding C 1-6 alkylamino group by alkylation with an equivalent of C 1-6 alkyl halide, heating in an inert solvent, or by reductive alkylation using a C 1-6 aldehyde and a reducing agent, such as sodium cyanoborohydride, in a protic solvent, such as water, alcohol, or a mixture thereof. In the case where one or more of the substituents R _b G _b G ₂ and R 4 is a hydroxyl group, it can be converted to the corresponding C 1-6 alkanoyloxy group by reaction with a suitable carboxylic acid chloride, anhydride, or mixed anhydride in an inert solvent using a pyridine or trialkylamine catalyst. If one or more of the substituents R _b G _b G ₂ and R 4 is a hydroxyl group, it can be converted to the corresponding C 1-6 alkenoyloxy group with the appropriate carboxylic acid chloride, anhydride or

- 19 by reaction with a mixed anhydride in an inert solvent, using a pyridine or trialkylamine catalyst. In the case where one or more of the substituents R _b Gi, G ₂ and R 4 is a hydroxyl group, it can be converted into the corresponding C 1-6 alkynyloxy group by reaction with a suitable carboxylic acid chloride, anhydride or mixed anhydride in an inert solvent, using a pyridine or trialkylamine catalyst. When one or more of the substituents R ₁₍ G], G ₂ and R 4 is a carboxyl group or a C 2-7 carboalkoxy group, it can be converted to the corresponding hydroxymethyl group by reduction with a suitable reducing agent, for example borane, lithium borohydride or lithium aluminum hydride in an inert solvent; the hydroxymethyl group, in turn, can be converted to the corresponding halomethyl group by reaction with a halogenating agent in an inert solvent, for example phosphorus tribromide to give a bromomethyl group, or phosphorus pentachloride to give a chloromethyl group. The hydroxymethyl group can be acylated with a suitable acid chloride, anhydride or mixed anhydride in an inert solvent using a pyridine or trialkylamine catalyst to give the corresponding compound of the invention containing a C 2-7 alkanoyloxymethyl group, a C 2-7 alkenoyloxymethyl group or a C 2-7 alkynyloxymethyl group. In that in the case where one or more of the substituents R _h G _b G ₂ and R ( is a halomethyl group, it can be converted into a C 2-7 alkoxymethyl group by replacing the halogen atom with sodium alkoxide, in an inert solvent. If one or more of the substituents R _b G _b G ₂ and R4 is a halomethyl group, it can be converted into an aminomethyl group, a C 2-7 N-alkylaminomethyl group, or a C 3-14 N,N-dialkylaminomethyl group by replacing the halogen atom with ammonia, a primary or secondary amine, in an inert solvent.

In addition to the processes described above, a number of patents describe processes that can be used to prepare the compounds of the invention. Although these processes are directed to the preparation of specific quinazolines, these processes can also be used for the corresponding substituted 3-cyanoquinolines. The chemical processes described in WO 96/33981 can also be used to prepare 3-cyanoquinoline intermediates used in the process of the invention in which R _h G _b G ₂ or R 4 is an alkoxyalkylamino group. The processes described in WO 96/339980 can be used to prepare 3-cyanoquinoline intermediates used in the process of the invention in which R _b G 1 , G ₂ or R 4 is an aminoalkylalkoxy group. The chemical processes described in WO 96/33979 can be used to prepare 3-cyanoquinoline intermediates useful in the process of the invention, wherein R _b G _b G ₂ or R 4 is an alkoxyalkylamino group. The chemical processes described in WO 96/33978 can be used to prepare 3-cyanoquinoline intermediates useful in the process of the invention, wherein R _b G _b G ₂ or R 4 is an aminoalkylamino group. The chemical processes described in WO 96/33977 can be used to prepare 3-cyanoquinoline intermediates useful in the process of the invention, wherein R _b G _b G ₂ or R 4 is an aminoalkylalkoxy group. Although the above patent publications describe compounds in which the indicated functional groups are introduced at the 6-position of the quinazoline ring, the same chemical procedure can be used to introduce the same groups at the positions occupied by the R _b G _b G ₂ and R 4 substituents in the compounds of the invention.

Some representatives of the compounds of the invention have been subjected to rigorous standard pharmacological tests.

- 20 were tested, which showed that the compounds of the invention show significant activity as protein tyrosine kinase inhibitors and antiproliferative agents. Based on the activity shown in standard pharmacological tests, the compounds of the invention can be used as antitumor agents. The tests and the results obtained therewith are described below.

Inhibition of epidermal growth factor receptor kinase (EGF-R) using recombinant enzyme

The test compounds of the invention were evaluated for their ability to inhibit the phosphorylation of a peptide substrate tyrosine residue catalyzed by epidermal growth factor receptor kinase. The sequence of the peptide substrate (RR-SRC) is arg-arg-leu-ile—glu-asp-ala-glu-tyr-ala-ala-arg-gly. The enzyme used in the assay is the histidine-tagged cytoplasmic domain of EGFR. A recombinant baculovirus (vHcEGFR52) was constructed containing the EGFR cDNA encoding amino acids 645-1186 following a Met-Ala-(His) ₆ leader sequence. Sf9 cells were infected at a density of 10 pfu/cell in 100 mm plates and the cells were harvested 48 hours after infection. A cytoplasmic extract was prepared using 1% Triton X-100 and loaded onto a Ni-NTA column. The column was washed with 20 mmol/l imidazole, and HcEGFR was eluted with 250 mmol/l imidazole (300 mmol/l NaCl in 50 mmol/l Na ₂ HPO ₄ buffer, pH 8.0). Fractions were pooled and dialyzed against a buffer containing 10 mmol/l HEPES (pH 7.0), 50 mmol/l NaCl, 10% glycerol, 1 pg/ml antipain and leupeptin, and 0.1 mmol/l Pefabloc SC. The protein fraction was frozen in dry ice/methanol and stored at -70 °C.

Test compounds were prepared as 10 mg/ml stock solutions in 100% dimethylsulfoxide (DMSO). Prior to the experiment, the stock solutions were diluted to 500 pmol/l with 100% DMSO and then serially diluted to the desired concentration with HEPES buffer (30 mmol/l HEPES, pH 7.4).

In the enzyme reaction, 10 μΙ of each inhibitor (at different concentrations) was added to each well of a 96-well plate. To this, 3 μΐ of enzyme [1:10 dilution in 10 mmol/l HEPES, pH 7.4) for a final concentration of 1:120] was added. The mixture was kept on ice for 10 min, then 5 μΐ of peptide (final concentration 80 umoVl), 10 μΐ of 4-fold buffer (Table A), 0.25 μΐ ³³ P-ATP and 12 μΐ H ₂ Ot were added. The reaction was allowed to proceed for 90 min at room temperature, then the entire volume was dropped onto pre-cut P81 filter papers. The filter paper discs were washed twice with 0.5% phosphoric acid, and radioactivity was measured using a liquid scintillation counter.

The table

Reagent Final concentration 100 Rxns 1M HEPES (pH 7.4) 12.5 mM 50 μΐ _{10mMNa3VO4 ​} 50 μΜ 20 μΐ 1 M _MnCl2 10 mM 40 μΐ 1 mM ATP 20 μΜ 80 μΐ 'p-ATP 2.5 μθί 25 μΐ

The inhibition data of some representatives of the compounds of the invention are given in Table 1. The

- The IC50 concentration of 21 test compounds is required to reduce the total amount of phosphorylated substrate by 50%. The percent inhibition by the test compound was determined at at least three different concentrations and the _IC50 value was determined from the dose-response curve. The percent inhibition was calculated using the following formula:

% inhibition = 100 - [CPM(times)/CPM(control)] x 100, where CPM(times) is given in units of counts/minute and is the number that represents the amount of radioactively labeled ATP (γ- ³³ P) incorporated into the RR-SRC peptide substrate by the enzyme in the presence of the test compound at room temperature over 90 minutes, as measured by liquid scintillation counting. CPM(control) is given in units of counts/minute and is the number that represents the amount of radioactively labeled ATP (γ- ³³ Ρ) incorporated into the RR-SRC peptide substrate by the enzyme in the absence of the test compound at room temperature over 90 minutes, as measured by liquid scintillation counting. CPM values were corrected for background counts in ATP without enzyme reaction. Where it was possible to determine the IC ₅₀ value, this is given in Table 1, otherwise the percentage inhibition of the test compound at a concentration of 0.5 μΜ is given in Table 1. Multiple values for the same compound mean that the compound was tested multiple times.

Table 1 (recombinant enzyme)

Epidermal growth factor receptor kinase inhibition

Compound _IC50 (μM) % inhibition at 0.5 μΜ concentration 173 0.5 172. 0.09 176. 0.01 96. >10 6 97. >10 7 101. >1 27 111. >1 10 148. >1 11 115. >0.5 49 167 >1 0 126. 0.45 168. >1 1 127. >1 25 144. >1 14 149. >1 9 156. >1 34 141. >1 5.5

- 22 continued from Table 1

Compound _IC50 (μM) % inhibition at 0.5 μΜ concentration 142. >1 24 130. >1 5 129. >1 6.7 131. >1 0 150. 0.0015 150. 0.004 151. >1 34 152. >1 24 132. >1 0 133. >1 0 134. >1 35 135. >1 0 153. >1 14 136. >1 33 137. 0.15

Epidermal cell kinase (ECK) inhibition

In this standard pharmacological assay, a biotinylated peptide substrate was first immobilized on neutravidin-coated microtiter plates. The microtiter wells containing the immobilized substrate were then loaded with the test compound, epithelial cell kinase (ECK), Mg ⁺⁺ , sodium vanadate (a protein tyrosine phosphatase inhibitor), and buffer to maintain pH 7.2. The phosphorylation reaction was then initiated by the addition of ATP. After incubation, the assay plates were washed with an appropriate buffer to leave the phosphorylated peptide behind, and the peptide was reacted with an anti-phosphotyrosine monoclonal antibody conjugated to horseradish peroxidase (HRP). The antibody-treated plates were washed again, and the HRP activity in each well was quantified as a measure of substrate phosphorylation. This non-radioactive form was used to identify inhibitors of ECK tyrosine kinase activity, where the IC ₅₀ value represents the concentration of the agent that inhibits substrate phosphorylation by 50%. The results obtained with some representatives of the compounds of the invention are summarized in Table 2. Multiple values given for individual compounds mean that they were tested multiple times.

Inhibition of kinase domain-containing receptor (KDR: catalytic domain of VEGF receptor)

In this standard pharmacological test, the KDR protein is mixed with a substrate peptide to be phosphorylated (a copolymer of glutamic acid and tyrosine, E:Y :: 4:1) and other cofactors, such as Mg ²⁺ and sodium vanadate (a protein tyrosine phosphatase inhibitor), in the presence or absence of an inhibitor compound, in a buffer suitable for maintaining pH 7.2. Phosphorylation is then initiated by the addition of ATP and a radioactive tracer (either ³² P- or ³³ P-labeled ATP). After incubation, the assay mixture

- The amount of radioactive phosphate bound to the acid-insoluble fraction of 23 is measured as a measure of substrate phosphorylation. This radioactive form was used to identify inhibitors of KDR tyrosine kinase activity, where IC ₅₀ is the concentration of the agent that inhibits substrate phosphorylation by 50%. The results obtained with representative compounds of the invention are presented in Table 2.

Multiple values given for a given compound mean that the compound was tested more than once.

Mitogen-activated protein kinase (MAPK) assay

To detect inhibitors of MAP (mitogen-activated protein) kinase, we used a two-component coupled standard pharmacological assay that measured the phosphorylation of serine/threonine residues in the corresponding sequence of a substrate in the presence and absence of a putative inhibitor. Recombinant human MEK 1 (MAPKK) was first used to activate recombinant human ERK2 (MAPK), and the activated MAPK (ERK) was incubated with substrate (MBP peptide or MYC peptide) in the presence of ATP, Mg ²⁺ and radioactively labeled ³³ P-ATP. The phosphorylated peptide was bound to P81 phosphocellulose filters (on filter paper or embedded in a microtiter plate), washed and the count was determined by scintillation counting.

The peptide substrates used in the above assay were the MBP peptide substrate (APRTPGGR) or the synthetic Myc substrate (KKFELLPTPPLSPSRR’5TFA). The recombinant enzymes used were prepared as GST fusion proteins of human ERK 2 and human MEK 1. The inhibitor samples were prepared as 10-fold stock solutions in 10% DMSO, and an appropriate aliquot was used for each test dose of 10 pg/ml, or 100, 10, 1 and 0.1 pmol/l final concentrations for the dose-response curve. The final DMSO concentration was no more than 1%.

The reaction was performed as follows in 50 mmol/l Tris kinase buffer (pH 7.4) in a reaction volume of 50 μΐ. The appropriate volume of kinase buffer and inhibitor sample were measured into a test tube. 2-5 pg of recombinant MAPK (Erk) was measured into each tube with appropriate dilutions of the enzyme. The inhibitor was incubated with MAPK (Erk) enzyme for 30 min at 0 °C. Erk was activated by adding 0.5 - 2.5 pg of recombinant Mek (MAPKK) or 0.05 - 0.1 units of fully activated Mek and incubated for 30 min at 30 °C. Then, substrate and gamma- ³³ P-ATP were added to a final concentration of 0.5 - 1 mmol/l MBPP or 250 - 500 pmol Myc; 0.2 - 0.5 pCi gamma- - ³³ P-ATP/tube; final concentration 50 pmol/l ATP. Samples were incubated at 30 °C for 30 min, then the reaction was stopped by adding 25 µl of ice-cold 10% TCA. Samples were cooled on ice for 30 min, then 20 µl of the sample was transferred to P 81 phosphocellulose filter paper or to an MTP suitable for embedded P 81 filters. The filter papers or MTP were washed twice with a large volume of 1% acetic acid, then twice with water. The filter papers or MTP were quickly air-dried, then scintillation fluid was added and the number of ³³ P isotope counts was counted in a suitable scintillation counter. Samples included a positive control (activated enzyme plus substrate); a control without enzyme; and a control without substrate; samples containing different concentrations of the putative inhibitor; and samples containing reference inhibitors (other active compounds or non-specific inhibitors such as staurosporine or K252 B).

Data were obtained in cpm. The replicates were averaged and corrected for background. The average cpm data were pooled and the percent inhibition of the test compound was calculated using the following equation:

(corrected cpm control - corrected cpm sample/control) x 100 = % inhibition

If the inhibitor was tested at multiple concentrations, IC ₅₀ values (the concentration causing 50% inhibition) were determined graphically from the dose-response curve based on the percentage inhibition, or by using an appropriate computer program. The results obtained with some representative compounds of the invention are summarized in Table 2, where multiple data for a given compound indicate that the compound was tested more than once.

Table 2

Inhibition of kinase domain-containing receptor (KDR), epithelial cell kinase (Eck) and mitogen-activated protein kinase (Mek-Erk)

Example number DRC μΜ Eck μΜ Mek-Erk μm 96. 8.0214 >53,476 2 <1 0.8 97. >2.5610 >2,561 55 98. 52.9872 >2,649 2.5 >2.6494 <1 0.4 <0.1 101. 5.3706 >53,706 0.8 <1 0.001 <0.001 102. 14.1123 >56,449 10 0.5 0.1 1 1 0.5 103. >53,419 1.5 0.5 <1 <0.001 105. 76.6479 >51,099 106. 23.0734 >46,147 1.1 0.2

- 25 Table 2 continued

Example number DRC μΜ ECKgM MEK-ERK μΜ 107. >71.8735 >47,916 108. >80.3428 >2,678 >2.6781 109. 23.9006 >47,801 >100 >100 110. >77.4393 0.155 >100 >25.8131 0.036 50 111. >77.0416 >51,361 >100 >100 112. >71.1744 >47,450 >100 113. 8.6630 115. 5.5648 >27,824 25 >2.7824 >2,782 119. 1.5504 22,148 2.2148 >2,215 125. 35 126. 8.3565 >27,855 >100 >2.7855 >2,786 >2.7855 >2,786 127. >67.3428 >44,895 >100 128. >79.9148 >53,277 >100 100 129. >25.8790 >25,879 >100 130. >26.5647 >26,565 >100 131. >26.4262 >26,426 >100 132. >28.0594 >28,059 90 133. >28.0594 >28,059 90 134. >28.0594 >28,059 >100 134. 26.8538 0.537 >100 136. >29.0377 0.871 1.8 >2.9038 3 137. 28.9553 >2,896 1.1 >2.8955 2 138. >86.8634 >28,954 >100 >2.8954 >2,895

- 26 Table 2 continued

Example number DRC μΜ Eck μΜ Mek-Erk μιη 139. 21.8093 >2,181 15 >2.1809 140. 21.7623 2,176 22 2.1762 15 141. 63.4242 >31,712 1.1 3 3 2 142. 94.8392 >31,613 30 143. 47.5682 >31,712 6 >3.1712 >3,171 6 2 144. >94.8392 >31,613 >100 94.8392 >100 146. 3 147. 148. >95.1363 >63,424 >100 149. >94.8392 >31,613 >100 >100 150. 0.5808 >29,038 <1 2 0.8 0.3 151. 28.9550 >28,955 20 152. >0.0000 >27,825 >100 153. >28.0594 >28,059 >100 154. 12.8256 0.770 0.5 >2.5651 <0.1 155. 4 156. >79.7071 >26,569 35 35 171. <1 0.001 0.0025 <0.001 166. >2.5391 0.762

- 27 continued from table 2

Example number DRC Eck μΜ Mek-Erk μm 167. 24.8472 0.025 8 2.4847 >2,485 168. 4.4995 >22,497 <1 3

Inhibition of cancer cell growth as determined by cell count

Human tumor cell lines were seeded in 96-well plates (250 μΐ/well, 1-6 x 10 ⁴ cells/ml) in RPMI 1640 medium containing 5% FBS (fetal fetal serum). 24 hours after seeding, test compounds were added at five log concentrations (0.01 - 100 mg/ml) or lower concentrations if more potent compounds were used. After 48 hours of exposure to the test compound, cells were fixed with trichloroacetic acid and stained with sulforhodamine-B. After washing with trichloroacetic acid, bound dye was solubilized with 10 mmol/l Tris base and the optical density was determined using a plate reader. Under the assay conditions, the optical density is proportional to the number of cells in the wells. IC ₅₀ values (concentrations that produce 50% inhibition of cell growth) were determined from the growth inhibition curves. The assay method is described in detail by Philip Skehan et al. [J. Natl. Cane. Inst. 82, 1107-1112 (1990)]. The data obtained are presented in Table 3. Information on the cell lines used in the above tests is available in: American Type Tissue Collection, Cell Lines and Hydridomas, 1994 Reference Guide, 8th edition.

Table 3

Inhibition of cancer cell growth as determined by cell count (IC ₅₀ pg/ml)

Example number MDA— MB- 435 A431 SK- -BR3 A2780 DDP SW620 3T3 3T3/c- -erbb2 99. 0.020 0.025 0.016 0.032 0.036 0.033 100. 0.067 0.369 0.429 0.270 0.249 0.325 101. 0.073 0.216 0.18 0.231 0.313 0.326 101. 0.365 0.123 0.0374 0.286 1.53 0.933 102. 0.490 1,309 0.780 0.491 3,054 2.18 103. 0.309 1,611 0.767 2,391 2,690 2,637 104. 0.021 0.049 0.034 0.044 0.107 0.207 105. 0.235 0.270 0.281 0.411 0.853 0.375 106. 2,045 1,961 >5 >5 >5 >5 107. >5 >5 >5 >5 >5 >5 108. 0.352 0.342 0.294 <0.005 0.525 0.0198 109. >5 >5 >5 2,922 >5 4,616

- 28 continuation of table 3

110. 0.0280 0.0244 0.0281 0.0181 0.0923 0.0311 111. 3,404 >5 >5 1,565 >5 3,301 112. 0.0033 0.257 0.336 0.146 0.392 0.251 115. 0.0359 0.0368 0.0220 0.0212 0.344 0.0267 126. 2,626 0.786 2,094 4,313 3,219 4,801 127. >5 >5 >5 >5 >5 >5

Inhibition of human colon cancer (SW620) growth in vivo

Some of the compounds of the invention (listed below) were evaluated for their ability to inhibit human colon cancer in a standard in vivo pharmacology test. Human colon cancer SW620 cells (American Type Culture Collection, Rockville, Maryland #CCL-227) were cultured in vitro as described above. Female BALB/c nu/nu mice (Charles River, Wilmington, MA) were used in the above in vivo standard pharmacology test. A dose of 7 x 10 ⁶ cells was injected subcutaneously into the mice. When the tumors reached a weight of 80 to 120 mg, the mice were randomly assigned to treatment groups (day 0). The mice were treated intraperitoneally (IP) once daily from day 0 to day 1-20 with 30, 10, 3, or 1 mg/kg of test compound per dose in 0.2% K.lucel. Control animals received vehicle only. Tumor weight was determined every 7 days (length x width ² /2) for 28 days, starting from day 0. Relative tumor growth (mean tumor weight on days 7, 14, 21, and 28 divided by the mean tumor weight on day 0) was determined for each treatment group. Statistical analysis of the logarithm of relative tumor growth (Student's t-test) compared the treated group with the control group. The p-value (p < 0.05) indicates a statistically significant decrease in relative tumor growth in the treated group compared with the vehicle-treated group.

The ability of the compound of Example 99 to inhibit the growth of human colon cancer in vivo was determined using the above standard pharmacological assay. The results are shown in Table 4.

Table 4

Inhibition of human colon cancer growth of SW620 (9791CD-186) in vivo in mice with the compound of Example 99

the b c d b c d b c d this Drug treatment mg/kg/dose Day 7 % T/C (p) Day 14 %T/C (Fri) Day 21 % T/C (p) S/T Klucel (placebo) 4.10 11.59 11.23 13/15

- 29 continued from table 4

Compound of Example 99 (30 IP) 1.81 44 <0.01 3.85 33 <0.01 4.44 40 0.02 4/5 Compound of Example 99 (10 IP) 3.69 90 0.37 7.88 68 0.18 9.75 87 0.36 5/5 Compound of Example 99 (3 IP) 3.80 93 0.62 12.53 108 0.78 16.47 147 0.54 5/5

a) compound was administered on days 1-20 IP mean tumor weight on days 7, 14, 21 b) relative tumor growth =-----mean tumor weight on day 0 relative tumor growth in the treated group

c) %T/C =-------------------- x 100 relative tumor growth in the placebo group

d) statistical analysis of the logarithm of relative tumor growth (Student's T-test);

the p value (p = 0.05) represents a statistically significant reduction in tumor growth in the treated group compared to the placebo group

e) S/T = number of survivors/number of treated patients on day 21 from day 0

As shown in Table 4, the compound of Example 99 inhibits tumor growth; for example, the compound, when administered i.p. at a dose of 30 mg/kg on days 1-20, reduced tumor growth by 56% on day 7, 67% on day 14, and 60% on day 21.

Based on the above results obtained with the compounds of the invention, it can be concluded that the compounds of the invention are antitumor agents that can be used to treat, inhibit or eliminate tumors. In particular, the compounds of the invention can be used to treat, inhibit or eliminate tumors that express EGFR, such as breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary and lung tumors. In addition, the compounds of the invention can be used to treat, inhibit or eliminate breast tumors that express the receptor protein produced by the erbB2 (Her2) oncogene. Based on the results obtained, the compounds of the invention

- 30 They can also be used to treat polycystic kidney disease.

The compounds of the invention can be formulated into pharmaceutical compositions, either neat or in combination with one or more pharmaceutically acceptable carriers. For example, by using solvents, diluents and the like, orally administrable compositions, such as tablets, capsules, dispersible powders, granules, suspensions containing about 0.05-5% of a suspending agent, syrups containing about 10-50% of sugar, and elixirs containing, for example, 20-50% of ethanol and the like, can be prepared, or sterile injectable solutions or suspensions containing about 0.05-5% of a suspending agent can be prepared with an isotonic medium for parenteral administration. Such pharmaceutical compositions can contain, for example, about 0.05-90% of the active ingredient in combination with the carrier, the amount of the active ingredient usually being about 5-60% by weight.

The effective dose of the active ingredient employed will depend on the particular compound employed, the route of administration and the severity of the condition being treated. However, generally satisfactory results are obtained when the compounds of the invention are administered in a daily dose of from about 0.5 to about 1000 mg/kg body weight, optionally in divided doses, 2-4 times daily, or in sustained release form. The total daily dose is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for topical administration contain from about 0.5 to 1000 mg of the active ingredient in admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage range can be adjusted to obtain the optimum therapeutic response. For example, several divided doses can be administered daily, or the dose can be gradually reduced as the therapeutic situation dictates.

The compounds of the invention can be administered orally, as well as intravenously, intramuscularly or subcutaneously. As solid carriers, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin can be used, while as liquid carriers, sterile water, polyethylene glycols, non-ionic surfactants and edible oils, such as corn, peanut and sesame oil, can be used, depending on the nature of the active ingredient and the desired dosage form. Adjuvants commonly used in the preparation of pharmaceutical preparations can also be used with advantage, for example, flavoring agents, coloring agents, preservatives and antioxidants, such as vitamin E, ascorbic acid, BHT and BHA.

Preferred pharmaceutical compositions for preparation and administration are solid compositions, especially tablets and solid-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

In some cases, it may be desirable to administer the compounds directly to the respiratory tract in the form of an aerosol.

The compounds of the invention may also be administered parenterally or intraperitoneally. Solutions and suspensions of the active compounds in the form of the free base or a pharmaceutically acceptable salt may conveniently be prepared in water mixed with a surfactant, for example hydroxypropylcellulose. Dispersions may also be prepared with glycerin, liquid polyethylene glycols and mixtures thereof with oils. Under ordinary conditions of storage and use, these preparations also contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for reconstitution into sterile injectable solutions prior to administration.

- 31 or dispersions. In all cases, the form must be sterile and sufficiently fluid to permit easy syringability. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms, e.g. bacteria and fungi. The carrier may be a solvent or dispersion medium, for example water, ethanol, polyols (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

For the treatment of tumors, the compounds of the invention may be used in combination with other antitumor agents or in combination with radiation therapy. These other agents or radiation treatments may be administered at the same time as the compounds of the invention or at different times. These combination therapies may also be synergistic and may result in enhanced efficacy. For example, the compounds of the invention may be used in combination with mitotic inhibitors, such as taxol or vinblastine, alkylating agents, such as cisplatin or cyclophosphamide, antimetabolites, such as 5-fluorouracil or hydroxyurea, DNA intercalating agents, such as adriamycin or bleomycin, topoisomerase inhibitors, such as etoposide or camptothecin, angiogenesis inhibitors, such as angiostatin, and antiestrogens, such as tamoxifen.

The preparation of the compounds of the invention is illustrated in more detail, without being intended to be limiting, by the following examples.

Example 1 1,4-Dihydro-7-methoxy-4-oxoquinoline-3-carbonitrile

A mixture of 30.2 g (245.2 mmol) of 3-methoxyaniline and 41.5 g (245.2 mmol) of ethyl-(ethoxymethylene)cyanoacetate was heated at 140 °C for 30 min without solvent. 1200 mL of Dowtherm was added to the resulting oil. The solution was refluxed under nitrogen with stirring for 22 h. The mixture was cooled to room temperature, the solid was collected, and washed with hexanes. The solid was recrystallized from acetic acid to give 17 g of 1,4-dihydro-7-methoxy-4-oxoquinoline-3-carbonitrile; mass spectrum (electrospray, m/e): M+H 200.9.

Example 2 1,4-Dihydro-7-methoxy-6-nitro-4-oxoquinoline-3-carbonitrile To a suspension of 1,4-dihydro-7-methoxy-4-oxoquinoline-3-carbonitrile in 160 ml of trifluoroacetic anhydride was added 6 g (74.9 mmol) of ammonium nitrate over 3 hours. The mixture was stirred for a further 2 hours. The excess anhydride was removed in vacuo at 45°C. The residue was stirred with 500 ml of water. The solid was collected and washed with water. The solid was dissolved in 100 ml of boiling acetic acid and the solution was clarified with charcoal. The mixture was filtered and concentrated to a volume of 300 ml. Cooling gave a solid which was collected to give 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxoquinoline-3-carbonitrile as a brown solid; mass spectrum (electrospray, m/e): M+H 246.

Example 3

4-Chloro-7-methoxy-6-nitroquinoline-3-carbonitrile

A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxoquinoline-3-carbonitrile and 9 g (43.2 mmol) of phosphorus pentachloride was heated at 165 °C for 2 h. The mixture was diluted with hexanes and the solid was collected. The solid was dissolved in 700 mL of ethyl acetate and washed with cold, dilute sodium hydroxide.

- Wash with 32 hydroxide solution. The solution is dried over magnesium sulfate and filtered through a pad of silica gel. 5.2 g

4-Chloro-7-methoxy-6-nitroquinoline-3-carbonitrile is obtained as a yellowish-brown solid.

Example 4

2-Cyano-3-(4-nitrophenylamino)acrylic acid ethyl ester

A mixture of 60.0 g (0.435 mol) of 4-nitroaniline and 73.5 g (0.435 mol) of ethyl-(ethoxymethylene)cyanoacetate was mechanically stirred in a flask. The mixture was heated at 100 °C for 0.5 h, after which it melted and solidified again. 114 g of the crude product was recrystallized from dimethylformamide to give 44.2 g of yellow crystals, melting at 227-228.5 °C.

Example 5

6-Nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A thick suspension of 25.0 g (95.8 mmol) of 2-cyano-3-(4-nitrophenylamino)acrylic acid ethyl ester in 1.0 L of Dowtherm A was heated at 260 °C under nitrogen for 12.5 h. The cooled reaction mixture was poured into 1.5 L of hexane. The product was collected, washed with hexane and hot ethanol, and dried in vacuo to give 18.7 g of a brown solid. Recrystallization from dimethylformamide/ethanol gave an analytical sample; mass spectrum (electrospray, m/e): M+H 216.

Example 6

4-Chloro-6-nitroquinoline-3-carbonitrile

A mixture of 31.3 g (0.147 mol) of 6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 160 ml of phosphorus oxychloride was heated under reflux for 5.5 hours. The phosphorus oxychloride was removed in vacuo and the residue was poured onto ice and neutralized with sodium bicarbonate. The product was collected, washed with water and dried in vacuo at 50 °C. 33.5 g of a tan solid were obtained; mass spectrum (electrospray, m/e): M+H 234.

Example 7

2-Cyano-3-(2-methyl-4-nitrophenyl)acrylic acid ethyl ester

A mixture of 38.0 g (250 mmol) of 2-methyl-4-nitroaniline, 50.8 g (300 mmol) of ethyl-(ethoxymethylene)cyanoacetate and 200 ml of toluene was refluxed for 24 hours, cooled, diluted with 1:1 diethyl ether/hexane and filtered. The resulting white solid was washed with hexane/diethyl ether and dried. 63.9 g of product was obtained, melting point 180-210 °C.

Example 8

A stirred mixture of 8-methyl-6-nitro-1,4-dihydroquinoline-3-carbonitrile g (230 mmol) of 2-cyano-3-(2-methyl-4-nitrophenyl)acrylic acid ethyl ester and 1.5 L of Dowtherm A was heated at 260 °C for 12 hours, cooled, diluted with hexane, and filtered. The resulting gray solid was washed with hexane and dried. 51.5 g of product were obtained, melting point 295-305 °C.

Example 9

4-Chloro-8-methyl-6-nitroquinoline-3-carbonitrile A stirred mixture of 8-methyl-6-nitro-1,4-dihydroquinoline-3-carbonitrile (g, 200 mmol) and phosphorus oxychloride (200 mL) was refluxed for 4 hours. The phosphorus oxychloride was removed in vacuo and the residue was stirred with methylene chloride at 0°C and treated with a suspension of ice and sodium carbonate. The organic phase was separated and washed with water. The solution was dried and concentrated to a volume of 700 mL. The product was precipitated with hexane and cooled to 0°C. The white solid was filtered and dried.

- 33 41.6 g of product are obtained, melting point 210-212 °C.

Example 10

7-Ethoxy-4-hydroxyquinoline-3-carbonitrile A mixture of 3-ethoxyaniline (g, 73 mmol) and ethyl (ethoxymethylene)cyanoacetate (12.3 g, 73 mmol) in 90 mL Dowtherm was heated at 140 °C for 7 h. 250 mL Dowtherm was added. The solution was refluxed under nitrogen with stirring for 12 h, while periodically distilling off the eliminated ethanol. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude solid was treated with hot ethanol and filtered. 9.86 g of a brown solid were obtained; mass spectrum (electrospray, m/e): M+H 214.7.

Example 11

7-Ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile g (23 mmol) To a suspension of 7-ethoxy-4-hydroxyquinoline-3-carbonitrile in 75 ml of trifluoroacetic anhydride was added 5.5 g (69 mmol) of ammonium nitrate over 6 hours at room temperature. The excess anhydride was removed in vacuo at 45 °C. The residue was stirred with 300 ml of water. The solid was collected and treated with hot ethanol. 3.68 g of a tan solid was obtained; mass spectrum (electrospray, m/e): M+H 259.8.

Example 12

4-Chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile

A mixture of 3.45 g (13 mmol) of 7-ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorus pentachloride and 10 ml of phosphorus oxychloride was refluxed for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold, dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a plug of silica gel. The solvent was removed to give 2.1 g of a beige solid; mass spectrum (electrospray, m/e): M+H 277.7.

Example 13

8-Methoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile

A mixture of 12.6 g (75 mmol) of 2-methoxy-4-nitroaniline and 12.7 g (75 mmol) of ethyl-(ethoxymethylene)cyanoacetate in 100 ml of Dowtherm was heated at 120 °C overnight and at 180 °C for 20 hours. 300 ml of Dowtherm was added to the mixture. The solution was refluxed under nitrogen with stirring for 12 hours, the ethanol eliminated being distilled off at intervals. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude solid was treated with hot ethanol and filtered. 12 g of a brown solid was obtained; mass spectrum (electrospray, m/e): M+H 245.8.

Example 14

4-Chloro-8-methoxy-6-nitroquinoline-3-carbonitrile A mixture of 8-methoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile (g, 16 mmol), phosphorus pentachloride (6.66 g, 32 mmol) and phosphorus oxychloride (15 mL) was refluxed for 2.5 h. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in ethyl acetate (500 mL) and washed with cold, dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a plug of silica gel. The solvent was removed to give 2.05 g of a tan solid; mass

- 34 spectrum (electrospray, m/e): M+H 263.7.

Example 15

4-Chlorobut-2-ynoic acid 1 ml (26.84 mmol) of propargyl chloride was dissolved in 40 ml of tetrahydrofuran under nitrogen and cooled to -78 °C. After addition of 5.4 ml (13.42 mmol) of 2.5 mol/l n-butyllithium solution in n-hexane, the mixture was stirred for 15 min and dry carbon dioxide gas was bubbled through at -78 °C for 2 h. The reaction mixture was filtered and neutralized with 3.5 ml of 10% sulfuric acid. The solution was evaporated and the residue was extracted with ether. The ethereal solution was washed with saturated brine and dried over sodium sulfate. Evaporation of the dry ethereal solution gave 0.957 g (60%) of the product as an oil; ESMS m/z: 116.6 (MH ⁺ ).

Example 16

4-Dimethylamino-but-2-ynoic acid ml A 2.5 mol/l solution of n-butyllithium in hexane was slowly added to 20 g (240 mmol) of 1-dimethylamino-2-propyne in 100 ml of tetrahydrofuran under nitrogen. The mixture was stirred at -78 °C for 1 h and then dry carbon dioxide was bubbled through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous phase was evaporated in vacuo to give the crude acid. The dry acid was dissolved in methanol and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo. 15.6 g of 4-dimethylamino-but-2-ynoic acid was obtained; mass spectrum (m/e): M-H 126.

Example 17

Bis(2-methoxyethyl)prop-2-ynylamine

17.8 g (150 mmol) of propargyl bromide were added dropwise to a mixture of 20 g (150 mmol) of bis(2-methoxyethyl)amine and 49 g (150 mmol) of cesium carbonate in 350 ml of acetone. The mixture was stirred overnight at room temperature under nitrogen. The inorganic salts were filtered off and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was evaporated to give 20 g of bis(2-methoxyethyl)prop-2-ynylamine; mass spectrum (m/e): M+H 172.

Example 18

4-[Bis(2-methoxyethyl)amino]but-2-ynoic acid mL A 2.5 M solution of n-butyllithium in hexanes was slowly added to 18 mg (105 mmol) of bis(2-methoxyethyl)prop-2-ynylamine in 80 mL of tetrahydrofuran under nitrogen. The mixture was stirred at 78 °C for 1 h and then carbon dioxide was bubbled through to dryness overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous phase was evaporated in vacuo to give the crude acid. The dry acid was dissolved in methanol and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo. 18 g of 4-[bis-(2-methoxyethyl)amino]but-2-ynoic acid was obtained; mass spectrum (m/e): M-H 214.

Example 19 1-Methyl-4-(prop-2-ynyl)piperazine

23.8 g (200 mmol) of propargyl bromide were added dropwise to a mixture of 20 g (200 mmol) of 1-methylpiperazine and 65 g (200 mmol) of cesium carbonate in 350 ml of acetone. The mixture was stirred under nitrogen at room temperature overnight. The inorganic salts were filtered off and the solvent was removed.

- 35 The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was evaporated to give 7.5 g of 1-methyl-4-(prop-2-ynyl)piperazine; mass spectrum (electrospray, m/e): M+H 139.

Example 20

4-(4-Methylpiperazin-1-yl)but-2-enoic acid

A 2.5 M solution of n-butyllithium in hexanes (17.2 mL) was slowly added to a mixture of 6.0 g (43.5 mmol) of 1-methyl-4-(prop-2-ynyl)piperazine in 40 mL of tetrahydrofuran under nitrogen. The mixture was stirred at -78 °C for 1 h and then dry carbon dioxide was bubbled through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous phase was evaporated in vacuo to give the crude acid. The dry acid was dissolved in methanol and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo to give 7 g of 4-(4-methylpiperazin-1-yl)but-2-acid; mass spectrum (m/e): M-H 181.

Example 21 (2-Methoxyethyl)methyl-(prop-2-ynyl)amine

26.8 g (225 mmol) of propargyl bromide were added dropwise to a mixture of 20 g (225 mmol) of N-(2-methoxyethyl)methylamine and 73 g (225 mmol) of cesium carbonate in 350 ml of acetone. The mixture was stirred overnight at room temperature under nitrogen. The inorganic salts were then filtered off and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated. 14 g of (2-methoxyethyl)methyl-(prop-2-ynyl)amine were obtained; mass spectrum (m/e): M+H 127.

Example 22

4-[(2-Methoxyethyl)methylamino]but-2-enoic acid

A 2.5 mol/l solution of n-butyllithium in hexane (37.8 ml) was slowly added to a mixture of 12.0 g (94.5 mmol) of (2-methoxyethyl)methyl-(prop-2-ynyl)amine in 90 ml of tetrahydrofuran under nitrogen. The mixture was stirred at -78 °C for 1 h and then dry carbon dioxide gas was bubbled through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous phase was evaporated in vacuo to give the crude acid. The dry acid was dissolved in methanol and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo to give 15 g of 4-[(2-methoxyethyl)methylamino]but-2-acid; mass spectrum (m/e): M-H 170.

Example 23

Allylmethyl-(prop-2-ynyl)amine

33.4 g (281 mmol) of propargyl bromide were added dropwise to a mixture of 20 g (281 mmol) of isopropylmethylamine and 90 g (281 mmol) of cesium carbonate in 350 ml of acetone. The mixture was stirred at room temperature under nitrogen overnight. The inorganic salts were then filtered off and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was evaporated to give 4.6 g of allylmethyl-(prop-2-ynyl)amine; mass spectrum (electrospray, m/e): M+H 110.

Example 24

4-(Allylmethylamino)but-2-enoic acid

16.4 ml of a 2.5 mol/l solution of n-butyllithium in n-hexane is slowly added to 4.5 g

- 36 (46 mmol) of allylmethyl-(prop-2-ynyl)amine in 50 ml of tetrahydrofuran under nitrogen. The mixture was stirred at -78 °C for 1 h and then dry carbon dioxide was bubbled through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous phase was evaporated in vacuo to give the crude acid. The dry acid was dissolved in methanol and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo. 4.1 g of 4-(allylmethylamino)but-2-acid was obtained; mass spectrum (m/e): M-H 152.

Example 25

4-Methoxymethoxybut-2-ynoic acid

To a suspension of 8.2 g of 60% sodium hydride in mineral oil in 271 ml of tetrahydrofuran at 0 °C, while stirring, under nitrogen, 10 g of propargyl alcohol were added dropwise over 15 minutes. The mixture was stirred for a further 30 minutes. To the stirred mixture at 0 °C, 15.8 g of chloromethyl methyl ether were added. Stirring was continued at room temperature overnight. The mixture was filtered and the solvent was removed from the filtrate. The residue was distilled at 35-38 °C (4 mm) to give 8.5 g of liquid. The distillate was dissolved in 200 ml of ether. The solution was stirred under nitrogen and cooled to -78°C, and 34.1 mL of a 2.5 M solution of n-butyllithium in hexanes was added over 15 min. Stirring was continued for an additional 1.5 h. Dry carbon dioxide gas was passed over the surface of the stirred reaction mixture as it was warmed from -78°C to room temperature. The mixture was stirred under a carbon dioxide atmosphere overnight. The reaction mixture was poured into a mixture of 14 mL of hydrochloric acid and 24 mL of water. The organic phase was separated and dried over magnesium sulfate. The solvent was removed and the residue was heated at 100°C at 4 mm for 1 h. 10.4 g of 4-methoxymethoxybut-2-acid was obtained.

Example 26

4-Bromocrotonic acid

According to the method of Braun [Giza Braun, J. Am. Chem. Soc. 52, 3167 (1930)] 11.76 ml (17.9 g, 0.1 mol) of methyl 4-bromocrotonate in 32 ml of ethanol and 93 ml of water are cooled to -11 °C. The reaction mixture is stirred vigorously and 15.77 g (0.05 mol) of finely powdered barium hydroxide are added in portions over about 1 hour. Cooling and vigorous stirring are continued for about 16 hours. The reaction mixture is then extracted with 100 ml of ether. The aqueous phase is treated with 2.67 ml (4.91 g, 0.05 mol) of concentrated sulfuric acid. The resulting mixture is extracted three times with 100 ml of ether. The combined ether extracts were washed with 50 ml of brine and dried over sodium sulfate. The solution was concentrated in vacuo. The resulting oil was taken up in about 400 ml of hot heptane, leaving a resin. The heptane solution was separated and evaporated to about 50 ml. After cooling, 3.46 g of product were obtained.

Example 27

4-(2-Methoxyethoxy)but-2-ynoic acid

To a suspension of 6.04 g (151 mmol) of 60% sodium hydride in 200 ml of tetrahydrofuran at 0 °C was added 10 g (131.4 mmol) of 2-methoxyethanol dropwise over 15 min. After 1 h, 19.54 g (131.4 mmol) of 80% propargyl bromide was added dropwise. The mixture was stirred at room temperature for 17 h, then filtered and the solvent was removed. The residue was distilled (48-51 °C, 4 mm) to give 11.4 g of a colorless liquid. This liquid was dissolved in 250 ml of ether and cooled to -78 °C with stirring under nitrogen. To the solution was added dropwise, over 15 minutes, 39.95 ml (99.9 mmol) of a 2.5 mol/l solution of n-butyllithium in hexane. After 1.5 hours, dry carbon dioxide was bubbled into the mixture while the mixture slowly warmed to room temperature. The mixture was kept under a carbon dioxide atmosphere overnight. 100 ml of 3N hydrochloric acid and solid sodium chloride were added to the mixture. The organic phase was separated and dried over magnesium sulfate. The solvent was removed and the residue was kept in vacuo. 11.4 g of the title compound were obtained; mass spectrum (electrospray, m/e, negative mode): M-H 156.8.

Example 28

4-(Methoxymethoxy)but-2-ynoic acid

To a suspension of 8.2 g (205 mmol) of 60% sodium hydride in 271 ml of tetrahydrofuran at 0 °C, 10.0 g (178.4 mmol) of propargyl alcohol were added dropwise with stirring. After 30 min, 15.8 g (196.2 mmol) of chloromethyl methyl ether were added to the mixture. The reaction mixture was stirred at room temperature over a weekend, then filtered and the solvent was removed. The residue was distilled (35-38 °C, 4 mm) to give 8.54 g of a colorless liquid. This was dissolved in 200 ml of ether and cooled to -78 °C with stirring under nitrogen. To the resulting solution, 34.1 ml (85.3 mmol) of a 2.5 mol solution of n-butyllithium in hexane was added dropwise over 15 min. After 1.5 hours, dry carbon dioxide was bubbled into the mixture while it slowly warmed to room temperature. The mixture was kept under a carbon dioxide atmosphere overnight. To the mixture was added 14 ml of hydrochloric acid in 24 ml of water. The organic phase was separated and dried over magnesium sulfate. The solvent was removed and the residue was kept under vacuum. 10.4 g of the title compound was obtained as a liquid.

Example 29

4-[(2S)-2-Methoxymethylpyrrolidin-1-yl]butyric acid

35.9 mmol of n-butyllithium were added as a solution in hexane at -78 °C under nitrogen over 10 min to a solution of 5.49 g (35.9 mmol) of (2S)-2-methoxymethyl-1-(prop-2-ynyl)pyrrolidine in 100 ml of tetrahydrofuran. The reaction mixture was stirred cold for 1 h, then carbon dioxide was bubbled into the solution as it slowly warmed to 25 °C. The reaction mixture was stirred overnight, then 100 ml of water was added and extracted with ethyl acetate, the extracts were discarded. The reaction mixture was adjusted to pH 7 with 20% sulfuric acid and the solvent was removed. The residue was suspended in methanol and filtered. The filtrate was evaporated and dried in vacuo. 7.06 g of 4-[(2S)-2-methoxymethylpyrrolidin-1-yl]butyric acid are obtained as a brown foam; mass spectrum (electrospray, m/e): M+H 198.0.

Example 30 (2S)-2-Methoxymethyl-1-(prop-2-ynyl)pyrrolidine

A mixture of 4.82 g (41.9 mmol) of (S)-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 ml of acetone was stirred at 25 °C overnight. The reaction mixture was filtered and the solvent was removed from the filtrate. The residue was diluted with a little water and saturated sodium bicarbonate solution and extracted with ether. The extract was treated with Darco, dried and evaporated. 5.93 g of (2S)-2-methoxymethyl-1-(prop-2-ynyl)pyrrolidine was obtained as a yellow-orange oil; mass spectrum (electrospray, m/e): M+H 153.8.

Example 31

4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic acid

55.8 mmol of n-butyllithium in hexane was added dropwise to a solution of 10.1 g (55.8 mmol) of 3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-yne in 185 ml of tetrahydrofuran at -78 °C under nitrogen. The

- 38 The reaction mixture was stirred at -78 °C for 1 hour, then carbon dioxide was bubbled into the solution as it slowly warmed to 25 °C. The reaction mixture was stirred overnight, then diluted with 150 ml of water, extracted with ethyl acetate, and the extracts were discarded. The solution was adjusted to pH 6 with 2M sulfuric acid and evaporated. The residue was suspended in methanol and filtered. The filtrate was evaporated and dried in vacuo. 4.5 g of 4-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-acid were obtained as a brown, amorphous solid; mass spectrum (electrospray, m/e): M+H 225.8.

Example 32

3-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)but-2-yne

A mixture of 10.0 g (69.9 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane, 22.8 g (69.9 mmol) of cesium carbonate and 8.32 g (69.9 mmol) of propargyl bromide in 165 ml of acetone was stirred at 25 °C overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. A little water and saturated sodium bicarbonate solution were added to the residue and the mixture was extracted with ether. The ether extract was treated with Darco, dried and evaporated. 10.8 g of 3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)but-2-yne were obtained as a yellowish orange oil; mass spectrum (electrospray, m/e): M+H 181.8.

Example 33

Methyl 4-benzyloxy-2-(dimethylaminomethyleneamino)-5-methoxybenzoate

A stirred mixture of 70.0 g (244 mmol) of methyl 2-amino-4-benzyloxy-5-methoxybenzoate [Phytochemistry 15. 1095 (1976)] and 52 ml of dimethylformamide dimethyl acetal was heated at 100 °C for 1.5 hours, cooled, and evaporated directly under high vacuum. 81.3 g of an off-white solid were obtained; melting point 134-140 °C; NMR (CDCl ₃ ) d 3.01 (s, Me ₂ N).

Example 34

7-Benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile

To a stirred solution of 26.9 mL of 2.5 M n-butyllithium in hexane in 50 mL of tetrahydrofuran was added 3.51 mL of acetonitrile in 20 mL of THF at -78 °C over 10 min. The reaction mixture was stirred at -78 °C for 30 min and then treated with 10 g of methyl 4-benzyloxy-2-(dimethylaminomethyleneamino)-5-methoxybenzoate in 20 mL of tetrahydrofuran over 5 min. The reaction mixture was stirred at -78 °C for 15 min and then warmed to 0 °C for an additional 30 min. The mixture was then treated with 5 mL of acetic acid, warmed to 25 °C and stirred for 30 min. The mixture was evaporated to dryness and diluted with aqueous sodium bicarbonate solution. The resulting off-white solid was filtered and washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile was obtained as an off-white solid, which decomposed at >255 °C; mass spectrum (electrospray, m/e): M+H 307.

Example 35

7-Benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile g To a stirred suspension of 7-benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile in 10 ml of methylene chloride was added 5 ml of oxalyl chloride (2 M in methylene chloride) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 20 minutes and aqueous sodium bicarbonate solution was added slowly until gas evolution ceased. The phases were separated, the organic phase was concentrated to a small volume and passed through a magnesol pad. Elution was carried out with 50 ml of methylene chloride and the product was evaporated. 0.6 g of 7-benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile was obtained.

- 39 as a pale yellow solid; melting point 282-284 °C; mass spectrum (electrospray, m/e):

M+H 325.

Example 36

4-Chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile

A stirred suspension of 0.54 g of 7-benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile in 10 ml of methylene chloride was cooled to 0 °C. To the suspension was added 10 ml of boron trichloride (1 M in methylene chloride). The mixture darkened as it warmed to room temperature and a solid precipitated. The mixture was stirred for 1 hour, after which no further reaction was observed. The solid (unreacted starting material) was filtered off, the remaining solution was cooled to 0 °C and the reaction was quenched by dropwise addition of methanol. The solvent was evaporated and the residue was dissolved in methylene chloride/methanol/acetone. The residue was purified by chromatography on silica gel, eluting with a 1-5% methanol/methylene chloride gradient. 0.075 g of 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile was obtained as a yellow solid which decomposed at >245°C; mass spectrum (electrospray, m/e): M+H 235.2.

Example 37

4-Chloro-6-methoxy-7-[3-(pyridin-4-yl)propoxy]quinoline-3-carbonitrile

A mixture of 0.070 g of 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile, 0.062 g of 3-(4-pyridyl)-1-propanol and 0.235 g of triphenylphosphine in 3 ml of methylene chloride was cooled to 0 °C under nitrogen. 0.14 ml of diethyl azodicarboxylate was added dropwise to the mixture. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated to 1 ml and purified by chromatography on silica gel, eluting with a 1 -> 2% methanol/methylene chloride solvent gradient. 0.090 g of 4-chloro-6methoxy-7-[3-(pyridin-4-yl)propoxy]quinoline-3-carbonitrile was obtained as an off-white resin.

Example 38

4-Chloro-7-methoxyquinoline-3-carbonitrile

A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxoquinoline-3-carbonitrile and 8.3 g (40 mmol) of phosphorus pentachloride was heated at 165 °C for 3 h. The mixture was diluted with hexanes and the solid was collected. The solid was mixed with brine and dilute sodium hydroxide solution and extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. 3.7 g of 4-chloro-7-methoxyquinoline-3-carbonitrile was obtained as a white solid; mass spectrum (electrospray, m/e): M+H 218.9.

Example 39

3-Carbethoxy-4-hydroxy-6,7-dimethoxyquinoline

A mixture of 30.6 g of 4-aminoveratrol and 43.2 g of diethyl ethoxymethylene malonate was heated at 100 °C for 2 hours and at 165 °C for 0.75 hours. The resulting intermediate was dissolved in 600 ml of diphenyl ether and the resulting solution was refluxed for 2 hours, cooled and diluted with hexane. The resulting solid was filtered, washed with hexane and then with ether and dried. The title compound was obtained as a brown solid, melting point 275-285 °C.

Example 40

3-Carbethoxy-4-chloro-6,7-dimethoxyquinoline

A mixture of 28.8 g of 3-carbethoxy-4-hydroxy-6,7-dimethoxyquinoline and 16.6 ml of phosphorus oxychloride was stirred at 110 °C for 30 min, cooled to 0 °C, and treated with a mixture of ice and ammonium hydroxide. The resulting

- 40 grey solids were filtered, washed with water and ether and dried. The title compound had a melting point of 147-150°C.

Example 41

Ethyl 2-cyano-3-(3,4-dimethoxyphenylamino)acrylate

7.6 A mixture of 6 g of 4-aminoveratrol, 8.49 g of ethyl ethoxymethylene cyanoacetate and 20 ml of toluene was heated at 100 °C for 90 minutes. The toluene was evaporated to give a solid, melting point 150-155 °C.

Example 42 1,4-Dihydro-6,7-dimethoxy-4-oxoquinoline-3-carbonitrile A mixture of 1 g ethyl 2-cyano-3-(3,4-dimethoxyphenylamino)acrylate and 1.2 L Dowtherm® A was refluxed for 10 hours and diluted with hexane. The resulting solid was filtered, washed with hexane, then with dichloromethane, and dried. The title compound had a melting point of 330-350 °C (decomposition).

Example 43

A stirred mixture of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (g), 1,4-dihydro-6,7-dimethoxy-4-oxoquinoline-3-carbonitrile (87 ml) and phosphorus oxychloride (87 ml) was refluxed for 2 hours, cooled and the volatiles were removed by evaporation. The residue was stirred at 0 °C with dichloromethane/water while solid sodium carbonate was added to adjust the aqueous phase to pH 8. The organic phase was separated, washed with water, dried and concentrated. Recrystallization from dichloromethane gave a solid, melting point 220-223 °C.

Example 44

Methyl 2-(dimethylaminomethyleneamino)benzoate

To a stirred solution of 7.56 g of methyl anthranilate in 50 ml of dimethylformamide at 0 °C was added 5.6 ml of phosphorus oxychloride over 15 min. The mixture was heated at 55 °C for 45 min, cooled to 0 °C, and diluted with dichloromethane. The mixture was basified to pH 9 with cold 1 M sodium hydroxide at 0 °C. The dichloromethane layer was separated, washed with water, dried, and concentrated to an oil.

Example 45 1,4-Dihydro-4-oxoquinoline-3-carbonitrile

A stirred mixture of 1.03 g of methyl 2-(dimethylaminomethyleneamino)benzoate, 0.54 g of sodium methoxide, 1.04 ml of acetonitrile and 10 ml of toluene was heated under reflux for 18 hours. The mixture was cooled, treated with water and the pH was adjusted to 3 with dilute hydrochloric acid. The resulting solid was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethanol to give a solid, melting point 290-300 °C.

46, example

4-(3-Chloropropoxy)-5-methoxybenzoic acid methyl ester

A mixture of 102.4 g (411.7 mmol) of (3-chloropropyl)-p-toluenesulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxybenzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate and 1.66 g (4.1 mmol) of methyl tricaprylammonium chloride in 900 ml of acetone was heated under reflux with vigorous stirring for 18 hours. The mixture was filtered and the solvent was removed. 106 g of the title compound were obtained as a chloro

- 41 after recrystallization from chloroform/hexane.

Example 47

4-(2-Chloroethoxy)-5-methoxybenzoic acid methyl ester

By proceeding as described in Example 46, 91.6 g of the title compound were prepared from 77 g of 4-hydroxy-5-methoxybenzoic acid methyl ester, 99.2 g of (2-chloroethyl)-p-toluenesulfonate, 77.7 g of potassium carbonate and 1.7 g (4.1 mmol) of methyltricapryl ammonium chloride; mass spectrum (electrospray, m/e): M+H 245.0.

Example 48

4-(3-Chloropropoxy)-5-methoxy-2-nitrobenzoic acid methyl ester

To a solution of 100 g (386.5 mmol) of 4-(3-chloropropoxy)-5-methoxybenzoic acid methyl ester in 300 ml of acetic acid was added dropwise 100 ml of 70% nitric acid. The mixture was heated at 50 °C for 1 hour and then poured into ice-water. The mixture was extracted with chloroform. The organic solution was washed with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was removed. Ether was added to the residue and the resulting mixture was stirred until a solid precipitated. The solid was collected by filtration to give 98 g of 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoic acid methyl ester as a white crystalline solid; mass spectrum (electrospray, m/e): M+H 303.8; 2M+ _NH4 623.9.

Example 49

4-(2-Chloroethoxy)-5-methoxy-2-nitrobenzoic acid methyl ester

Proceeding as described in Example 48, 85 g of methyl 4-(2-chloroethoxy)-5-methoxybenzoate were nitrated to give 72 g of the title compound; mass spectrum (electrospray, m/e): 2M+NH ₄ 595.89.

Example 50

2-Amino-4-(3-chloropropoxy)-5-methoxybenzoic acid methyl ester g (299.6 mmol) 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoic acid methyl ester and 55.2 g (988.8 mmol) iron are heated under reflux for 5.5 hours with mechanical stirring in a mixture containing 60.1 g ammonium chloride, 500 ml water and 1300 ml methanol. The reaction mixture is concentrated and mixed with ethyl acetate. The organic phase is washed with water and saturated sodium bicarbonate solution. The solution is dried over magnesium sulfate and filtered through a short silica gel column. The solvent is removed and the residue is mixed with 300 ml of a 2/1 ether/hexane mixture. After standing, 73.9 g of the title compound were obtained as a pink solid; mass spectrum (electrospray, m/e): 2M-HCl+H 511.0; M+H 273.8.

Example 51

2-Amino-4-(2-chloroethoxy)-5-methoxybenzoic acid methyl ester

A mixture of 68.2 g (235.4 mmol) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzoic acid methyl ester and 52.6 g (941.8 mmol) of iron was refluxed for 15 hours with mechanical stirring in a mixture containing 62.9 g of ammonium chloride, 393 ml of water and 1021 ml of methanol. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate solution. The solution was dried over magnesium sulfate and filtered through a short silica gel column. The solution was concentrated to 200 ml and diluted with 250 ml of hot hexane. After standing, 47.7 g of the title compound was obtained as a solid; mass spectrum (electrospray, m/e): M+H 259.8.

Example 52

A mixture of 7-(2-Chloroethoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile g (96.3 mmol) of 2-amino-4-(2-chloroethoxy)-5-methoxybenzoic acid methyl ester and 17.2 g (144.4 mmol) of dimethylformamide dimethylacetal was heated at reflux for 1.5 hours. The excess reactants were removed in vacuo to give a residue of 30.3 g, which was dissolved in 350 ml of tetrahydrofuran. In another flask, to a stirred solution of 80.9 ml of 2.5 mol of n-butyllithium in hexane in 300 ml of tetrahydrofuran at -78 °C, 8.3 g (202.1 mmol) of acetonitrile was added dropwise over 40 minutes. After 30 minutes, the above amidine solution was added dropwise over 45 minutes at -78 °C. After 1 hour, 27.5 ml of acetic acid was added to the reaction mixture and allowed to warm to room temperature. The solvent was removed and water was added to the residue. The solid was filtered and washed with water and ether. After drying in vacuo, 18.5 g of the title compound was obtained as a tan powder; mass spectrum (electrospray, m/e): M+H 278.8.

Example 53

7-(3-Chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile

Proceeding as described in Example 52, starting from 6.01 g of the appropriate amidine, 1.58 g of acetonitrile and 15.35 ml of n-butyllithium solution, 3.7 g of the title compound were obtained as a yellowish-brown powder; mass spectrum (electrospray, m/e): M+H 292.8; 2M+H 584.2.

Example 54

7-(3-Chloropropoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile

A mixture of 3.5 g (12 mmol) of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile and 28 ml of phosphorus oxychloride was refluxed for 1.5 h. The excess reactant was removed in vacuo. The residue was stirred with ice-cold dilute sodium hydroxide solution and ethyl acetate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and filtered through a short silica gel column. The solvents were removed to give 3.2 g of the title compound as a pink solid, which was used without further purification.

Example 55

7-(2-Chloroethoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile A solution of 7-(2-chloroethoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile (g, 28.7 mmol) and oxalyl chloride (18.2 g, 143.5 mmol) in 80 ml of methylene chloride containing 0.26 g of dimethylformamide was refluxed for 2.5 hours with stirring. The solvent was removed. The residue was stirred with cold, dilute sodium hydroxide solution and extracted several times with ethyl acetate and tetrahydrofuran. The combined extracts were dried over magnesium sulfate and the solution was filtered through a short silica gel column. The solvents were removed to give 6.0 g of the title compound as an off-white solid, which was used without further purification.

Example 56

4-Chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile

A mixture of 7.95 g (32.6 mmol) of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 ml of phosphorus oxychloride was heated under reflux for 3 hours and 40 minutes. The phosphorus oxychloride was removed in vacuo and the residue was suspended in ice water. Solid sodium bicarbonate

- 43 the mixture was adjusted to pH 8 and the product was collected by filtration, washed thoroughly with water and dried in vacuo at 40°C. 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile was obtained as a tan solid; mass spectrum (electrospray, m/e): M+H 262.8, 264.8.

Example 57

A solution of 6-Ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile,2 (45.3 mmol) methyl 2-amino-5-ethoxy-4-methoxybenzoate and 10.8 g (90.7 mmol) dimethylformamide dimethyl acetal in 50 ml dimethylformamide was refluxed for 3 hours. The volatiles were removed and the residue was azeotroped with toluene and dried in vacuo. Formamidine was obtained as a purple syrup. 100 mmol n-butyllithium in hexane was diluted with 60 ml tetrahydrofuran at -78 °C. A solution of 4.18 g (102 mmol) acetonitrile in 80 ml tetrahydrofuran was added over 15 minutes and the resulting solution was stirred for 20 minutes. The crude formamidine was dissolved in 80 ml of tetrahydrofuran and added dropwise to the cold solution over 0.5 h. The reaction mixture was stirred for 2 h and then quenched at -78 °C by adding 13 ml of acetic acid. The mixture was allowed to warm to room temperature and the volatiles were removed in vacuo. The residue was suspended in water and the crude product was collected by filtration, washed with water and dried. The resulting material was then washed with chloroform and dried. 7.95 g of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile was obtained as a yellow crystalline solid; mass spectrum (electrospray, m/e): M-H 243.2.

Example 58

Methyl 2-amino-5-ethoxy-4-methoxybenzoate

A mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of iron powder and 17.7 g (334 mmol) of ammonium chloride in 95 ml of water and 245 ml of methanol was heated under reflux for 4.5 hours. An additional 13.1 g of iron was added and the mixture was heated under reflux for 2.5 hours. An additional 13.1 g of iron and 17.7 g of ammonium chloride were then added and the mixture was heated under reflux for 12 hours. The reaction mixture was filtered through celite and the methanol was removed from the filtrate. The filtrate was extracted with chloroform and the extract was treated with Darco, concentrated and dried in vacuo at 50°C. 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate was obtained as a yellowish brown crystalline solid; mass spectrum (electrospray, m/e): M+H 225.9.

Example 59

Methyl 5-ethoxy-4-methoxy-2-nitrobenzoate

A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 ml of acetic acid was treated dropwise over 12 minutes with 15 ml of concentrated nitric acid. The reaction mixture was kept at 55 °C for 45 minutes, cooled to 25 °C and poured into ice-water. The product was extracted with methylene chloride and the extracts were washed with water and dilute sodium hydroxide solution, dried and evaporated. 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate were obtained as yellow crystals; mass spectrum (electrospray, m/e): M+H 256.0.

Example 60

Methyl 3-ethoxy-4-methoxybenzoate

A mixture of 24.3 g (134 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhydrous potassium carbonate and 31.4 g (201 mmol) of ethyl iodide in 500 ml of dimethylformamide was stirred at 100 °C for 5.5 hours. An additional 31.4 g of ethyl iodide and 18.4 g of potassium carbonate were added to the mixture and the heating was continued.

- 44 Continue for 2 hours. The reaction mixture is filtered and the volatile material is removed from the filtrate in vacuo. The residue is suspended in water, collected, and the product is washed with water and dried. Recrystallization from heptane affords 15.6 g of methyl 3-ethoxy-4-methoxybenzoate as a white crystalline solid; mass spectrum (electrospray, m/e): M+H 210.9.

Example 61

Methyl 3-hydroxy-4-methoxybenzoate

A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 ml of concentrated sulfuric acid in 600 ml of methanol was refluxed overnight. The bulk of the solvent was removed and the remaining solution was poured into 60 ml of water containing 25 g of sodium bicarbonate. The product was extracted with ether, treated with Darco, dried and evaporated. 31.8 g of methyl 3-hydroxy-4-methoxybenzoate was obtained as a pale yellow crystalline solid.

Example 62

N’-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine

To a stirred solution of 15.7 g (50 mmol) of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (WO 96/130347) in 50 ml of DMF at 0 °C was added 5.6 ml (60 mmol) of phosphorus oxychloride over 15 min. The resulting solution was heated at 55 °C for 45 min, then cooled, diluted with methylene chloride and treated with 200 ml of 1 M sodium hydroxide solution at 0 °C for 2 min. The organic phase was separated and washed with water at 0 °C. The solution was dried and evaporated by adding toluene. 18.4 g of an amber oil were obtained; NMR (CDCl ₃ ) δ: 3.02 (s, Me ₂ N).

Example 63

5,6-Bis(2-methoxyethoxy)-1,4-dihydroquinoline-3-carbonitrile To a stirred mixture of n-butyllithium (110 mmol) in hexane (2.5 M) and 65 mL of THF at -78 °C was added 5.85 mL (112 mmol) of acetonitrile in 110 mL of THF over 10 min. The reaction mixture was stirred at -78 °C for 15 min and then treated with a solution of N’-[2-carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine in 75 mL of THF for 20 min. The reaction mixture was stirred at -78 °C for 30 min and then treated with 14.3 mL (250 mmol) of acetic acid. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was evaporated to dryness and diluted with water. The resulting white solid was filtered, washed with water and dried. 10.7 g of product was obtained; mass spectrum (electrospray, m/e): M+H 319.2.

64, example

4-Chloro-5,6-bis(2-methoxyethoxy)quinoline-3-carbonitrile

A mixture of 9.68 g (30.4 mmol) of 5,6-bis(2-methoxyethoxy)-1,4-dihydroquinoline-3-carbonitrile and 30 ml of phosphorus oxychloride was refluxed for 1.5 hours with stirring. The resulting solution was concentrated in vacuo and the residue was stirred with methylene chloride at 0 °C while adjusting the pH of the mixture to 8-9 by adding ice water and sodium carbonate. The organic phase was separated, washed with water, dried and concentrated. A yellowish-brown solid was obtained; mass spectrum (electrospray, m/e): M+H 337.1, 339.1.

Example 65

Methyl 4-methoxy-3-[3-(morpholin-4-yl)propoxy]benzoate

22.6 g (124 mmol) methyl isovanilate, 25.4 g (155 mmol) N-(3-chloropropyl)morpholine, 18.8 g

- A mixture of 45 (136 mmol) potassium carbonate, 0.92 g (2.5 mmol) tetrabutylammonium iodide and 248 ml 2-butanone is refluxed with stirring for 20 hours. The 2-butanone is evaporated and the residue is stirred with water at 0 °C. The resulting white solid is filtered, washed with water and then with hexane and dried; the melting point of the solid is 90-94 °C.

Example 66

Methyl 4-methoxy-5-[3-(morpholin-4-yl)propoxy]-2-nitrobenzoate

To a stirred solution of 30.9 g (100 mmol) of methyl 4-methoxy-3-[3-(morpholin-4-yl)propoxy]benzoate in 100 mL of acetic acid at 25 °C was added 50 mL of 70% nitric acid over 30 min. The solution was heated to 45 °C, at which point the reaction began and became self-sustaining at this temperature. The reaction mixture was maintained at 45-50 °C for a total of 1.5 h, then cooled to 0 °C, treated with ice water and 240 g (1.75 mol) of potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. A yellow solid was obtained, mp 78-82 °C.

Example 67

Methyl 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzoate

A solution of 32.5 g (91.7 mmol) of methyl 4-methoxy-3-[3-(morpholin-4-yl)propoxy]-2-nitrobenzoate in 110 ml of methanol and 220 ml of ethyl acetate was hydrogenated at 3.79-10 ⁶ Pa (55 psi) in the presence of 2.0 g of 10% metal palladium-on-carbon catalyst at 25 °C. After 4 hours, the mixture was filtered and the filtrate evaporated to dryness. The residue was crystallized from acetone/hexane to give a tan solid, mp 78-82 °C.

Example 68

Ethyl 2-(dimethylaminomethyleneamino)-4-methoxy-5-[3-(morpholin-4-yl)propoxylbenzoate

6.4 A mixture of 9 g (20 mmol) of methyl 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzoate and 4.25 ml (30 mmol) of dimethylformamide dimethylacetal was heated at 100 °C for 1.5 h. All volatiles were evaporated directly at 70 °C to give a syrup; mass spectrum (electrospray, m/e): M+H 380.5.

Example 69 1,4-Dihydro-7-methoxy-6-(3-morpholin-4-ylpropoxy)-4-oxoquinoline-3-carbonitrile

To a stirred solution of 17.6 mL of 2.5 mol n-butyllithium in hexane (44 mmol) in 26 mL of THF at -78 °C was added 1.85 mL (45 mmol) of acetonitrile dissolved in 44 mL of THF over 10 min. The reaction mixture was stirred at -78 °C for 15 min and then treated with a solution of 7.6 g (20 mmol) of ethyl 2-(dimethylaminomethyleneamino)-4-methoxy-5-[3-morpholin-4-yl)propoxy]benzoate in 30 mL of THF for 20 min. The reaction mixture was maintained at -78 °C for 90 min and then treated with carbon dioxide while slowly warming to 25 °C and then evaporated to dryness. The residue was partitioned between 200 mL of n-butanol and 40 mL of half-saturated sodium chloride solution. The organic phase is separated, washed with saturated sodium chloride solution and evaporated to dryness. The resulting solid is triturated with hot acetone and then methanol, filtered and dried. A yellowish-brown solid is obtained, melting point 255-260 °C.

70, example

4-Chloro-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile

A stirred mixture of 4.75 g (13.8 mmol) of 1,4-dihydro-7-methoxy-6-[3-(morpholin-4-yl)propoxy]-4-oxoquinoline-3-carbonitrile, 0.10 ml of DMF and 55 ml of thionyl chloride was heated under reflux for 3 hours.

- 46 volatiles are removed by evaporation at 30 °C and the residue is adjusted to pH 9-10 by stirring with a mixture of water and methylene chloride containing potassium carbonate at 0 °C. The organic phase is separated, washed with water, dried and concentrated. A brown solid is obtained; mass spectrum (electrospray, m/e):

M+H 362.4, 364.4.

Example 71

4-Chloro-7-ethoxy-6-methoxyquinoline-3-carbonitrile

A mixture of 122 mg (0.50 mmol) of 7-ethoxy-1,4-dihydro-6-methoxy-4-oxoquinoline-3-carbonitrile and 2.0 ml of methylene chloride was kept under nitrogen at a temperature of about 25 °C. To the mixture were added 218 μΐ (2.5 mmol) of oxalyl chloride and 10 μΐ (0.125 mmol) of DMF. The mixture was stirred overnight, diluted with chloroform and stirred with saturated sodium bicarbonate solution until it became basic. The phases were separated and the organic phase was dried over magnesium sulfate, the solvent was evaporated and the residue was dried in vacuo. 117 mg of a yellowish brown solid were obtained; mass spectrum (electrospray, m/e): M+H 262.8, 264.8.

Example 72

7-Ethoxy-1,4-dihydro-6-methoxy-4-oxoquinoline-3-carbonitrile

To 150 mL of THF was added 54.0 mL (135 mmol) of n-butyllithium and the mixture was cooled to -78 °C under nitrogen. To the mixture was added 7.05 mL (135 mmol) of acetonitrile in 200 mL of THF dropwise over 20 min. The reaction mixture was stirred for 15 min and 17.99 g (64.2 mmol) of methyl 4-ethoxy-5-methoxy-2-(dimethylaminomethyleneamino)benzoate dissolved in 150 mL of THF was added dropwise over 20 min. The reaction mixture was stirred at -78 °C for 0.5 h. Acetic acid (11.0 mL (193 mmol) was added and the mixture was gradually warmed to 25 °C. After 2.5 hours, the solvent was evaporated, the residue was suspended in water, the solid was collected and dried in vacuo to give 13.025 g of a yellow solid; mass spectrum (electrospray, m/e): M+H 245.2.

Example 73

Methyl 4-ethoxy-5-methoxy-2-(dimethylaminomethyleneamino)benzoate

A mixture of 15.056 g (66.9 mmol) of methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 ml (100 mmol) of N,N-dimethylformamide dimethyl acetal was heated at 100 °C under nitrogen. After 4.5 h, 4.7 ml (33.3 mmol) of DMF/DMA were added and heating was stopped after 0.5 h. The solvent was evaporated, azeotroped with toluene and dried in vacuo. 18.211 g of a solid was obtained; mass spectrum (electrospray, m/e): M+H 281.3.

Example 74

Methyl 2-amino-4-ethoxy-5-methoxybenzoate

A mixture of 24.110 g (94.5 mmol) of methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) of iron powder, 25.28 g (472 mmol) of ammonium chloride, 135 ml of water and 350 ml of methanol was heated to reflux under nitrogen. At 3 and 5.5 hours, equal amounts of iron and ammonium chloride were added to the mixture. At 6.5 hours, the heating was stopped, ethyl acetate and saturated sodium bicarbonate were added to the mixture, the mixture was filtered through celite and the phases were separated. The organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, the solvent was evaporated and the residue was dried in vacuo. 17.594 g of a pink solid were obtained; mass spectrum

- 47 (electrospray, m/e): M+H 226.2.

Example 75

Methyl 4-ethoxy-5-methoxy-2-nitrobenzoate

5.00 g (23.7 mmol) of methyl 4-methoxy-3-methoxybenzoate were dissolved in 25 ml of acetic acid under nitrogen and 6.1 ml (95.1 mmol) of 69% nitric acid were added dropwise over 30 min. The reaction mixture was heated at 50 °C for 1.5 h and poured into an ice bath. The mixture was extracted with chloroform, washed with dilute sodium hydroxide solution and filtered through magnesium sulfate. The solvent was evaporated and the residue was dried in vacuo. 5.268 g of an off-white solid were obtained; mass spectrum (electrospray, m/e): M+H 255.8.

Example 76

Methyl 4-ethoxy-3-methoxybenzoate

A mixture of 25.0 g (137 mmol) of methyl vanillate, 38.87 g (274 mmol) of potassium carbonate, 500 ml of DMF and 16.5 ml (206 mmol) of ethyl iodide was heated at 100 °C under nitrogen. After 2.5 hours, the mixture was cooled and the solid was removed. The solvent was distilled off and the residue was partitioned between water and methylene chloride. After distillation of the solvent and vacuum drying, 25.85 g of a white solid were obtained; mass spectrum (EI m/e): M = 210.0.

Example 77

7-Ethoxy-4-hydroxyquinoline-3-carbonitrile A mixture of 3-ethoxyaniline (12.3 g, 73 mmol) and ethyl (ethoxymethylene)cyanoacetate (12.3 g, 73 mmol) in 90 mL Dowtherm was heated at 140 °C for 7 h. 250 mL Dowtherm was added. The solution was refluxed under nitrogen with stirring for 12 h, while the eliminated ethanol was distilled off occasionally. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude solid was treated with hot ethanol and filtered. 9.86 g of a brown solid were obtained; mass spectrum (electrospray, m/e): M+H 214.7.

Example 78

7-Ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile g (23 mmol) of 7-ethoxy-4-hydroxyquinoline-3-carbonitrile in 75 ml of trifluoroacetic anhydride was added with 5.5 g (69 mmol) of ammonium nitrate over 6 hours at room temperature. The excess anhydride was removed in vacuo at 45 °C. The residue was stirred with 300 ml of water. The solid was collected and stirred with hot ethanol. 3.68 g of a yellowish-brown solid was obtained; mass spectrum (electrospray, m/e): M+H 259.8.

79, example

4-Chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile

A mixture of 3.45 g (13 mmol) of 7-ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorus pentachloride and 10 ml of phosphorus oxychloride was refluxed for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold, dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed to give 2.1 g of a beige solid; mass spectrum (electrospray, m/e): M+H 277.7.

Example 80

8-Methoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile

A mixture of 12.6 g (75 mmol) of 2-methoxy-4-nitroaniline and 12.7 g (75 mmol) of ethyl-(ethoxymethylene)cyanoacetate in 100 ml of Dowtherm was heated at 120 °C overnight and at 180 °C for 20 hours. 300 ml of Dowtherm was added to the mixture. The solution was stirred and refluxed under nitrogen for 12 hours, while the eliminated ethanol was distilled off occasionally. The mixture was cooled to room temperature, the solid was collected and washed with hexane. The crude solid was treated with hot ethanol and filtered. 12 g of a brown solid was obtained; mass spectrum (electrospray, m/e): M+H 245.8.

Example 81

4-Chloro-8-methoxy-6-nitroquinoline-3-carbonitrile A mixture of 8-methoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile (g, 16 mmol), phosphorus pentachloride (6.66 g, 32 mmol) and phosphorus oxychloride (15 mL) was refluxed for 2.5 h. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in ethyl acetate (500 mL) and washed with cold, dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through silica gel. The solvent was removed to give 2.05 g of a tan solid; mass spectrum (electrospray, m/e): M+H 263.7.

Example 82

4-Hydroxy-6,7,8-trimethoxyquinoline-3-carbonitrile

A mixture of 4.82 g of methyl 3,4,5-trimethoxyanthranilate in 20 ml of N,N-dimethylformamide dimethylacetal was refluxed for 18 hours and concentrated in vacuo. The crude amidine product was used in the next step without further purification.

To 17.6 ml of 2.5 M n-butyllithium in hexanes was added at -78 °C. Then 2.35 ml of acetonitrile in 45 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Then a solution of the crude amidine in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78 °C for 30 min, then 5.7 ml of acetic acid was added. The mixture was warmed to room temperature and 100 ml of water was added. The product was collected, washed with water, and dried. 4.14 g of 4-hydroxy-6,7,8-trimethoxyquinoline-3-carbonitrile was obtained as a solid, mp 280 °C (dec.); mass spectrum (electrospray, m/e): M+H 261.2.

Example 83

4-Chloro-6,7,8-trimethoxyquinoline-3-carbonitrile

A mixture of 1.30 g of 4-hydroxy-6,7,8-trimethoxyquinoline-3-carbonitrile, 10 ml of phosphorus oxychloride and one drop of N,N-dimethylformamide was refluxed for 10 minutes with stirring, and the volatiles were evaporated. The residue was stirred with 20 ml of 5% methanol in ethyl acetate. The product was collected and dried. 1.12 g of 4-chloro-6,7,8-trimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 161-163 °C; mass spectrum (El, m/e): M+H 278.0452.

Example 84

2-(Dimethylaminomethyleneamino)-3,6-dimethoxybenzoic acid methyl ester

A mixture of 3.46 g of 2-amino-3,6-dimethoxybenzoic acid (Manouchehr Azadi-Ardakani and Timothy W. Wallace, Tetrahedron 44(18), 5939--5952 (1988)) with 20 ml of Ν,Ν-dimethylformamide dimethyl acetal

- 49 Reflux for 18 hours and concentrate in vacuo. To the residue is added 180 mL of ethyl acetate. The mixture is filtered and 200 mL of hexanes is added to the filtrate. The mixture is then

Concentrate to 100 ml. Collect the product and dry. 3.25 g of 2-(dimethylaminomethyleneamino)-3,6-dimethoxybenzoic acid methyl ester are obtained as a solid, mp 81-83°C; mass spectrum (EI, m/e): M+H 266.1263.

Example 85

4-Hydroxy-5,8-dimethoxyquinoline-3-carbonitrile

To 12.5 ml of tetrahydrofuran at -78 °C was added 8.8 ml of 2.5 M n-butyllithium in hexanes. Then 1.18 ml of acetonitrile in 25 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78 °C for 15 min. Then 62 ml of a solution of 2-(dimethylaminomethyleneamino)-3,6-dimethoxybenzoic acid methyl ester in tetrahydrofuran was added dropwise. The mixture was stirred at -78 °C for 10 min and then warmed to room temperature over 15 min. To the mixture was added 3 ml of acetic acid, followed by 200 ml of water. The product was collected, washed with water, and dried. 1.57 g of 4-hydroxy-5,8-dimethoxyquinoline-3-carbonitrile is obtained as a solid, melting point 300-305°C; mass spectrum (EI, m/e): M 230.0685.

Example 86

4-Chloro-5,8-dimethoxyquinoline-3-carbonitrile

A stirred mixture of 1.30 g of 4-hydroxy-5,8-dimethoxyquinoline-3-carbonitrile, 10 ml of phosphorus oxychloride and two drops of N,N-dimethylformamide was refluxed for 10 minutes and the volatiles were evaporated. The residue was stirred with 50 ml of water. The product was collected and dried. 1.74 g of 4-chloro-5,8-dimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 165-167 °C; mass spectrum (EI, m/e): M 248.0346.

Example 87

Methyl 2-(dimethylaminomethyleneamino)-4,5-diethoxybenzoate

To a stirred solution of 4.79 g (20 mmol) of methyl 2-amino-4,5-diethoxybenzoate in 20 mL of DMF at 0 °C was added 2.24 mL (24 mmol) of phosphorus oxychloride over 15 min. The reaction mixture was heated to 55 °C and stirred for 45 min. The resulting solution was diluted with methylene chloride, cooled to 0 °C, and treated with 80 mL of precooled 1 M sodium hydroxide solution for 5 min. The organic phase was separated and washed with water at 0 °C. The solution was dried and concentrated. An amber oil was obtained;

NMR (CDCl ₃ ) δ: 3.00 (s, Me ₂ N).

Example 88 1,4-Dihydro-6,7-diethoxy-4-oxoquinoline-3-carbonitrile

To a stirred solution of 17.6 ml of a 2.5 M (44 mmol) solution of n-butyllithium in hexane in 25 ml of THF at -78 °C was added 2.35 ml (45 mmol) of acetonitrile and 44 ml of THF over 10 min. The reaction mixture was stirred at -78 °C for 15 min and then treated with a solution of 5.83 g (19.8 mmol) of ethyl 2-(dimethylaminomethyleneamino)-4,5-diethoxybenzoate in 30 ml of tetrahydrofuran for 30 min. The mixture was kept at -78 °C for 30 min and then treated with 5.7 ml (100 mmol) of acetic acid and evaporated to dryness. The residue was stirred with water and the resulting precipitate was filtered, washed with water and dried. 4.01 g of an off-white solid was obtained; NMR (DMSO-d 2 ): d 8.58 (s, 2-H).

Example 89

4-Chloro-6,7-diethoxyquinoline-3-carbonitrile 1,4-Dihydro-6,7-diethoxy-4-oxoquinoline-3-carbonitrile was treated with phosphorus oxychloride as described in Example 64 to give the title compound as a pink solid, m.p. 170-175 °C.

Example 90

2-(Dimethylaminomethyleneamino)-3-methoxybenzoic acid methyl ester

5.0 g (29.9 mmol) of 2-amino-3-methoxybenzoic acid in 25.0 ml of DMF/DMA were heated at 100-105 °C for 2.5 h, then the solvent was removed to give a reddish-purple viscous oil, which solidified on cooling. 5.8 g (82.8%) of the product was obtained as a reddish-purple solid; mass spectrum (electrospray, m/e): M+H 236.9.

Example 91 1,4-Dihydro-8-methoxy-4-oxoquinoline-3-carbonitrile

To 35.0 mL of THF was added 26.6 mL (66.4 mmol) of n-BuLi over 5 min at -78 °C. To the stirred solution was added 3.55 mL (67.9 mmol) of acetonitrile in 65 mL of THF over 10 min, during which time the solution turned into a white suspension, which was further stirred at -78 °C for 15 min. To the suspension was added 5.8 g (24.5 mmol) of 1-(dimethylaminomethyleneamino)-3-methoxybenzoic acid methyl ester in 45 mL of THF over 30 min, and the mixture was then further stirred at -78 °C for 30 min, during which time the mixture gradually became clear. The solution was treated with 8.5 mL of acetic acid. The resulting thick suspension was stirred and warmed to room temperature. The bulk of the solvent was evaporated and the residue was diluted with cold water. The precipitate was collected by filtration, washed with water and dried in vacuo to give 3.8 g (77.6%) of the product as an off-white solid, mp 270 °C (dec), mass spectrum (electrospray, m/e): M+H 201.1.

Example 92

4-Chloro-8-methoxyquinoline-3-carbonitrile

A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxoquinoline-3-carbonitrile with 40 mL of phosphorus oxychloride and 5 drops of DMF was refluxed for 0.5 h. The mixture was evaporated to dryness and diluted with hexanes. The solid was collected and stirred with cold, dilute sodium carbonate solution and extracted several times with ethyl acetate. The organic phase was dried over sodium sulfate and filtered through a plug of silica gel. Removal of the solvent gave 3.8 g (91%) of 4-chloro-8-methoxyquinoline-3-carbonitrile as an off-white solid; mass spectrum (electrospray, m/e): M+H 219.1.

Example 93

4- Chloro-7-methoxyquinoline-3-carbonitrile

Treatment of 1,4-dihydro-7-methoxy-4-oxoquinoline-3-carbonitrile with phosphorus oxychloride as described in Example 64 afforded the title compound as a tan solid; mass spectrum (electrospray, m/e): M+H 219.2, 221.1.

Example 94

7-Benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile

To a stirred solution of 26.9 mL of 2.5 M n-butyllithium in hexane in 50 mL of THF at -78 °C was added 3.51 mL of acetonitrile in 20 mL of THF over 10 min. The reaction mixture was stirred at -78 °C for 30 min.

- 51 then treated with 10 g of L17741-150 (B. Floyd) in 20 ml of THF over 5 min. The mixture was stirred at -78 °C for 15 min and then warmed to 0 °C for a further 30 min. The mixture was treated with 5 ml of acetic acid, warmed to 25 °C and stirred for 30 min. The mixture was evaporated to dryness and diluted with aqueous sodium bicarbonate solution. The resulting off-white solid was filtered and washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile were obtained as an off-white solid which decomposed at >255 °C; mass spectrum (electrospray, m/e): M+H 307.

Example 95

7-Benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile g To a stirred suspension of 7-benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile in 10 ml of methylene chloride was added 5 ml of 2 M oxalyl chloride in methylene chloride and 2 drops of Ν,Ν-dimethylformamide. The mixture was refluxed for 20 minutes and aqueous sodium bicarbonate solution was added slowly until gas evolution ceased. The phases were separated, the organic phase was concentrated to a small volume and then passed through a pad of magnesol. Elution with 50 ml of methylene chloride and evaporation gave 0.6 g of 7-benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile as a pale yellow solid, melting point 282-284 °C; mass spectrum (electrospray, m/e): M+H 325.

Example 96

4-(2,3-Dihydro-1H-indol-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 258 mg (1.88 mmol) of 6-aminoindoline dihydrochloride salt in 10 ml of ethanol was heated under reflux for 3 hours. 1 ml of 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. The solid was dissolved in 50:50 methanol/chloroform and dried on silica gel and purified by chromatography, eluting with 20%→50% acetone/hexane. 496 mg of the title compound was obtained as a tan solid; mass spectrum (electrospray, m/e): M+H 375.1; melting point: 121-124 °C.

Example 97

4-(Benzothiazol-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile HCl salt

A solution of 500 mg (1.8 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 353 mg (2.35 mmol) of 6-aminobenzothiozole in 15 ml of ethanol was heated under reflux for 3 hours. Two drops of concentrated hydrochloric acid were added to the hot solution and the mixture was heated at 100 °C for 5 minutes, then the solid was separated by filtration. The solid was taken up in 20 ml of ethanol and digested for 1 hour. The hot solution was filtered and the separated solid was washed with ethanol and dried in vacuo at 80 °C. 666 mg of 4-(benzothiazol-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile HCl salt were obtained as an amber solid; mass spectrum (electrospray, m/e): M+H 391.0; melting point: 285-287 °C.

Example 98

4-(Benzo(1,3|dioxol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 258 mg (1.88 mmol) of 3,4-(methylene

- A solution of 52 dioxy)aniline in 10 ml ethanol was refluxed for 3 hours. 1 ml 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 526 mg of 4-(benzo[1,3]dioxol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile were obtained as a yellowish-brown solid; mass spectrum (electrospray, m/e): M+H 378.0; melting point: 200-203 °C.

Example 99

6,7-Diethoxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 250 mg (1.88 mmol) of 6-aminoindazole in 10 ml of ethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 448 mg of 6,7-diethoxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile was obtained as a yellowish-brown solid; mass spectrum (electrospray, m/e): M+H 374.1; melting point: 143-145 °C.

Example 100

6,7-Diethoxy-4-(4-methyl-2-oxo-2H-chromen-7-ylamino)quinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 330 mg (1.88 mmol) of 7-amino-4-methylcoumarin in 15 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 431 mg of 6,7-diethoxy-4-(4-methyl-2-oxo-2H-chromen-7-ylamino)quinoline-3-carbonitrile was obtained as a yellowish-brown solid; mass spectrum (electrospray, m/e): M+H 416.0; melting point: 282-284 °C.

Example 101

6,7-Diethoxy-4-(1H-indol-6-ylamino)quinoline-3-carbonitrile

A solution of 964 mg (3.50 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 830 mg (6.29 mmol) of 6-aminoindole in 5 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 712 mg of 6,7-diethoxy-4-(1H-indol-6-ylamino)quinoline-3-carbonitrile was obtained as a yellow solid; mass spectrum (electrospray, m/e): M+H 373.0; melting point: 128-130 °C.

Example 102

6,7-Dimethoxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile

A solution of 500 mg (2.00 mmol) of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile and 975 mg (2.61 mmol) of 6-aminoindazole in 15 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 738 mg of the title compound was obtained as a tan solid; mass spectrum (electrospray, m/e): M+H 345.9; melting point: 180-183 °C.

Example 103

4-(1H-Benzotriazol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 1.07 mg (3.87 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 675 mg (5.00 mmol) of 5-aminobenzotriazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. 1 ml of 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solution was acidified with concentrated hydrochloric acid and the solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. The solid was taken up in 200 ml of methanol and 50 μΐ of 5 M sodium hydroxide solution and refluxed for 20 minutes. To the resulting heterogeneous mixture was added 100 ml of glacial acetic acid and the volume of the mixture was reduced to a total of 100 ml by boiling. To the mixture was added 500 ml of ice-cold water at room temperature and the solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 738 mg of the title compound was obtained as a brown solid; mass spectrum (electrospray, m/e): M+H 375.0; melting point: 115 °C, decomposition.

104, example

4-(1,3-Dioxo-2,3-dihydro-1H-isoindol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 305 mg (1.88 mmol) of 4-aminophthalimide in 10 ml of ethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 348 mg of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile was obtained as a yellow solid; mass spectrum (electrospray, m/e): M+H 402.9; melting point: 248-251 °C.

Example 105

4-(2 _r 3-Dihydro-benzo[1,4]dioxin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 232 mg (1.54 mmol) of 1,4-benzodioxan-6-amine in 15 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 526 mg of 4-(2,3-dihydrobenzo[1,4]dioxin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile was obtained as a yellow solid; mass spectrum (electrospray, m/e): M+H 402.9; melting point: 225-227 °C.

Example 106

4-(1H-Indazol-6-ylamino)-6,7-bis(2-methoxyethoxy)quinoline-3-carbonitrile

A solution of 400 mg (1.19 mmol) of 4-chloro-6,7-(2-methoxyethoxy)quinoline-3-carbonitrile and 174 mg (1.31 mmol) of 6-aminoindazole in 12 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 362 mg of 4-(1H-indazol-6-ylamino)-6,7-bis(2-methoxyethoxy)quinoline-3-carbonitrile was obtained as an orange solid; mass spectrum (electrospray, m/e): M+H 434.0; melting point 105-110 °C.

- 54 Example 107

4-(1,4-Dioxo-1,2,3,4-tetrahydrophthalazin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 273 mg (1.54 mmol) of 5-aminophthalhydrazide hydrate in 15 ml of 2-methoxyethanol was refluxed for 3 hours. 1 ml of 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solution was acidified with concentrated hydrochloric acid and the solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. The solid was taken up in 200 ml of methanol and 50 μΐ of 5 M sodium hydroxide solution and refluxed for 20 minutes. To the resulting heterogeneous mixture was added 100 ml of glacial acetic acid and the volume of the mixture was reduced to a total of 100 ml by boiling. To the mixture was added 500 ml of ice-cold water at room temperature and the solid was collected, washed with water and then with ether and dried under vacuum at 80 °C. The solid was digested with 400 ml of ethanol until the volume was reduced to 150 ml. The hot solution was filtered and the solid was washed with ethanol and dried under vacuum at 80 °C. 121 mg of the title compound was obtained as a white solid; mass spectrum (electrospray, m/e): M+H 418.0; melting point: >270 °C.

Example 108

6,7-Diethoxy-4-(indan-5-ylamino)quinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile and 205 mg (1.54 mmol) of 5-aminoindane in 12 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried under vacuum at 80 °C. The brown solid was digested with 200 ml of ethanol and the volume was reduced to 100 ml. The solid was separated from the warm solution and washed with ethanol and then with ether and finally dried under vacuum at 80 °C. 435 mg of 6,7-diethoxy-4-(indan-5-ylamino)quinoline-3-carbonitrile were obtained as a brown solid; mass spectrum (electrospray, m/e): M+H 374.0; melting point: 85-88 °C.

Example 109

4-(2,4-Dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile, 274 mg (1.54 mmol) of 5-aminoisotoic anhydride and 161 mg (1.44 mmol) of pyridine hydrochloride in 15 ml of 2-methoxyethanol was refluxed for 3 hours. The hot solution was filtered and the solid was washed with ethanol and dried in vacuo at 60 °C. 482 mg of 4-(2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile HCl salt were obtained as a gray solid; mass spectrum (electrospray, m/e): M+H 418.9; melting point: >270 °C.

Example 110

6,7-Diethoxy-4-(1-oxoindan-5-ylamino)quinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile, 227 mg (1.54 mmol) of 6-amino-1-indanone and 161 mg (1.44 mmol) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 483 mg of 6,7-diethoxy-4-(1-oxoindan-5-yl-55 amino)quinoline-3-carbonitrile was obtained as a white solid; mass spectrum (electrospray, m/e):

M+H 388.0; mp: 263 °C, decomposes.

Example 111

6,7-Diethoxy-4-(3-oxo-1,3-dihydroisobenzofuran-5-ylamino)quinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile, 230 mg (1.54 mmol) of 6-aminophthalide and 161 mg (1.44 mmol) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was heated under reflux for 3 hours. 1 ml of 1M sodium carbonate was added to the warm solution and the mixture was stirred at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried in vacuo at 80 °C. 535 mg of 6,7-diethoxy-4-(3-oxo-1,3-dihydroisobenzofuran-5-ylamino)quinoline-3-carbonitrile was obtained as a white solid; mass spectrum (electrospray, m/e): M+H 390.1; melting point: 280-284 °C.

Example 112

4-(1,1-Dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile

A solution of 400 mg (1.44 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile, 230 mg (1.54 mmol) of 6-amino-1,1dioxobenzo[b]thiophene and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 6 hours. 1 ml of 1 M sodium carbonate was added to the warm solution and the mixture was heated at 100 °C for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water and then with ether and dried at 80 °C in vacuo. The solid was dissolved in acetone and dried on silica gel in high vacuum. The resulting compound was purified by chromatography, eluting with a 30 -► 50% acetone/hexane gradient. The desired product was isolated from the column first of the three components of the mixture. The solvent was removed by evaporation to give 69 mg of 4-(1,1-dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile as a yellow solid; mass spectrum (electrospray, m/e): M+H 421.9; melting point: 155-160 °C.

Example 113

4-(2,3-Dihydro-1H-indol-6-ylamino)-6,7-methoxyquinoline-3-carbonitrile

A solution of 400 mg (1.61 mmol) of 4-chloro-6,7-methoxyquinoline-3-carbonitrile and 366 mg (1.77 mmol) of 6-aminoindoline dihydrochloride in 12 ml of 2-methoxy ethanol was refluxed for 3 hours. The hot solution was filtered and the separated solid was washed with water and then with ether and dried in vacuo at 80 °C. The solid was dissolved in a 1:1 methanol/chloroform mixture and dried on silica gel in high vacuum. The product was purified by chromatography, eluting with a 30-60% acetone/hexane gradient. The desired product was isolated from the three components of the mixture on the column first. The column fractions were concentrated to a volume of 10 ml and then diluted with 250 ml of hexane. The resulting solid was collected, washed with hexane and dried under vacuum at 80°C. 16 mg of 4-(2,3-dihydro-1H-indol-6-ylamino)-6,7-methoxyquinoline-3-carbonitrile was obtained as an amber solid; mass spectrum (electrospray, m/e): M+H 347.0; melting point: 175°C, decomposition.

Example 114

4-(1H-Indol-5-ylamino)-6-nitroquinoline-3-carbonitrile

A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml of ethanol and 3.40 g (25.8 mmol) of 5-aminoindole was refluxed under nitrogen for 3.5 hours. The heating was stopped, the mixture was basified with saturated sodium bicarbonate and the solvents were distilled off, then

- 56 is azeotroped with ethanol. The collected solid is washed with hexane and then with water,

Dissolve in 200 ml of ethyl acetate, add Darco and filter. The solvent is evaporated and the residue is dried in vacuo at 50 °C overnight. Wash with ether twice more to remove the starting aminoindole. 4.372 g of a reddish-brown solid is obtained; mass spectrum (electrospray, m/e): M+H 330.2.

Example 115

7-Ethoxy-4-(indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

A mixture of 500 mg (1.90 mmol) of 4-chloro-7-ethoxy-6-methoxyquinoline-3-carbonitrile, 30 ml of ethanol and 304 mg (2.28 mmol) of 6-aminoindazole was heated to reflux under nitrogen. After 4 hours, the heating was stopped and the mixture was basified with saturated sodium bicarbonate. The solvents were evaporated, the residue was suspended in hexane, the solid was collected and dried, then washed with water and dried in vacuo. 546 mg of a tan solid were obtained; mass spectrum (electrospray, m/e): M+H 359.9.

Example 116

7-Benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile

A total of 500 mg (1.63 mmol) of 7-benzyloxy-4-hydroxy-6-methoxyquinoline-3-carbonitrile was taken up in 3 ml of a 2 mol/l solution of oxalyl chloride in chloroform and the mixture was allowed to stand for 15 min and then refluxed for 1 h. The solution was allowed to cool and diluted with 300 mg of hexane. The resulting green solid was separated and washed with excess hexane and dried in vacuo at 40 °C. 586 mg of 7-benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile was obtained as the hydrochloride salt. The compound was used immediately in the next step.

Example 117

7-Benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

A solution of 586 mg (1.60 mmol) of 7-benzyloxy-4-chloro-6-methoxyquinoline-3-carbonitrile, 560 mg (1.70 mmol) of 6-aminoindoline dihydrochloride salt and 208 mg (1.80 mmol) of pyridine hydrochloride in 13 ml of 2-methoxyethanol was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid was separated, washed with excess ethanol and dried under vacuum at 80°C. The resulting solid was digested with 300 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the hot solution and the digestion operation was repeated once more. The solid was again separated from the hot solution. 206 mg of 7-benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxyquinoline-3-carbonitrile are obtained as a yellowish-brown solid.

Example 118

4-(23-Dihydro-1H-indol-6-ylamino)-7-hydroxy-6-methoxyquinoline-3-carbonitrile (Scheme 16) To 206 mg of trifluoroacetic acid was added 7-benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxyquinoline-3-carbonitrile and the reaction mixture was refluxed for 1.5 hours. The TFA was removed in vacuo and the resulting film was dissolved in 7 ml of methanol and 50 ml of ice-cold saturated sodium bicarbonate solution was added. The solution was allowed to stand at 10 °C for 1 hour. The resulting solid was separated, washed with excess water and dried in vacuo at 80 °C. 107 mg of 4-(2,3-dihydro-1H-indol-6-ylamino)-7-hydroxy-6-methoxyquinoline-3-carbonitrile are obtained. The obtained compound is used directly in the next step without purification.

Example 119

To a solution of 4-(2,3-Dihydro-1H-indol-6-ylamino)-6-methoxy-7-[3-(pyridin-4-yl)propoxy]quinoline-3-carbonitrile in 1 ml chloroform, 1 ml tetrahydrofuran, 167 mg (0.64 mmol) triphenylphosphine, 52 μΐ (0.40 mmol) 4(hydroxypropyl)pyridine and 107 mg (0.32 mmol) 4-(2,3-dihydro-1H-indol-6-ylamino)-7-hydroxy-6-methoxyquinoline-3-carbonitrile at 0 °C was slowly added 101 μΐ (0.64 mmol) DEAD. The reaction mixture was kept at 0 °C for 15 min and then allowed to warm to room temperature. The heterogeneous solution was stirred at room temperature for 7 h. TLC and ES-MS analysis showed no signs of product formation. An additional 1 mL of chloroform and 500 mL of tetrahydrofuran were added to the reaction mixture and refluxed for 14 h. Again, no signs of product formation were found. The reaction mixture was reduced to 1 mL by heating and then made up to 4 mL with tetrahydrofuran. The reaction mixture was cooled to room temperature and another 80 mg (0.32 mmol) of triphenylphosphine, 25 μΐ (0.20 mmol) of 4-(hydroxypropyl)pyridine were added, followed by the slow addition of 50 μΐ (0.32 mmol) of DEAD. The reaction mixture rapidly turned into a clear, brown solution. The reaction was complete after 6 h at room temperature by TLC and mass spectrum. To the reaction mixture was added 10 ml of 1 M HCl, followed by 20 ml of water. The solution was extracted five times with 25 ml of chloroform. The aqueous phase was allowed to stand at room temperature for 3 hours and the resulting brown solid was separated by filtration. The filtrate was treated with solid sodium bicarbonate until a yellow solid separated from the solution. The precipitate was separated, washed with excess water and then with 1 ml of diethyl ether and dried at 80 °C under vacuum. 57 mg of 4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxy-7-[3-(pyridin-4-yl)propoxy]quinoline-3-carbonitrile were obtained as a yellow solid; mass spectrum (electrospray, m/e): 452.3 M+H, 226.7 M+2H/2; melting point: 100-105 °C.

Example 120

2,3-Dihydrobenzo[1,4]dioxin-6-carboxylic acid methyl ester

A solution of 19.6 g (109 mmol) of 2,3-dihydrobenzo[l,4]dioxin-6-carboxylic acid [J. Chem. Soc., 3445 (1957)] in 400 ml of methanol containing 4 ml of H ₂ SO ₄ was refluxed overnight. To the mixture was added 18 g of sodium hydrogen carbonate, the solvent was removed, and the residue was triturated several times with diethyl ether. The washings were combined, filtered through anhydrous magnesium sulfate, and evaporated. 20.7 g of the title compound were obtained as a pale yellow oil; mass spectrum (electron impact, m/e): 194.

121, example

7-Nitro-2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid methyl ester

To a solution of 15.0 g (77.3 mmol) of 2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid methyl ester in 45 ml of acetic acid was added dropwise 18 ml of nitric acid. The solution was heated at 60 °C for 1.5 h. A further 9 ml of nitric acid was added and the mixture was heated at 70 °C for 1.5 h. The reaction mixture was poured into ice water and the solid product was collected, washed with water and dried. Recrystallization from heptane/toluene gave 16.8 g of the title compound as yellow crystals; mass spectrum (electron impact, m/e): 239.

Example 122

5-Amino-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester

A mixture of 12.0 g (50.2 mmol) of 7-nitro-2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid methyl ester, 11.2 g (201 mmol) of powdered iron and 13.3 g (257 mmol) of ammonium chloride in 175 ml of methanol and 70 ml of water was heated under reflux for 5.5 hours. A further 11.2 g of iron and 13.3 g of ammonium chloride were added to the mixture and the mixture was heated for a further 5.5 hours. Finally, 5.5 g of iron and 6.5 g of ammonium chloride were added to the mixture and the mixture was heated for 4 hours. The cooled reaction mixture was filtered through celite, the filter pad was washed thoroughly with methanol, and the filtrate and washings were combined. The solvent was removed and the residue was suspended in water and collected. The crude product was filtered through silica gel (chloroform). 9.5 g of the title compound was obtained as a tan crystalline solid; mass spectrum (electrospray, m/e): M+H 209.9.

Example 123

9-Oxo-2,3,6,9-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile

A solution of 9.71 g (46.5 mmol) of 7-amino-2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid methyl ester and 11.1 g (92.9 mmol) of dimethylformamide-dimethylacetal in 45 ml of dimethylformamide was refluxed under nitrogen for 6 hours. The volatiles were removed and the residue was azeotroped with toluene and dried in vacuo. Formamidine was obtained as a purple syrup.

102 mmol of n-butyllithium in hexane was diluted with 70 mL of THF at -78 °C under nitrogen. A solution of 4.31 g (105 mmol) of acetonitrile in 85 mL of THF was added over 15 min and the mixture was stirred for 25 min. The crude formamidine was dissolved in 90 mL of THF and added dropwise to the cold solution over 0.5 h. The reaction mixture was stirred for 1.25 h and quenched by the addition of 13.4 mL of acetic acid at -78 °C. The mixture was allowed to warm to room temperature and the volatiles were removed in vacuo. The residue was suspended in water and the crude product was collected by filtration, washed with water and dried. The solid was boiled with methanol, collected and dried in vacuo at 50 °C. 7.62 g of the title compound were obtained as a yellowish-brown powder; mass spectrum (electrospray, m/e): M+H 228.8.

Example 124

9-Chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile

A mixture of 7.06 g (31.0 mmol) of WAY 170839 and 35 ml of POC1 ₃ was heated under reflux for 3.5 h. The POCl ₃ was removed, ice water was added, and the pH was adjusted to 8 with solid sodium bicarbonate. The product was collected, washed thoroughly with water, and dried in vacuo. 7.42 g of 9-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile was obtained as a tan solid; mass spectrum (electrospray, m/e): M+H 246.8.

Example 125

9-(1H-Indazol-6-ylamino)-2,3-dihydro[1,4]dioxino[2,3-g|quinoline-8-carbonitrile

A mixture of 1.00 g (4.07 mmol) of 9-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile and 0.649 g (4.88 mmol) of 6-aminoindazole in 25 ml of ethanol was refluxed under nitrogen for 5.7 hours. Saturated sodium bicarbonate solution was added to the mixture and the solvent was removed. The residue was suspended in water, filtered, washed with water and cold ethanol and dried. The crude product was boiled in ethanol, filtered and dried in vacuo at 50 °C. 1.06 g of 9-(1H-indazol-6-yl-59 amino)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile was obtained as a yellowish-brown crystalline solid; mass spectrum (electrospray, m/e): M+H 344.3.

Example 126

6-Ethoxy-4-(1H-indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile

A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.609 g (4.58 mmol) of 6-aminoindazole in 20 ml of ethanol was refluxed under nitrogen for 8 hours. Saturated sodium bicarbonate solution was added, the solvent was removed, and the residue was azeotroped twice with ethanol. The solid was suspended in cold ethanol, collected, washed twice with water, and dried. Recrystallization from ethanol gave 0.646 g of 6-ethoxy-4-(1H-indazol-6ylamino)-7-methoxyquinoline-3-carbonitrile as tan crystals; mass spectrum (electrospray, m/e): M+H 359.9.

Example 127

6,7-Diethoxy-4-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7ylamino)quinoline-3-carbonitrile

A mixture of 0.5 g (1.8 mmol) of 4-chloro-6,7-diethoxyquinoline-3-carbonitrile, 0.35 g (1.8 mmol) of 7-amino-1-methyl-2,5dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine and 0.21 g of pyridine hydrochloride in ethoxyethanol was refluxed for 5 hours. The solvent was removed in vacuo. The residue was stirred with ammonium hydroxide and the insoluble material was collected. 0.8 g of the title compound was obtained as a yellowish-brown, crystalline solid; mass spectrum (electrospray, m/e): M+H 446.0.

Example 128

4-(1H-Indazol-6-ylamino)-6,7,8-trimethoxyquinoline-3-carbonitrile

A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxyquinoline-3-carbonitrile, 0.147 g of 6-aminoindazole, 0.020 g of pyridine hydrochloride and 15 ml of ethoxyethanol was refluxed under nitrogen for 1 hour with stirring. The mixture was cooled and added to 100 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.332 g of 4-(1H-indazol-6-ylamino)6,7,8-trimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 243-245 °C; mass spectrum (EI, m/e): M 375.1331.

Example 129

6,7-Dimethoxy-4-(4-methyl-2-oxo-1,2-dihydroquinolin-7-ylamino)quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.174 g of carbostyril 124, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was refluxed under nitrogen for 30 min with stirring. The mixture was cooled and added to 40 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.356 g of 6,7-dimethoxy-4-(4methyl-2-oxo-1,2-dihydroquinolin-7-ylamino)quinoline-3-carbonitrile was obtained as a solid, melting point >300 °C; mass spectrum (electrospray, m/e): M+H 387.1446.

Example 130

6,7-Dimethoxy-4-(2-methylbenzothiazol-5-ylamino)quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole dihydrochloride, 0.158 g of pyridine and 10 ml of ethoxyethanol was refluxed under nitrogen for 20 minutes with stirring. The mixture was cooled and added to 40 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.356 g of 6,7-dimethoxy4-(2-methylbenzothiazol-5-ylamino)quinoline-3-carbonitrile was obtained as a solid, melting point

118-120°C; mass spectrum (EI, m/e): M 376.0973.

Example 131

6,7-Dimethoxy-4-(2-oxo-2H-dihydrobenzothiazol-6-ylamino)quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.166 g of 6-amino-2-benzothiazolinone, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was refluxed under nitrogen with stirring for 20 minutes. The mixture was cooled and added to 40 ml of water. Sodium carbonate and concentrated hydrochloric acid were added to the mixture to adjust the pH to 7. The product was collected, washed with water and dried. 0.326 g of 6,7-dimethoxy-4-(2-oxo-2,3-dihydrobenzothiazol-6-ylamino)quinoline-3-carbonitrile was obtained as a solid; melting point 285-287 °C; mass spectrum (electrospray, m/e): M+H 379.0858.

Example 132

6,7-Dimethoxy-4-(quinolin-5-ylamino)quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.288 g of 5-aminoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was heated at 200 °C for 2 hours in a sealed bomb tube under nitrogen. The mixture was cooled and added to 100 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.132 g of 6,7-dimethoxy-4-(quinolin-5-ylamino)quinoline-3-carbonitrile was obtained as a solid, melting point 115 °C (decomposition); mass spectrum (EI, m/e): M 356.1276.

Example 133

4-(Isoquinolin-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.288 g of 5-aminoisoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was heated at 200 °C for 2 hours in a sealed bomb tube under nitrogen. The mixture was cooled and added to 100 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.100 g of 4-(isoquinolin-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 140 °C (decomposition); mass spectrum (EI, m/e): M 356.1279.

Example 134

6,7-Dimethoxy-4-(quinolin-8-ylamino)quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.288 g of 8-aminoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was heated at 200 °C for 2 hours in a sealed bomb tube under nitrogen. The mixture was cooled and added to 100 ml of water. The resulting mixture was adjusted to pH 9 with sodium carbonate. The product was collected, washed with water and dried. 0.167 g of 6,7-dimethoxy-4-(quinolin-8-ylamino)quinoline-3-carbonitrile was obtained as a solid, melting at 150 °C with decomposition; mass spectrum (EI, m/e): M 356.1271.

Example 135

4-(8-Hydroxyquinolin-8-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.233 g of 5-amino-8-hydroxyquinoline hydrochloride, 0.158 g of pyridine and 10 ml of ethoxyethanol was refluxed under nitrogen with stirring for 2 hours. The mixture was cooled and added to 40 ml of water. Sodium carbonate and concentrated hydrochloric acid were added to the mixture to adjust the pH to 7. The product was collected, washed with water and dried. 0.210 g of 4-(8-hydroxyquinolin-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 150 °C (decomposition); mass spectrum (El, m/e): M+H 372.1228.

Example 136

4-(1H-Indol-4-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was refluxed under nitrogen with stirring for 2 hours. The mixture was cooled and added to 40 ml of water. Sodium carbonate and concentrated hydrochloric acid were added to the mixture to adjust the pH to 7. The product was collected, washed with water and dried. 0.249 g of 4-(1H-indol-4-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 260 °C (decomposition); mass spectrum (El, m/e): M+H 344.1282.

Example 137

4-(1H-Indazol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile, 0.132 g of 5-aminoindazole, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was refluxed under nitrogen with stirring for 2 hours. The mixture was cooled and added to 40 ml of water. Sodium carbonate and concentrated hydrochloric acid were added to the mixture to adjust the pH to 7. The product was collected, washed with water and dried. 0.252 g of 4-(1H-indazol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile was obtained as a solid, melting point 290-295 °C; mass spectrum (El, m/e): M+H 345.1217.

Example 138

4-(1H-Indazol-6-ylamino)-5,8-dimethoxyquinoline-3-carbonitrile

A mixture of 0.148 g of 4-chloro-5,8-dimethoxyquinoline-3-carbonitrile, 0.093 g of 6-aminoindazole, and 5 mL of ethoxyethanol was refluxed under nitrogen with stirring for 30 min. The mixture was cooled and added to 50 mL of water. The pH was adjusted to 9 with sodium carbonate. The product was collected, washed with water, dried, and washed with 10 mL of 4:1 hexanes/ethyl acetate. 0.189 g of 4(1H-indazol-6-ylamino)-5,8-dimethoxyquinoline-3-carbonitrile was obtained as a solid, mp 302-305 °C; mass spectrum (EI, m/e): M 345.1223.

Example 139

4-(1H-Indazol-6-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile hydrochloride

A mixture of 0.362 g of 4-chloro-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile, 0.267 g of 6-aminoindazole, and 10 ml of ethoxyethanol was heated to reflux with stirring for 30 minutes. The mixture was cooled and added to 50 ml of 5:5:2 ethyl acetate/acetone/methyl alcohol. The product was collected, washed with water, dried, and washed with 10 ml of 4:1 hexanes/ethyl acetate. 0.189 g of 4(1H-indazol-6-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile hydrochloride was obtained as a solid, mp 100 °C (decomposition); mass spectrum (electrospray, m/e): M+H 459.2146.

- 62 Example 140

4-(3H-Benzotriazol-5-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile hydrochloride

A mixture of 0.362 g of 4-chloro-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile, 0.268 g of 5-aminobenzotriazole, and 10 ml of ethoxyethanol was refluxed with stirring for 30 minutes. The mixture was cooled and added to 50 ml of 5:5:2 ethyl acetate/acetone/methyl alcohol. The product was collected, washed with water, dried, and washed with 10 ml of 4:1 hexanes/ethyl acetate. 0.142 g of 4-(3H-benzotriazol-6-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile hydrochloride was obtained as a solid, mp 260 °C (decomposition); mass spectrum (electrospray, m/e): M+H 460.2096.

141, example

4-(1H-Indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 159.8 mg (1.2 mmol) of 6-aminoindazole in 10 ml of 2-ethoxyethanol was added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hour, then cooled, the bulk of the solvent was evaporated, and the residue was diluted with ether. The precipitate was collected by filtration and taken up in water. The aqueous suspension was adjusted to pH 7-8 by adding saturated aqueous sodium carbonate solution and stirred for 15 minutes. The precipitated solid was filtered, washed with water and ether, and dried in vacuo. 297.5 mg (94.3%) of product were obtained as a dark yellow solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 315.8; HRCIMS m/z: calcd for C| ₈ H| ₃ N ₅ O (M ⁺ ): 315.112; found: 315.1124.

Example 142

4-(3H-Benzotriazol-5-ylamino)-6-methoxyquinoline-3-carbonitrile

The procedure described in Example 141 was followed by the reaction of 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole to give 302.9 mg (95.8%) of the product as a yellow solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 316.9; HRCIMS m/z: calculated for the formula C ₇ H| ₂ N ₆ O (M ⁺ ): 316.107; found: 316.1081.

Example 143

4-(1H-Indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile

As described in Example 141, 200.0 mg (0.914 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol in the presence of 105.6 mg (0.914 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.1 mmol) of 6-aminoindazole to give 280.0 mg (97.3%) of the product as _a dark yellow solid, _melting point >250 °C; mass spectrum (electrospray, m/e): M+H 315.9; HRCIMS m/z: calculated for the formula _C18H13N5O (M ⁺ ): 315.112; found: 315.1124.

144, example

4-(3H-Benzotriazol-5-ylamino)-7-methoxyquinoline-3-carbonitrile

The procedure is as described in Example 141, 218.6 mg (1.0 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol in the presence of 115.6 mg (1.0 mmol) of pyridine hydrochloride 161.0 mg

- 63 (1.2 mmol) was reacted with 5-aminobenzotriazole to give 231.0 mg (73.1%) of the product as a light brown solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 316.9;

HRCIMS m _/ z: calcd for _C17H12N6O ( ^M+ ₎ : 316.107; found: 316.1063.

Example 145

7-Hydroxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile

A mixture of 1.74 g (5.52 mmol) of 4-(1H-indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile and 15.3 pyridine hydrochloride was heated at 200-210 °C for 1.5 h. After cooling, the mixture was taken up in 3% aqueous ammonium hydroxide solution. The precipitate was collected by filtration, washed with water, and dried in vacuo. 1.66 g (63.8%) of the product was obtained as a dark solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 301.9; HRCIMS m/z: calcd for C| ₇ HhN _s O (M ⁺ ): 302.1042; found: 302.1079.

Example 146

4-(1H-Indol-5-ylamino)-7-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 141, 1.0 g (4.57 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile, 724.8 mg (5.48 mmol) of 5-aminoindole and 528.3 mg (4.57 mmol) of 5-aminoindole in 35 mL of 2-ethoxyethanol were heated at 120 °C for 2 h. The reaction mixture was worked up to give 1.38 g of product as a greenish-gray solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 314.9; HRCIMS m/z: calcd for C ₁₉ H| ₄ N ₄ O (M ⁺ ): 314.117; found: 314.1135.

Example 147

7-Hydroxy-4-(3-benzotrizol-5-ylamino)quinoline-3-carbonitrile

Following the procedure described in Example 145, 1.45 g (4.58 mmol) of 4-(3H-benzotriazol-5-ylamino)-7-methoxyquinoline-3-carbonitrile and 10 g of pyridine hydrochloride were heated for 1 hour. Workup of the reaction mixture afforded 1.04 g (75.4%) of the product as a dark brown solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 303.3; HRCIMS m/z: calcd for C| ₆ H| ₀ N ₆ O (M ⁺ ): 301.0838; found: 301.0833.

Example 148

4-(1H-Indazol-6-ylamino)-8-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 141, 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 219.7 mg (1.65 mmol) of 6-aminoindazole, and 105.6 mg (173.3 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol were heated at 100 °C for 2 h. The reaction mixture was worked up to give 373.8 mg (79%) of the product as a yellow solid, mp 242 °C (dec); mass spectrum (electrospray, m/e): M+H 315.9. HRCIMS m/z: calcd for C| ₈ H| ₃ N ₅ O (M ⁺ ): 315.112; found: 315.1126.

Example 149

4-(3H-Benzotriazol-5-ylamino)-8-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol were heated at 100 °C for 2 h. The reaction mixture was worked up to give 213.5 mg (67.6%) of the product as a yellow solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 316.9; HRCIMS m/z: calcd for Ci ₇ H ₁₂ N ₆ O (M ⁺ ): 316.107; found: 316.1079.

Example 150

4-(1H-Indol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

Following the procedure described in Example 141, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 158.6 mg (1.2 mmol) of 5-aminoindole and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 10 mL of 2-ethoxyethanol for 0.5 h. The reaction mixture was worked up to give 338.7 mg (98.5%) of the product as a yellow solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 344.9; HRCIMS m/z: calcd for C ₂ oH| _ö N ₄ 0 ₂ (M ⁺ ): 344.127; found: 344.1277.

Example 151

4-(1H-Benzimidazol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

Following the procedure described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 159.8 mg (1.2 mmol) of 5-aminobenzimidazole and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 10 mL of 2-ethoxyethanol for 1 hour. The reaction mixture was worked up to give 233.6 mg (67.7%) of the product as a brown solid, melting point 230 °C (decomposition); mass spectrum (electrospray, m/e): M+H 345.9; HRCIMS m/z: calcd for Ci ₉ H|5N ₅ O ₂ (M ⁺ ): 346.1304; found: 346.1325.

Example 152

6,7-Dimethoxy-4-(2-methyl-1H-benzimidazol-5-ylamino)quinoline-3-carbonitrile

Following the procedure described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 294.4 mg (2.0 mmol) of 2-methyl-5-aminobenzimidazole and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 10 mL of 2-ethoxyethanol for 4 h. The reaction mixture was worked up to give 220.2 mg (61.3%) of the product as a sandy solid, melting point 207 °C (decomposition); mass spectrum (electrospray, m/e): M+H 359.9; HRCIMS m/z: calcd for C ₂₀ H ₁₇ N ₅ O ₂ (M ⁺ ): 359.138; found: 359.1403.

Example 153

6,7-Dimethoxy-4-(quinolin-6-ylamino)quinoline-3-carbonitrile

Following the procedure described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 173.8 mg (1.2 mmol) of 6-aminoquinoline and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 15 mL of 2-ethoxyethanol for 6 hours. The reaction mixture was worked up to give 212.5 mg (59.5%) of the product as an orange solid, mp 241-243 °C; mass spectrum (electrospray, m/e): M+H 356.8; HRCIMS m/z: calcd for C ₂ oH| ₇ N ₅ 0 ₂ (M ⁺ ): 356.127; found: 356.1275.

Example 154

4-(4-Chloronaphthalene-1-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile

Following the procedure described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 213.2 mg (1.2 mmol) of 1-amino-4-chlorophthalein and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 12 mL of 2-ethoxyethanol overnight. The reaction mixture was worked up to give 290.1 mg (74.4%) of the product as a yellowish-green solid, melting point >250 °C; mass spectrum (electrospray, m/e): M+H 390.2; HRCIMS m/z: C ₂₂ H|6NjO ₂ C1 (MJ calcd for the formula: 389.093; found: 389.0938.

Example 155

6,7-Dimethoxy-4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)-quinoline-3-carbonitrile

Following the procedure described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 176.7 mg (1.2 mmol) of 1-amino-5,6,7,8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 12 mL of 2-ethoxyethanol for 2 hours. The reaction mixture was worked up to give 195.1 mg (54.3%) of the product as a yellow solid; mp 248 °C (decomposition); mass spectrum (electrospray, m/e): M+H 360.1; HRCIMS m/z: calcd for C ₂₂ H| ₆ N ₃ O ₂ C1 (M ⁺ ): 359.163; found: 359.1632.

Example 156

4-(3H-Benzotriazol-5-ylamino)-6,7,8-trimethoxyquinoline-3-carbonitrile

Following the procedure described in Example 150, 278.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 161.3 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride were refluxed in 10 ml of 2-ethoxyethanol for 10 min. The reaction mixture was worked up to give 246.3 mg (65.4%) of the product as a yellow solid, mp 205 °C (decomposition); mass spectrum (electrospray, m/e): M+H 376.9; HRCIMS m/z: calcd for C _l9 H|6N ₆ O ₃ (M ⁺ ): 376.128; found: 376.1264.

157, example

4-(1H-Indazol-6-ylamino)-6-methoxy-7-|2-(4-methylpiperazin-1-yl)ethoxylquinoline-3-carbonitrile

A mixture of 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 500.9 mg (5 mmol) of 1-methylpiperazine and 74.5 mg (0.5 mmol) of sodium iodide in 10 mL of DME was heated at 135 °C under nitrogen for 15 h in a sealed tube. After cooling, the solvent was removed and the residue was taken up in 15 mL of brine. The aqueous solution was extracted with 15% methanol/methylene chloride. The organic phase was dried over sodium sulfate and filtered. Removal of the solvent gave a solid crude product. The crude product was purified by preparative TLC (eluent: 15% methanol/methylene chloride). A solid was obtained as a yellow foam. Trituration of the foam with ether gave 117.9 mg (51.6%) of the product as a yellow solid, mp 179 °C (dec.), mass spectrum (electrospray, m/e): M+H 458.0.

Example 158

7-{2-[(2-Hydroxyethyl)amino|ethoxy}-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 157, 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 375.6 mg (5.0 mmol) of 2-(methylamino)ethanol, and 75.0 mg (0.5 mmol) of sodium iodide were heated in 5 mL of DME at 135 °C for 15 h. The reaction mixture was worked up to give 116.4 mg (54.0%) of the product as a yellow solid, mp 179 °C (dec); mass spectrum (electrospray, m/e): M+H 433.0.

Example 159

7-{2-[Bis-(2-hydroxyethyl)amino]ethoxy}-4-(1H-indazol-6-ylamino)-6-methoxyquinol-3-carbonitrile

Following the procedure described in Example 157, 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 525.7 mg (5.0 mmol) of diethanolamine, and 75.0 mg (0.5 mmol) of sodium iodide were heated in 6 mL of DME at 135 °C for 15 h. The reaction mixture was worked up

- 66 190.1 mg (47.2%) of product are obtained as a yellow solid, melting point 150 °C (decomposition); mass spectrum (electrospray, m/e): M+H 463.0.

Example 160

7-[2-(4-Hydroxypiperidin-1-yl)ethoxy-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 157, 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 505.8 mg (5.0 mmol) of 4-hydroxypiperidine, and 75.0 mg (0.5 mmol) of sodium iodide were heated in 5 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 97.9 mg (42.8%) of the product as an off-white solid, mp 174 °C (dec); mass spectrum (electrospray, m/e): M+H 459.0.

Example 161

7-{2-[(4-(2-Hydroxyethyl)piperazin-1-yl)ethoxy-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 157, 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 651.0 mg (5.0 mmol) of 1-(2-hydroxyethyl)piperazine, and 75.0 mg (0.5 mmol) of sodium iodide were heated in 5 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 90.5 mg (37.1%) of the product as a yellow solid, mp 174 °C (dec); mass spectrum (electrospray, m/e): M+H 488.0.

Example 162

7-[2-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3carbonitrile

Following the procedure described in Example 157, 196.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 716.0 mg (5.0 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 75.0 mg (0.5 mmol) of sodium iodide were heated in 5 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 173.1 mg (69.2%) of the product as an off-white solid, mp 245 °C (decomposition); mass spectrum (electrospray, m/e): M+H 501.0.

Example 163

4-(1H-Indazol-6-ylamino)-6-methoxy-7-[2-(thiomorpholin-4-yl)ethoxy|quinoline-3-carbonitrile

Following the procedure described in Example 157, 173.0 mg (0.44 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 454.0 mg (4.4 mmol) of thiomorpholine, and 66.0 mg (0.44 mmol) of sodium iodide were heated in 4 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 108.4 mg (53.5%) of the product as a pale yellow solid, mp 213-215 °C; mass spectrum (electrospray, m/e): M+H 461.0.

Example 164

7-[2-([1.3]Dioxolan-2-ylmethyl-methylamino)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3carbonitrile

Following the procedure described in Example 157, 173.0 mg (0.44 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 515.5 mg (4.4 mmol) of 2-([1,3]dioxolan-2-ylmethylmethylamine, and 66.0 mg (0.44 mmol) of sodium iodide were heated in 4 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 136.1 mg (65.2%) of the product as a yellow solid, mp 185-187 °C; mass spectrum (electrospray, m/e): M+H 475.1.

- 67 Example 165

7-(2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 157, 173.0 mg (0.44 mmol) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 586.0 mg (4.4 mmol) of 1,2,3,4-tetrahydroisoquinoline, and 66.0 mg (0.44 mmol) of sodium iodide were heated in 4 mL of DME at 135 °C for 16 h. The reaction mixture was worked up to give 109.3 mg (50.6%) of the product as a yellow solid, mp 170-173 °C; mass spectrum (electrospray, m/e): M+H 491.0.

Example 166

7-(2-Chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

A mixture of 0.50 g (1 equivalent) of 7-(2-chloroethoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile, 0.25 g (1.1 equivalent) of 6-aminoindazole, 0.22 g (1.1 equivalent) of pyridine hydrochloride and 15 ml of 2-methoxyethanol was heated at 120 °C in an oil bath for 2 hours. The course of the reaction was monitored by thin layer chromatography (acetone/hexane = 1:1). After 2 hours, the reaction mixture was cooled to room temperature, a total of 25 ml of 1 M sodium bicarbonate was added and the reaction mixture was stirred for 1 hour. The resulting precipitate was collected, washed with water and dried in vacuo at 60 °C overnight. 0.645 g (97%) of the desired product was obtained; mass spectrum (electrospray, m/e): M+H 393.9 (M+H) ⁺ .

Elemental analysis results based on the formula C ₂ oHi ₆ C1N ₅ 0 ₂ -2H ₂ 0:

calculated: C = 55.88%, H = 4.69%, N = 16.29%;

Found: C = 55.63%, H = 4.78%; N = 15.24%.

Example 167

7-(2-Dimethylaminoethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

A mixture of 0.67 g (1 equiv) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equiv) of sodium iodide and 15 ml of 2 M dimethylamine in tetrahydrofuran was heated at 135 °C for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, the organic phase was dried over magnesium sulfate and concentrated. The resulting 0.50 g of crude product was purified by chromatography (silica gel; ethyl acetate, 6:4:0.1 ethyl acetate/methyl alcohol/triethylamine). 0.312 g (46%) of pure product was obtained, melting point 218-219 °C; mass spectrum (electrospray, m/e): M+H 402.9.

Example 168

4-(1H-Indazol-6-ylamino)-6-methoxy-7-[2-(morpholin-4-yl)ethoxy]quinoline-3-carbonitrile

Following the procedure described in Example 167, using 0.616 g of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.094 g of sodium iodide and 2.03 ml of morpholine, chromatographic purification (silica gel; ethyl acetate, 6:4:0.1 ethyl acetate/methyl alcohol/triethylamine) afforded 0.196 g (28%) of the title product, mp 133-135 °C; mass spectrum (electrospray, m/e): M+H 445.0.

Example 169

4-(3H-Benzotriazol-5-ylamino)-7-(2-chloroethoxy)-6-methoxyquinoline-3-carbonitrile

Proceeding as described in Example 166, using 0.442 g of 7-(2-chloroethoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile, 0.22 g of 5-aminobenzotriazole, 0.190 g of pyridine hydrochloride and 15 ml of 2-methoxyethanol, 0.48 g (82%) of the title product were obtained; mass spectrum (electrospray, m/e): M+H 394.8.

Example 170

7-(3-Chloropropoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile

Following the procedure described in Example 166, 0.311 g of 7-(3-chloropropoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile, 0.147 g of 6-aminoimidazole, 0.128 g of pyridine hydrochloride and 12 ml of ethoxyethanol were used to obtain 0.367 g (90%) of the title product, mp 280-285 °C; mass spectrum (electrospray, m/e): M+H 407.9.

Example 171

4-(1H-Indazol-6-ylamino)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile

Proceeding as described in Example 167, using 0.408 g of 7-(3-chloropropoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 1.4 ml of morpholine, 0.060 g of sodium iodide and 12 ml of ethylene glycol dimethyl ether, 0.255 g (56%) of the desired product was obtained, melting point 143-145 °C; HRMS: C ₂₅ H ₂₆ N ₆ O ₃ : m/z 458.2084; δ (mu)-1.7.

Example 172

4-[3-Chloro-4-(1-methyl-2-imidazolylthio)phenylamino]-6,7-diethoxy-3-quinolinecarbonitrile

Following the procedure described in Example 141, 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile was reacted with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO 96/15118) to give the title compound as a tan solid, m.p. 285-290 °C.

Example 173

4-[3-Chloro-4-(1-methyl-2-imidazolylthio)phenylamino]-6,7-diethoxy-3-quinolinecarbonitrile

As described in Example 141, 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile was reacted with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO 96/15118) to give the title compound as a white solid, m.p. 302-307 °C.

Example 174

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-nitroquinoline-3-carbonitrile

A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml of ethanol and 6.18 g (25.8 mmol) of 3chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)aniline (WO 96/15118) was heated to reflux under nitrogen. After 3.5 hours, the heating was stopped and the solution was basified with saturated sodium bicarbonate. The solvents were distilled off and the residue was azeotroped with ethanol. The residue was suspended in hexane and the solid was collected, washed with water and dried in vacuo. The solid was boiled in hexane to remove excess aniline and air dried. The residue was boiled in 2 L of ethyl acetate and, due to extreme insolubility, the solid was collected and dried in vacuo to give 5.90 g of a yellow solid; mass spectrum (electrospray, m/e): M+H 437.2, 439.1.

Example 175

6-Amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]quinoline-3-carbonitrile

A mixture of 5.734 g (13.1 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-nitroquinoline-3-carbonitrile, 250 ml of ethanol and 14.83 g (65.6 mmol) of tin chloride dihydrate is heated to reflux under nitrogen. After 2.5 hours, the heating is stopped and a large amount of ice water is added to the reaction mixture. The reaction mixture is basified with sodium bicarbonate and stirred for 2 hours. The still basic mixture is extracted with chloroform, the organic phase is stirred with Darco, dried over sodium sulfate and filtered. The solvent is evaporated and the residue is dried in vacuo.

2.86 g of a yellowish-brown solid were obtained; mass spectrum (electrospray, m/e):

M+H 407.3, 409.3.

Example 176

N-{4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfonyl)phenylaminol-3-cyanoquinolin-6-yl}acrylamide

1.00 g (2.46 mmol) of 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]quinoline-3carbonitrile was dissolved in 3.5 mL of hot DMF, 12 mL of THF was added, and the solution was cooled to 0 °C. 377 µL of triethylamine and 225 µL (2.70 mmol) of acryloyl chloride were added. The ice bath was removed after 15 min, and at the 2-h time point the solvent was distilled off. The residue was suspended in water, the solid was collected, and air-dried overnight. The material was boiled in ethyl acetate, the solid was collected, and dried in vacuo. 670 mg of a tan solid was obtained; mass spectrum (electrospray, m/e): M+H 461.1, 462.2.

Example 177

6-Amino-4-(1H-indol-5-ylamino)quinoline-3-carbonitrile

200 mg of palladium catalyst on a metal support containing 10% metal were covered with 75 ml of ethanol. 2.00 g (6.07 mmol) of 4-(1H-indol-5-ylamino)-6-nitroquinoline-3-carbonitrile and 477 μΐ (15.2 mmol) of hydrazine were added. The reaction mixture was refluxed under nitrogen for 2 h. The mixture was filtered hot through celite and washed with hot methanol. Removal of the solvent and drying in vacuo at 50 °C gave 1.89 g of a brown solid; mass spectrum (electrospray, m/e): M+H 300.2.

Example 178

3-Chloro-4-(1,3-thiazol-2-ylsulfanyl)aniline

To a suspension of 3.8 g of 60% sodium hydride in mineral oil in 100 ml of dimethylformamide was slowly added a solution of 10.0 g of 2-mercaptothiazole in 100 ml of dimethylformamide. After 15 minutes, 15.0 g of 3-chloro-4-fluoronitrobenzene dissolved in 50 ml of dimethylformamide was added. After 4 hours, the mixture was poured into water. The resulting solid was collected, washed with water and dried in vacuo. This material was refluxed under mechanical stirring in a mixture of 830 ml of methanol, 230 ml of water, 37.0 g of ammonium chloride and 30.1 g of iron powder for 4 hours. The hot mixture was filtered. The solvent was removed from the filtrate and the residue was extracted with hot ethyl acetate. The ethyl acetate solution was filtered through a short silica gel column. The solvent was removed and the residue was recrystallized from ether and hexane to give 17.7 g of an off-white solid; mass spectrum (electrospray, m/e): M+H 243.1.

By proceeding as above, we can also prepare the following intermediates required for the preparation of the compounds of the invention:

3-chloro-4-(1H-imidazol-1-yl)aniline,

2-[(4-amino-2-chlorophenyl)sulfanyl]-4(3H)-quinazolinone, N-(4-amino-2-chlorophenyl)-N-(3-pyridinylmethyl)acetamide, 2-chloro-N ^l -[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-l,4-benzenediamine, 3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]aniline,

- 70 3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]aniline,

4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-(trifluoromethyl)aniline,

4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-chloroaniline.

Example 179 1-(2-Chloro-4-aminobenzyl)-1H-imidazole A solution of 4-bromomethyl-3-chloronitrobenzene and 5.44 g of imidazole in 125 ml of tetrahydrofuran was heated at reflux for 4 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and dried over magnesium sulfate. The solvent was removed and the residue was extracted several times with ether. The ether extract was diluted with two volumes of hexanes. 4.3 g of 1-(2-chloro-4-nitrobenzyl)-1H-imidazole crystallized as a white solid. 4 g of the above material were mechanically stirred at reflux with 153 ml of methanol, 52 ml of water, 8.1 g of ammonium chloride and 6.6 g of iron powder for 2 hours. The hot mixture was filtered and the solid was washed with hot methanol/tetrahydrofuran. The solvents were removed from the combined filtrates. The residue was extracted several times with hot ethyl acetate. The ethyl acetate solution was treated with magnesium sulfate and activated charcoal. After filtration and removal of the solvent, 3.9 g of the title compound was obtained.

The compounds of the invention described in Table 5 are prepared using the methods described in Examples 1-179, as well as the methods described in WO 98/43960 and WO 99/09016.

Table 5

Example number Compound M.P. (°C) Mass spectrum 180. 4-(2-hydroxynaphthalene-1-ylamino)-6,7-dimethoxyquinoline- 3-carbonitrile 240 (decomposes) 371.9 (M+H) 181. 4-(2,3-Dihydrobenzo[1,4]dioxin-6-ylamino)-6,7- dimethoxyquinoline-3-carbonitrile 200-201 364.0 (M+H) 182. 4-(2-Mercaptobenzothiazol-6-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile >255 (decomposes) 394.8 (M+H) 183. 4-(6-Hydroxynaphthalen-1-ylamino)-6,7-dimethoxyquinoin- 3-carbonitrile 205 (decomposes) 372.0 (M+H) 184. 4-(1H-Indazol-6-ylamino)-5-Methoxyquinoline-3carbonitrile >260 315.8 (M+H) 185. 4-(2-Chloro-5-methoxyanilino)-5-methoxyquinoline-3-carbonitrile 185-187 339.9 (M+H) 186. 4-[(2-amino-4-chlorophenyl)amino]-6,7-dimethoxy-3quinolinecarbonitrile 215 (decomposes 354.9 (M+H)

- 71 continued from Table 5

Example number Compound M.P. (°C) Mass spectrum 187. 4-[(3-hydroxy-2-naphthyl)amino]-6,7-dimethoxy-3quinolinecarbonitrile 277-282 (decomposes 372.2 (M+H) 188. 4-{3-chloro-4-[(1-methyl-1H-imidazol-2yl)sulfanyl]anilino}-7-methoxy-6-nitro-3quinolinecarbonitrile 467.2 (M+H) 189. 6-amino-4-{3-chloro-4-[(1-methyl-1H-imidazole-2- yl)sulfanyl]anilino}-7-methoxy-3-quinolinecarbonitrile 437.0 (M+H) 190. (E)-N-(4-{3-chloro-4-[(1-methyl-1H-imidazol-2yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quinolinyl)-4- (dimethylamino)-2-butenamide 548.1 (M+H), 274.7 (M+2H) ⁺² 191. 4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-7-methoxy- 6-nitro-3-quinolinecarbonitrile 470.0 (M+H) 192. 6-amino-4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]- 7-Methoxy-3-quinolinecarbonitrile 440.1 (M+H) 193. (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 551.1 (M+H), 276.2 (M+2H) ⁺² 194. 4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-7-methoxy-6nitro-3-quinolinecarbonitrile 421.3 (M+H), 211.1 (M+2H) ⁺² 195. 6-Amino-4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-7-methoxy-3-quinolinecarbonitrile 391.2 (M+H), 196.2 (M+2H) ⁺² 196. (E)-N-{4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 502.4 (M+H), 251.7 (M+2H) ⁺² 197. 4- {3-chloro-4-[(4-oxo-3,4-dihydro-2- quinazolinyl)sulfanyl]amino}-7-methoxy-6-nitro-3quinolinecarbonitrile 531.2 (M+H), 266.2 (M+2H) ⁺² 198. 6-Amino-4-{3-chloro-4-[(4-oxo-3,4-dihydro-2quinazolinyl)sulfanyl]anilino}-7-methoxy-3quinolinecarbonitrile 501.3 (M+H), 251.1 (M+2H) ⁺² 199. (E)-N-(4-{3-chloro-[(4-oxo-3,4-dihydro--2- quinazolinyl)sulfanyl]anilino}-3-cyano-7-methoxy-6quinolinyl)-4-(dimethylamino)-2-butenamide 612.4 (M+H), 306.7 (M+2H) ⁺² 200. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(4-pyridinylmethyl)anilino]-3-quinolinecarbonitrile 139-141 510.2 (M+H), 255.7 (M+2H) ⁺²

- 72 continued from Table 5

Example number Compound M.P. (°C) Mass spectrum 201. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3-pyridinylmethyl)anilino]-3-quinolinecarbonitrile 112-114 510.3 (M+H), 255.7 (M+2H) ⁺² 202. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-pyridinylmethyl)anilino]-3-quinolinecarbonitrile 168-170 510.2 (M+H), 255.7 (M+2H) ⁺² 203. (E)-N-(4-{4-[acetyl-(3-pyridinylmethyl)amino]-3-chloroanilino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide 584.1 (M+H), 292.7 (M+2H) ⁺² 204. N-{2-chloro-4-[(3-cyano-7-methoxy-6-nitro-4quinolinyl)amino]phenyl}-N-(3-pyridinylmethyl)acetamide 503.1 (M+H), 252.1 (M+2H) ⁺² 205. N-{4-[(6-amino-3-cyano-7-methoxy-4-quinolinyl)amino]- 2-Chlorophenyl}-N-(3-pyridinylmethyl)acetamide 473.1 (M+H), 237.2 (M+2H) ⁺² 206. N-(4-{[6-(Acetylamino)-3-cyano-7-methoxy-4quinolinyl]amino}-2-chlorophenyl)-N-(3pyridylmethyl)acetamide 515.1 (M+H) 207. 4-[3-chloro-4-(1,3-dimethyl-2,4,6-trioxo-hexahydro-5-pyrimidinyl)anilino]-7-methoxy-6-mtro-3-quinolinecarbonitrile 270-272 509.2 (M+H) 208. 4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino} - 7-Methoxy-6-nitro-3-quinolinecarbonitrile 256-262 546.2 (M+H) 209. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3thienylmethyl)anilino]-3-quinolinecarbonitrile 152-153 515.3 (M+H), 258.3 (M+2H) ⁺² 210. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2thienylmethyl)aniline]-3-quinolinecarbonitrile 152-154 515.3 (M+H), 258.3 (M+2H) ⁺² 211. 6-Methoxy-4-(4-phenoxyanilino)-7-[2-(2H-1,2,3-triazol- 2-yl)ethoxy]-3-quinolinecarbonitrile 154-155 479.3 (M+H) 212. 6-Methoxy-4-(4-phenoxyanilino)-7-[2-(1H-1,2,3-triazole- 1-yl)ethoxy]-3-quinolinecarbonitrile 188-189 479.3 (M+H) 213. 4-(4-benzylanilino)-6-methoxy-7-[2-(2H-1,2,3-triazol2-yl)ethoxy]-3-quinolinecarbonitrile 167-170 477.4 (M+H) 214. 4-(4-benzylanilino)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-3-quinolinecarbonitrile 477.5 (M+H) 215. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-pyridinyloxy)anilino]-3-quinolinecarbonitrile 127-130 512.6 (M+H), 256.8 (M+2H) ⁺² 216. 4-{3-chloro-4-[(1-methyl-1H-imidazole-2- -yl)sulfanyl]anilino}-6-methoxy-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 234-235 565.4 (M+H), 283.5 (M+2H) ⁺²

- 73 continued from Table 5

Example number Compound Op. CQ Mass spectrum 217. 4-[4-(2-furylmethyl)anilino]-6-methoxy-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 149-151 499.5 (M+H), 250.3 (M+2H) ⁺² 218. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(tetrahydro- 2-furanylmethyl)anilino]-3-quinolinecarbonitrile 132-134 503.4 (M+H), 252.4 (M+2H) ⁺² 219. 4-[4-(3-furanylmethyl)anilino]-6-methoxy-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 163-165 499.5 (M+H), 250.3 (M+2H)* ² 220. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(tetrahydro- 3-furanylmethyl)aniline]-3-quinone linkercarbonitrile 123-125 503.4 (M+H), 252.2 (M+2H) ⁺² 221. 4-(3-chloro-4-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]anilino}anilino)-7-ethoxy-6-nitro-3quinolinecarbonitrile 536.1 (M+H) 222. (E)-N-[4-(3-chloro-4- {[5-(trifluoromethyl)-1,3,4-thiadiazol- 2-yl]amino}anilino)-3-cyano-7-ethoxy-6-quinolinyl]-4- -(dimethylamino)-2-butenamide 617.3 (M+H), 309.3 (M+2H) ⁺² 223. 4-[3-chloro-4-(4-pyridinyloxy)anilino]-7-ethoxy-6-nitro-3quinolinecarbonitrile 462.2 (M+H), 231.6 (M+2H) ⁺² 224. 6-amino-4-[3-chloro-4-(4-pyridinyloxy)anilino]-7-ethoxy-3quinolinecarbonitrile 432.4 (M+H), 216.6 (M+2H) ⁺² 225. (E)-N-{4-[3-chloro-4-(4-pyridinyloxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl} — 4-(dimethylamino)-2-butenamide 543.4 (M+H), 272.2 (M+2H) ⁺² 226. 4-{3-chloro-4-[(3-pyridinylmethyl)amino]anilino}-7- methoxy-6-nitro-3-quinolinecarbonitrile 461.3 (M+H), 231.4 (M+2H) ⁺² 227. 6-amino-4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2- yl)sulfanyl]anilino}-7-methoxy-3-quinolinecarbonitrile 166-172 516.2 (M+H) 228. 6-amino-4-(3-chloro-4-{[5-(trifluoromethyl)-1,3,4thiadiazol-2-yl]amino}anilino)-7-ethoxy-3- quinolinecarbonitrile 506.3 (M+H) 229. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-phenylethyl)anilino]-3-quinolinecarbonitrile 106-108 523.5 (M+H), 262.4 (M+2H) ⁺² 230. (E)-N-(4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2- yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide 154-157 627.3 (M+H), 314.3 (M+2H) ⁺² 231. 4-[3-Chloro-4-(1H-imidazol-1-yl)anilino]-6-methoxy-7-[3(4-morpholinyl)propoxy]-3-quinolinecarbonitrile 130-133 519.3 (M+H), 260.3 (M+2H) ⁺² 232. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3-pyridyloxy)anilino]-3-quinolinecarbonitrile 135-137 512.2 (M+H), 256.7 (M+2H) ⁺²

- 74 continued from Table 5

Example number Compound Op· (°C) Mass spectrum 233. 4-[3-Chloro-4-(4-pyridinyloxy)anilino]-6-methoxy-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 174 (decomposes) 546.1 (M+H), 273.8 (M+2H) ⁺² 234. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(4-pyridinyloxy)anilino]-3-quinolinecarbonitrile 129-131 512.1 (M+H), 256.8 (M+2H) ⁺² 235. 4-[2-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-6methoxy-7-[3-(4-morpholinyl)propoxy]-3- quinolinecarbonitrile 122 568.0 (M+H), 284.7 (M+2H) ⁺² 236. N-[2-chloro-4-({3-cyano-6-methoxy-7-[3-(4morpholinyl)propoxy]-4-quinolinyl}amino)phenyl]-N-(3pyridinylmethyl)acetamide 120 (decomposes) 601.1 (M+H), 301.3 (M+2H) ⁺² 237. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1Htetrazol-5-ylmethyl)anilino]-3-quinolinecarbonitrile 208 (decomposes) 501.2 (M+H), 251.0 (M+2H) ⁺² 238. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2H-1,2,3- triazol-2-ylmethyl)anilino]-3-quinolinecarbonitrile 186-187 500.3 (M+H), 250.8 (M+2H) ⁺² 239. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1H-1,2,3triazol-1-ylmethyl)anilino]-3-quinolinecarbonitrile 200-201 500.2 (M+H), 250.7 (M+2H) ⁺² 240. 4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[2-(2H1,2,3-triazol-2-yl)ethoxy]-3-quinolinecarbonitrile 223-226 485.1 (M+H) 241. 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[2-(1H- 1,2,3-triazo (1-1-yl)ethoxy]-3-quinol incarbonitrile 196-197 485.1 (M+H) 242. 7-ethoxy-6-nitro-4-[4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]- 3-(trifluoromethyl)anilino]-3-quinolinecarbonitrile 594.0 (M+H) 243. 6-amino-7-ethoxy-4-[4-[(4-phenyl-1,3-thiazol-2yl)sulfanyl]-3-(trifluoromethyl)anilino]-3quinolinecarbonitrile 564.0 (M+H) 244. (E)-N-{3-cyano-7-ethoxy-4-[4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-(trifluoromethyl)anilino]-6-quinolinyl}-4-(dimethylamino)-2-butenamide 675.0 (M+H), 338.3 (M+2H) ⁺² 245. 4-[3-chloro-4-(1H-imidazol-1-ylmethyl)anilino]-7-ethoxy-6nitro-3-quinolinecarbonitrile 449.1 (M+H), 225.2 (M+2H) ⁺² 246. 6-amino-4-[3-chloro-4-(1H-imidazol-1-ylmethyl)anilino]- 7-ethoxy-3-quinolinecarbonitrile 419.2 (M+H), 210.3 (M+2H) ⁺² 247. (E)-N-{4-[3-chloro-4-(1H-imidazol-1-ylmethyl)anilino]3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 530.2 (M+H), 265.8 (M+2H) ⁺²

- 75 continued from Table 5

Example number Compound Op. ( ⁿ C) Mass spectrum 248. 4-p-chloro-4-[(4-methyl-Z-pyrinyl)sulfonyl]7-ethoxy-6-nitro-3-quinolinecarbonitrile 493.0 (M+H) 249. 6-amino-4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-3-quinolinecarbonitrile 463.1 (M+H) 250. (E)-N-(4-{3-chloro-4-[(4-methyl-2-pyri- midinyl)sulfanyl]anilino}-3-cyano-7-ethoxy-6quinolinyl)-4-(dimethylamino)-2-butenamide 574.1 (M+H), 287.8 (M+2H) ⁺² 251. 4- {3 -chloro-4- [(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-6-nitro-3quinolinecarbonitrile 507.1 (M+H) 252. 6-amino-4-{3-chloro-4-[(4,6-dimethyl-2- -pinamiinyl)sulfanyl]anilino}-7-ethoxy-3-quinolinecarbonitrile 477.1 (M+H) 253. (E)-N-(4-{3-chloro-4-[(4,6-dimethyl-2-pi- rimidinyl)sulfanyl]anilinoJ-3-cyano-7-ethoxy-6- quinolinyl)-4-(dimethylamino)-2-butenamide 588.1 (M+H), 294.8 (M+2H) ⁺² 254. 4-[4-(1H-imidazol-2-ylmethyl)anilino]-6-methoxy-7-[3(4-morpholinyl)propoxy]-3-quinolinecarbonitrile 156-158 499.3 (M+H), 250.3 (M+2H) ⁺² 255. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1Htetrazol-1-ylmethyl)anilino]-3-quinolinecarbonitrile 180 (decomposes) 501.3 (M+H), 251.3 (M+2H) ⁺² 256. 6-Methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2Htetrazol-2-ylmethyl)anilino]-3-quinolinecarbonitrile 123 (decomposes) 501.2 (M+H), 251.3 (M+2H) ⁺² 257. 4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidine- nyl)sulfanyl]anilino}-6-methoxy-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 110-113 591.1 (M+H), 296.2 (M+2H) ⁺² 258. 4-{3-Chloro-4-[(4-methyl-2-pyrimiamyl)sulfanyl]anilino}6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile 10-113 577.1 (M+H), 289.2 (M+2H) ⁺² 577.1 (M+H), 289.2 (M+2H) ⁺² 259. (E)-N-[4-(3-chloro-4-{[2-(phenylsulfa- nyl)acetyl]amino}anilino)-3-cyano-7-methoxy-6quinolinyl]-4-(dimethylamino)-2-butenamide 194-198 601.3 (M+H), 301.1 (M+2H) ⁺² 260. 4-[4-(2,6-dimethoxyphenoxy)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile 160-162 571.4 (M+H)

- 76 continued from Table 5

Example number Compound M.P. (°C) Mass spectrum 261. 6-Methoxy-4-[4-(3-methoxyphenoxy)anilino]-7-[3-(4morpholinyl)propoxy]-3-quinolinecarbonitrile 132-134 541.5 (M+H) 262. 6-Methoxy-4-{4-[(1-methyl-1H-imidazole-2- yl)sulfanyl]anilino}-7-[3-(4-morpholinyl)propoxy]-3quinolinecarbonitrile 208-210 531.4 (M+H) 263. (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-[(2-methoxyethyl)( methyl)amino]-2-butenamide 595.1 (M+H), 298.1 (M+2H) ⁺² 264. (E)-N-(4-{3-chloro-4-[(5-phenyl-1,3-thiazol-2- yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quinolinyl)- 4-(Dimethylamino)-2-butenamide 627.1 (M+H), 314.1 (M+2H) ⁺² 265. (E)-N-(4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2- yl)sulfanyl]anilino}-3-cyano-7-ethoxy-6-quinolinyl)- 4-(dimethylamino)-2-butenamide 641.3 (M+H), 321.2 (M+2H) ⁺² 266. 4- {3 -chloro-4- [(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-6,7-dimethoxy-3- quinolinecarbonitrile 173-176 478.4 (M+H) 267. 6,7-dimethoxy-4-( {6-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]- 3-pyridinyl}amino)-3-quinolinecarbonitrile 250 (decomposes) 498.3 (M+H) 268. 4- {3 -chloro-4- [(1 -methyl-1 H-imidazol-2- -yl)sulfanyl]anilino}-6-methoxy-7-[3-(2H-1,2,3-triazol2-yl)propoxy]-3-quinolinecarbonitrile 232-234 547.3 (M+H) 269. 4-{3-chloro-4-[( 1 -methyl-1H-imidazol-2- -yl)sulfanyl]anilino}-6-methoxy-7-[3-(1H-1,2,3-triazol-1-yl)propoxy]-3-quinolinecarbonitrile 208-210 547.3 (M+H)

Claims (32)

1.(1) compound of general formula - in the formula X is (A) a bicyclic aryl or bicyclic heteroaryl ring system of 8-12 carbon atoms, wherein the bicyclic heteroaryl ring contains 1-4 heteroatoms selected from N, O, and S, with the proviso that the bicyclic heteroaryl ring does not contain an O-O, S-S, or S-O bond, and wherein the bicyclic aryl or bicyclic heteroaryl ring is optionally halogen, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl group, C2-7 carboalkoxy group, C2-7 carboalkyl group, phenoxy group, phenyl group, thiophenoxy group, benzoyl group, benzyl group, amino group, C1-6 alkylamino group, C2-12 dialkylamino group, phenylamino group, benzylamino group, C1-6 alkanoylamino group, C3-8 alkenoylamino group, C3-8 alkynylamino group, C2-7 carboxyalkyl group, C3-8 carboalkoxyalkyl group, C1-5 aminoalkyl group, C2-9 N-alkylaminoalkyl group, C3-10 N,N-dialkylaminoalkyl group, C2-9 N-alkylaminoalkoxy group, C3-10 N,N-dialkylaminoalkoxy group, mercapto group and benzoylamino group may be mono-, di-, tri- or tetrasubstituted with a substituent; or X is a group of the general formula (B) -A-T-L, in which A is a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring is optionally halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl, C2-7 carboalkoxy, C2-7 carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, C1-6 alkylamino, C2-12 dialkylamino, phenylamino, may be mono- or disubstituted with a substituent selected from benzylamino, C1-6 alkanoylamino, C3-8 alkenoylamino, C3-8 alkynylamino, C2-7 carboxyalkyl, C3-8 carboalkoxyalkyl, C1-5 aminoalkyl, C2-9 N-alkylaminoalkyl, C3-10 N,N-dialkylaminoalkyl, C2-9 N-alkylaminoalkoxy, C3-10 N,N-dialkylaminoalkoxy, mercapto, methylmercapto and benzoylamino; - 78 T is attached to a carbon atom of A and is -0(CH2), _n -, -S( _CH2 ) _m -, -NR( _CH2 ) _m -, -( _CH2 ) _m NH-, -( _CH2 ) _m O-, -( _CH2 ) _m S-, or -( _CH2 ) _m NR-; L is an unsubstituted phenyl ring or a phenyl ring optionally substituted with a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an azido group, a C1-6 hydroxyalkyl group, a halomethyl group, a C2-7 alkoxymethyl group, a C2-7 alkanoyloxymethyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a hydroxyl group, a trifluoromethyl group, a cyano group, a nitro group, a carboxyl group, a C2-7 carboalkoxy group, a C2-7 carboalkyl group, a phenoxy group, a phenyl group, a thiophenoxy group, a benzoyl group, a benzyl group, an amino group, a C1-6 alkylamino group, a C2-12 dialkylamino group, a phenylamino group, a benzylamino group, a C1-6 is mono-, di- or trisubstituted with a substituent selected from alkanoylamino, C3-8 alkenoylamino, C3-8 alkynylamino, C2-7 carboxyalkyl, C3-8 carboalkoxyalkyl, C1-5 aminoalkyl, C2-9 N-alkylaminoalkyl, C3-10 N,N-dialkylaminoalkyl, C2-9 N-alkylaminoalkoxy, C3-10 N,N-dialkylaminoalkoxy, mercapto and benzoylamino; with the proviso that L can only be an unsubstituted phenyl group if m > 0 and T is other than -CH ₂ NH- or -CH ₂ O-; or L is a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain O-O, S-S or S-O bonds, and wherein the heteroaryl ring is optionally halogen, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, azido, C1-6 hydroxyalkyl, halomethyl, C2-7 alkoxymethyl, C2-7 alkanoyloxymethyl, C1-6 alkoxy, C1-6 alkylthio, hydroxyl, trifluoromethyl, cyano, nitro, carboxyl, C2-7 carboalkoxy, C2-7 carboalkyl, phenoxy, phenyl, may be mono- or disubstituted with a substituent selected from thiophenoxy group, benzoyl group, benzyl group, amino group, C1-6 alkylamino group, C2-12 dialkylamino group, phenylamino group, benzylamino group, C1-6 alkanoylamino group, C3-8 alkenoylamino group, C3-8 alkynylamino group, C2-7 carboxyalkyl group, C3-8 carboalkoxyalkyl group, C1-5 aminoalkyl group, C2-9 N-alkylaminoalkyl group, C3-10 N,N-dialkylaminoalkyl group, C2-9 N-alkylaminoalkoxy group, C3-10 N,N-dialkylaminoalkoxy group, mercapto group and benzoylamino group; Z is -NH-, -O-, -S- or -NR-; R is a C1-6 alkyl group or a C2-7 carboalkyl group; - 79 G _b G ₂ , R| and R4 is independently hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkenyloxy, C2-6 alkynyloxy, hydroxymethyl, halomethyl, C1-6 alkanoyloxy, C3-8 alkenoyloxy, C3-8 alkinoyloxy, C2-7 alkanoyloxymethyl, C4-9 alkenoyloxymethyl, C4-9 alkinoyloxymethyl, C2-7 alkoxymethyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C2-6 alkenylsulfonamido group, C2-6 alkynylsulfonamido group, hydroxyl group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, carboxyl group, C2-7 carboalkoxy group, C2-7 carboalkyl group, phenoxy group, phenyl group, thiophenoxy group, benzyl group, amino group, hydroxylamino group, C1-4 alkoxyamino group, C1-6 alkylamino group, C2-12 dialkylamino group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, C4-12 N-alkyl-N-alkenylamino group, C6-12 N,N-dialkenylamino group, phenylamino group, benzylamino group, group of general formula (a), (b), (c), (d) or (e); or R| and R4 is as defined above and G1 or _G2 or both are _R2 -NH-; or if any of the substituents _{Rb G2} , _G3 or R4 are located on adjacent carbon atoms, they may together form a divalent group of the formula -OC(R6) ₂ -O-; Y is -(CH ₂ ) _a divalent group selected from -, -O- and -NR 6 -; R7 ^is -NR6, -OR6, -J, -N(R6) ₃₊ or -NR6OR6; M is >NR6, -O-, >N-(C( _R6 ) _{2 ) pNR6R6} or >N-(C( _R6 ) _{2 ) p} - _OR6 ; W is >NR6, -O- or a bond; Seven is morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran or a heterocycle of general formula (f); where H is optionally mono- or disubstituted on a carbon or nitrogen atom with a U group, optionally mono- or disubstituted on a carbon atom with a hydroxyl group, a group of the general formula -N(R ₆ ) ₂ or -O¾, optionally mono- or disubstituted on a carbon atom with a monovalent group of the general formula -(C(R 6 ) ₂ ) _s OR6 or -(C(R 6 ) ₂ ) _S N(R 6 ) ₂ , or optionally mono- or disubstituted on a saturated carbon atom with a divalent group of the general formula -O- or -O(C(R 6 ) ₂ ) _S O-; R* represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 cycloalkyl group, a C2-7 carboalkyl group, a C2-7 carboxyalkyl group, a phenyl group or optionally a halogen atom, a C1-6 alkoxy group, a trifluoromethyl group, an amino group, a C1-3 alkylamino group, a C2-6 dialkylamino group, a nitro group, a cyano group, an azido group, a halomethyl group, a C2-7 alkoxymethyl group, a C2-7 alkanoyl group - a phenyl group substituted with one or more substituents selected from 80 oxymethyl groups, C1-6 alkylthio groups, hydroxyl groups, carboxyl groups, C2-7 carboalkoxy groups, phenoxy groups, phenyl groups, thiophenoxy groups, benzoyl groups, benzyl groups, phenylamino groups, benzylamino groups, C1-6 alkanoylamino groups and C1-6 alkyl groups; with the proviso that the alkenyl or alkynyl residue is attached to a nitrogen or oxygen atom through a saturated carbon atom; R ₂ is a group of general formula (g), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q), (r), (s), (t), (x), (y), (v), (w), (z), (aa), (bb), (cc), (dd), (ee) or (ff); R ₃ is independently selected from hydrogen, C 1-6 alkyl, carboxyl, C 1-6 carboalkoxy, phenyl, C 2-7 carboalkyl, (gg), (hh), (ii), (jj) or (kk); R 5 independently represents a hydrogen atom, a C 1-6 alkyl group, a carboxyl group, a C 1-6 carboalkoxy group, a phenyl group, a C 2-7 carboalkyl group, a group of general formula (gg), (hh), (ii), (jj) or (kk); R ₈ and R ₉ independently represent a group of the general formula -(C(R ₆ ) ₂ ) _r NR ₆ R _< 5 or -(C(R ₆ ) ₂ ) _r OR ₆ ; J is independently hydrogen, chlorine, fluorine or bromine; Q is C1-6 alkyl or hydrogen; the value of a is 0 or 1; g has a value of 1-6; k value is 0-4; n has a value of 0-1; m has a value of 0-3; p value is 2-4; q value is 0-4; r has a value of 1-4; s has a value of 1-6; u is 0-4 and v is 0-4, wherein the sum of u and v is 2-4 or a pharmaceutically acceptable salt thereof, with the proviso that when R^ is a C2-7 alkenyl group or a C2-7 alkynyl group, such alkenyl or alkynyl residue is attached to a nitrogen or oxygen atom through a saturated carbon atom; and with the further proviso that when Y is -NR 1 - and R ₇ is -NR 1 , -N 1 R 2 or -NR 1 R 3 , then g is 2-6; if M is -O- and _R7 is -OR7, then p is 1-4; when Y is -NRé-, then k is 2-4; if Y is -O- and M or W is -O-, then k is 1-4; if W is a bond to the Het group other than through its nitrogen atom, then q is 2-4; and if W is bonded to the Het group through a nitrogen atom thereof and Y is -O- or -NR ₆ -, - 81 then the value of k is 2-4. 2. A compound of general formula (1) or a pharmaceutically acceptable salt thereof, wherein X is as defined in claim 1 (A); or X is a group of the general formula (B) -A-T-L, wherein A has the meaning given in claim 1; T is attached to a carbon atom of A and is -NH(CH ₂ ) _m -, -O(CH ₂ ) _m -, -S(CH ₂ ) _ra -, -NR(CH ₂ ) _m -, -(CH ₂ ), _n -, -(CH ₂ ) _m NH-, -(CH ₂ ), _n O-, -(CH ₂ ) _m S-, or -(CH ₂ ), _n NR-; m is 0 or 3; R and L are as defined in claim 1; and Z, n, G _h G ₂ , R| and its declaration are as given in claim 1. 3. A compound of general formula (1) or a pharmaceutically acceptable salt thereof, wherein X is as defined in claim 1 (A); or X is a group of the general formula (B) -A-T-L, in which A has the meaning given in claim 1; T is attached to a carbon atom of A and is -NH(CH ₂ ) _m -, -O(CH ₂ ) _m -, -S(CH ₂ ) _in -, -NR(CH ₂ ) _in -, -(CH ₂ ) _m -, -(CH ₂ ) _m NH-, -(CH ₂ ) _m O-, -(CH ₂ ) _m S-, or -(CH ₂ ) _ra NR-; m is 0-3; L and R are as defined in claim 1, with the proviso that L is other than unsubstituted phenyl; and Z, n, G|, G ₂ , R| and Its statement is as given in claim 1. 4. A compound according to any one of claims 1-3, wherein Z is -NH- and n is 0, or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, wherein X is a substituted or unsubstituted bicyclic aryl or bicyclic heteroaryl ring system, or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 4, wherein X is a group of the general formula -A-T-L, wherein T and L are as defined in any one of claims 1-3, and A is an optionally substituted phenyl ring, or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 5, wherein R and R are hydrogen, or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 6, wherein R1 and R2 are hydrogen, or a pharmaceutically acceptable salt thereof. 9. The compound of claim 5, wherein the bicyclic aryl or bicyclic heteroaryl ring system is selected from the group consisting of naphthalene, 1,2,3,4-tetrahydronaphthalene, indane, Ι-χο-indane, 1,2,3,4-tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-1,3-dihydroisobenzofuran, benzothiaphene, 1,1-dioxobenzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, ΙΗ-indazole, indoline, benzopyrazole, 1,3benzodioxole, benzoxazole, purine, phthalimide, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyridine-, pyrido[3,4-b]pyrazine-, pyrido[3,2-c]pyridazine-, pyrido[3,4-b]pyridine-, lH-pyrazolo[3,4-d]pyrimidine-, 1,4-benzodioxane-, pteridine-, 2(lH)-quinolone-, l(2H)-isoquinolone-, 2-oxo-2,3-dihydro-benzthiazole-, 1,2-methylenedioxybenzene-, 2-oxindole-, 1,4-benzisoxazine-, benzothia- - 82 selected from azole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoazine, phthalazine, 1,4-dioxo-l,2,3,4-tetrahydrophthalazine, 2-oxo-1,2-dihydroquinoline, 2,4-dioxo-1,4-dihydro-2Hbenzo[d][l,3]oxazine, 2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepine and cinnoline rings, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 6, wherein L is an optionally substituted 5- or 6-membered heteroaryl ring, or a pharmaceutically acceptable salt thereof. 11. The compound of claim 7, wherein the heteroaryl ring is a pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole, or 1,2,4-triazole ring, or a pharmaceutically acceptable salt thereof. 12. The compound of claim 6, wherein L is a substituted phenyl group, or a pharmaceutically acceptable salt thereof. 13. A compound according to any one of claims 1-3, which compound is a compound of formula (24) or a pharmaceutically acceptable salt thereof, wherein R _h G ₂ , R 4 , Z, n and X are as defined in any one of claims 1-3, and R ₂ ' is a group of formula (11), (mm), (nn), (00), (pp), (qq), (rr), (ss), (tt), (uu), (vv), (xx), (yy) or (zz), wherein R ₆ , R ₃ , R 5 , J, p, s, r, u and v are as defined in claim 1. 14. The compound of claim 13, wherein Z is -NH- and n is 0, or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 14, wherein X is a group of the general formula -A-T-L, wherein T and L are as defined in any one of claims 1-3, and A is an optionally substituted phenyl ring, or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 15, wherein L is an optionally substituted 5- or 6-membered heteroaryl ring, or a pharmaceutically acceptable salt thereof. 17. The compound of claim 16, wherein the heteroaryl ring is a pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole, or 1,2,4-triazole ring, or a pharmaceutically acceptable salt thereof. 18. A compound according to any one of claims 13-17, wherein R1 and R2 are hydrogen, or a pharmaceutically acceptable salt thereof. 19. A compound of formula (64) or a pharmaceutically acceptable salt thereof, wherein R, s, _R , _{R ,} R, Z, n and X are as defined in any one of claims 1-3, and (R') ₂ N- is such that (R') ₂ NH is selected from list A, wherein R, p, r and s are as defined in claim 1. 20. The compound of claim 19, wherein Z is -NH- and n is 0, or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 20, wherein X is a group of the general formula -A-T-L, wherein T and L are as defined in any one of claims 1-3, and A is optionally - 83 substituted phenyl ring, or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 21, wherein L is an optionally substituted 5- or 6-membered heteroaryl ring, or a pharmaceutically acceptable salt thereof. 23. The compound of claim 22, wherein the heteroaryl ring is a pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole, or 1,2,4-triazole ring, or a pharmaceutically acceptable salt thereof. 24. A compound according to any one of claims 19-22, wherein R1 and R4 are hydrogen, or a pharmaceutically acceptable salt thereof. 25. A compound according to any one of claims 1-3, which compound is a compound of formula (61) or a pharmaceutically acceptable salt thereof, wherein R _b G ₂ , R 4 , Z, n and X are as defined in any one of claims 1-3. 26. A compound of formula (62) or a pharmaceutically acceptable salt thereof, wherein J' represents _a halogen atom selected from chlorine, bromine or iodine, or a tosylate group (p-toluenesulfonate) or a mesylate group (methanesulfonate), and K, R3, s, _RbG2 , R4, Z, n and X are as defined in any one of claims 1-3. 27. A compound that a) 4-(2,3-dihydro-1H-indol-6-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; b) 4-(benzothiazol-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; c) 4-(benzo[1,3]dioxol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; d) 6,7-diethoxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; e) 6,7-diethoxy-4-(4-methyl-2-oxo-2H-chromen-7-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; f) 6,7-diethoxy-4-(1H-indol-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; g) 6,7-dimethoxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; h) 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; i) 4-(2,3-dihydrobenzo[1,4]dioxin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; j) 4-(1H-indazol-6-ylamino)-6,7-bis(2-methoxyethoxy)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; k) 4-(1,4-dioxo-1,2,3,4-tetrahydrophthalazin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; - 84 1) 6,7-diethoxy-4-(indan-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; m) 4-(2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; n) 6,7-diethoxy-4-(3-oxo-1,3-dihydroisobenzofuran-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; o) 4-(1,1-dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; p) 4-(2,3-dihydro-1H-indol-6-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; q) 7-ethoxy-4-(indazol-6-ylamino)-6-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; r) 4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxy-7-[3-(pyridin-4-yl)propoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; s) 9-(1H-indazol-6-ylamino)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile, or a pharmaceutically acceptable salt thereof; t) 6,7-diethoxy-4-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; u) 4-(1H-indazol-6-ylamino)-6,7,8-trimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; v) 6,7-dimethoxy-4-(4-methyl-2-oxo-1,2-dihydroquinolin-7-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; w) 6,7-dimethoxy-4-(2-methylbenzothiazol-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; x) 6,7-dimethoxy-4-(2-oxo-2,3-dihydrobenzothiazol-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; y) 6,7-dimethoxy-4-(quinolin-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; z) 4-(isoquinolin-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; aa) 6,7-dimethoxy-4-(quinolin-8-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; bb) 4-(8-hydroxyquinolin-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; cc) 4-(1H-indol-4-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; dd) 4-(1H-indazol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ee) 4-(1H-indazol-6-ylamino)-5,8-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ff) 4-(1H-indazol-6-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile, or - 85 pharmaceutically acceptable salts thereof; gg) 4-(3H-benzotriazol-5-ylamino)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; hh) 4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ii) 4-(3H-benzotriazol-5-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; jj) 4-(1H-indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; kk) 4-(3H-benzotriazol-5-ylamino)-7-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 11) 7-hydroxy-4-(1H-indazol-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; mm) 4-(1H-indol-5-ylamino)-7-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; nn) 7-hydroxy-4-(3H-benzotriazol-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; oo) 4-(1H-indazol-6-ylamino)-8-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; pp) 4-(3H-benzotriazol-5-ylamino)-8-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; qq) 4-(1H-indol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; rr) 4-(1H-benzoimidazol-5-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ss) 6,7-dimethoxy-4-(2-methyl-1H-benzoimidazol-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; tt) 6,7-dimethoxy-4-(quinolin-6-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; uu) 4-(4-chlorophthalin-1-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; w) 6,7-dimethoxy-4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ww) 4-(3H-benzotriazol-5-ylamino)-6,7,8-trimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; xx) 4-(1H-indazol-6-ylamino)-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; yy) 7-{2-[(2-hydroxyethyl)amino]ethoxy}-4(1H)-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; zz) 7-{2-[bis(2-hydroxyethyl)amino]ethoxy}-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; aaa) 7-[2-(4-hydroxypiperidin-1-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; bbb) 7-{2-[(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ccc) 7-[2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ddd) 7-[2-([1,3]dioxolan-2-ylmethylmethylamino)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; eee) 7-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethoxy]-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; fff) 4-(1H-indazol-6-ylamino)-6-methoxy-7-[2-(thiomorpholin-4-yl)ethoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ggg) 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; hhh) 7-(2-dimethylaminoethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; iii) 4-(1H-indazol-6-ylamino)-6-methoxy-7-[2-(morpholin-4-yl)ethoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; jjj) 4-(3H-benzotriazol-5-ylamino)-7-(2-chloroethoxy)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; kkk) 7-(3-chloropropoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 111) 4-(1H-indazol-6-ylamino)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; mmm) 4-[3-chloro-4-(1-methyl-2-imidazolylthio)phenylamino]-6,7-diethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; nnn) 4-[3-chloro-(4-(1-methyl-2-imidazolylthio)phenylamino]-6,7-dimethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; ooo) 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ppp) N-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-3-cyanoquinolin-6-yl}acrylamide, or a pharmaceutically acceptable salt thereof; qqq) 6-amino-4-(1H-indol-5-ylamino)quinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; rrr) 4-(1H-indol-5-ylamino)-6-nitroquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; sss) 4-(2-hydroxynaphthalen-1-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; ttt) 4-(2,3-dihydrobenzo[1,4]dioxin-6-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; - 87 uuu) wv) www) xxx) yyy) zzz) aaaa) bbbb) cccc) dddd) eeee) ffff) gggg) hhhh) iiii) jjjj) kkkk) 1111) mmmm) nnnn) 4-(2-mercaptobenzothiazol-6-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 4-(6-hydroxynaphthalen-1-ylamino)-6,7-dimethoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 4-(1H-indazol-6-ylamino)-5-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 4-(2-chloro-5-methoxyanilino)-5-methoxyquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof; 4-[(2-amino-4-chlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-[(3-hydroxy-2-naphthyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilo}-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-(4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-7-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-7-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-{4-[3-chloro-4-(1H-imidazol-1-yl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]anilinol·7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]anilino}-7-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-(4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]amino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(4-pyridinylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3-pyridinylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; - 88 oooo) PPPP) qqqq) rrrr) ssss) tttt) uuuu) vvw) wwww) xxxx) yyyy) zzzz) aaaaa) bbbbb) ccccc) ddddd) eeeee) fffff) ggggg) hhhhh) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-pyridylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-(4-{4-[acetyl-(3-pyridinylmethyl)amino]-3-chloroanilino}-3-cyano-7-methoxy-6-quinolinyl)4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; N-{2-chloro-4-[(3-cyano-7-methoxy-6-nitro-4-quinolinyl)amino]phenyl}-N-(3-pyridinylmethyl)acetamide, or a pharmaceutically acceptable salt thereof; N-{4-[(6-amino-3-cyano-7-methoxy-4-quinolinyl)amino]-2-chlorophenyl}-N-(3-pyridinylmethyl)acetamide, or a pharmaceutically acceptable salt thereof; N-(4-{[6-(acetylamino)-3-cyano-7-methoxy-4-quinolinyl]amino}-2-chlorophenyl)-N-(3-pyridinylmethyl)acetamide, or a pharmaceutically acceptable salt thereof; 4-[3-chloro-4-(1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl)anilino]-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino}-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3-thienylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-thienylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-4-(4-phenoxyanilino)-7-[2-(2H-1,2,3-triazol-2-yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-4-(4-phenoxyanilino)-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-(4-benzylanilino)-6-methoxy-7-[2-(2H-1,2,3-triazol-2-yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-(4-benzylanilino)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-pyridinyloxy)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-[4-(2-furylmethyl)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(tetrahydro-2-furanylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-[4-(3-furylmethyl)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(tetrahydro-3-furanylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-(3-chloro-4-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]amino}-7-ethoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; nm) (E)-N-[4-(3-chloro-4-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]amino|anilino)-3-cyano-7-ethoxy- 6-quinolinyl]-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; JJJJJ) 4-[3-chloro-4-(4-pyridinyloxy)anilino]-7-ethoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; kkkkk) 6-amino-4-[3-chloro-4-(4-pyridinyloxy)anilino]-7-ethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 11111) (E)-N-{4-[3-chloro-4-(4-pyridinyloxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)2-butenamide, or a pharmaceutically acceptable salt thereof; mmmmm) 4-{3-chloro-4-[(3-pyridinylmethyl)amino]anilino}-7-methoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino }-7-methoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-(3-chloro-4-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]amino}anilino)-7-ethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; PPPPP) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2-phenylethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; qqqqq) (E)-N-(4-{3-chloro-4-[(4-phenyl-l,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quino- rrrrr) linyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-[3-chloro-4-( 1 H-imidazol-1 -yl)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; sssss) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(3-pyridinyloxy)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; ttttt) 4-[3-chloro-4-(4-pyridinyloxy)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; uuuuu) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(4-pyridinyloxy)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; vww) 4-[2-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; wwwww) N-[2-chloro-4-({3-cyano-6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl|amino)phenyl]-N-(3pyridinylmethyl)acetamide, or a pharmaceutically acceptable salt thereof; xxxxx) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1H-tetrazol-5-ylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; yyyyy) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2H-1,2,3-triazol-2-ylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; zzzzz) 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1H-1,2,3-triazol-1-ylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; aaaaaa) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[2-(2H-1,2,3-triazol-2-yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[2-( 1 H-1,2,3-triazol-1 -yl)ethoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; - 90 cccccc) dddddd) eeeeee) ffffff) gggggg) hhhhhh) iiiiii) jjjjjj) kkkkkk) 111111) mmmmmm) nnnnnn) oooooo) PPPPPP) qqqqqq) rrmr) ssssss) tttttt) uuuuuu) vwvw) 7-ethoxy-6-nitro-4-[4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-(trifluoromethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-7-ethoxy-4-[4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-(trifluoromethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-{3-cyano-7-ethoxy-4-[4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-(trifluoromethyl)anilino]-6-quinolinyl}-4-(dimethylamino)-3-butenamide, or a pharmaceutically acceptable salt thereof; 4-[4-chloro-4-(1H-imidazol-1-ylmethyl)anilino]-7-ethoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-[3-chloro-4-(1H-imidazol-1-ylmethyl)anilino]-7-ethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-{4-[3-chloro-4-(1H-imidazol-1-ylmethyl)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-(4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-6-nitro-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-amino-4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-(4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-[4-(1H-imidazol-2-ylmethyl)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(1H-tetrazol-1-ylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-[4-(2H-tetrazol-2-ylmethyl)anilino]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; (E)-N-[4-(3-chloro-4-{[2-(phenylsulfanyl)acetyl]amino}anilino)-3-cyano-7-methoxy-6-quinolinyl]4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; 4-[4-(2,6-dimethoxyphenoxy)anilino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; 6-methoxy-4-[4-(3-methoxyphenoxy)anilino]-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; - 91 wwwwww) 6-methoxy-4-{4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; xxxxxx) (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6-quinolinyl}-4-[(2methoxyethyl)methylamino]-2-butenamide, or a pharmaceutically acceptable salt thereof; yyyyyy) (E)-N-(4-{3-chloro-4-[(5-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; zzzzzz) (E)-N-(4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7-ethoxy-6-quinolinyl)4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof; aaaaaaa) 4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-6,7-dimethoxy-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; bbbbbbb) 6,7-dimethoxy-4-( {6-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]-3-pyridinyl} amino)-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof; or ccccccc) 4- {3-chloro-4-[( 1 -methyl-1H-imidazol-2-yl)sulfanyl]anilino} -6-methoxy-7-[3-( 1H-1,2,3-triazol-1-yl)propoxy]-3-quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof. 28. Use of a compound for the preparation of a pharmaceutical composition for treating, inhibiting the growth of, or eliminating tumors in a mammal in need thereof, wherein the compound used is a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein X, η, Z, R _b R 4, G 1 and G ₂ are as defined in any one of claims 1-3. 29. The use according to claim 28, wherein the tumor is a breast, kidney, bladder, oral, larynx, esophagus, stomach, colon, ovary or lung tumor. 30. Use of a compound for the preparation of a pharmaceutical composition for treating, inhibiting or ameliorating polycystic kidney disease in a mammal in need thereof, wherein the compound used is a compound of formula (1) according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof. 31. A pharmaceutical composition comprising a compound of formula (1) according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 32. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, comprising the steps of: a) a compound of general formula (99) - wherein R _b G _b G ₂ , R4, Z, n and X are as defined above, is reacted with a dehydrating agent to convert the aminocarbonyl group to a cyano group, or b) reacting a compound of the general formula A _r NH-A ₂ or a salt thereof with a compound of the general formula QA ₃ , where Q is a leaving group and A _b A ₂ and A ₃ are such that A _r NA ₂ -A ₃ forms a compound conforming to the general formula (1); or c) reacting a compound of the general formula A4-OH or a salt thereof with a compound of the general formula _QA5 , where Q is as defined above and A4 and _A5 are such that A4-O-A5 forms a compound conforming to the general formula (1); or d) the compound of general formula (1) is converted into an acid addition salt by reacting it with an acid.