MXPA01003227A - Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors - Google Patents

Abstract

This invention provides compounds of formula (1), wherein R1, G1, G2, R4, Z, X and n are defined herein, or a pharmaceutically acceptable salt thereof, which are useful as antineoplastic agents and in thetreatment of polycystic kidney disease.

Description

3-CYANOQUINOLINES SUBSTITUTED AS PROTEIN INHIBITORS TYROSINE KINASES BACKGROUND OF THE INVENTION This invention relates to certain substituted 3-cyano quinoline compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain protein tyrosine kinases (PTK) of the growth factor receptor, and other protein kinases which therefore inhibit the abnormal growth of certain cell types. The compounds of this invention are therefore useful for the treatment of certain diseases which are the result of the deregulation of those PTK. The compounds of this invention are anticancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. This invention also relates to the manufacture of 3-cyano quinolines, their use for the treatment of cancer and polycystic kidney disease, and the pharmaceutical preparations containing them. Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from an ATP to a tyrosine residue located on a protein substrate Ref: 127996. The protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is through this process that they carry out the signaling. The interaction of growth factors with these receptors is a necessary event in the normal regulation of cell growth. However, under certain conditions, as a result of any mutation or overexpression, these receptors may be deregulated; the result of which is uncontrolled cell proliferation, which can lead to tumor growth and finally to the disease known as cancer [Wilks A.F., Adv. Cancer Res. , 60, 43 (1993) and Parsons, J.T .; Parsons, S.J., Importan t Advances in Oncology, DeVita V.T. Ed., J.B. Lippincott Co. , Phila., 3 (1993)). Among the receptor kinases of the growth factor and its proto-oncogenes that have been identified and that are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 oncogene (also known as neu or HER2). Since the event of phosphorylation is a necessary signal for cell division to occur and since overexpressed kinases or mutants have been associated with cancer, an inhibitor of this event, an inhibitor of the protein tyrosine kinase, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the product of the erbB-2 oncogene receptor kinase has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, 1146 (1987)]. The deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer Res. , 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anti cancer Res. , 1, 459 (1987)], and tumors involving other major organs [Gullick, W.J., Bri t. Med. Bull. 41, 87 (1991)]. Due to the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have struggled with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke. T.R., Drugs Future, 1 1, 119 (1992) and Chang, C.J .; Geahlen, R.L., J. Na t. Prod., 55, 1529 (1992)]. The compounds of this invention inhibit the kinase activity of EGF-R and are therefore useful for treating certain disease states, such as cancer, which result, at least in part, from the deregulation of this receptor. The compounds of this invention are also useful for the treatment and prevention of certain precancerous conditions, such as the growth of polyps in the colon, which result, at least in part, from the deregulation of this receptor. It is also known that the deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease.

[Du J., Wilson P. D., Amer. J. Physiol. , 269 (2 Pt 1), 487 (nineteen ninety five); Nauta J., et al., Pedia tric Research 31 (6), 755 (nineteen ninety five); Gattone V.H., et al., Developmental. Biology, 1 69 (2), 504 (1995); Wilson P.D., et al., Eur J. Cell Biol. , 61 (1), 131, (1993)]. The compounds of this invention, which inhibit the catalytic function of EGF receptors, are consequently useful for the treatment of this disease. The pathway of mitogen-activated protein kinase (MAPK) is a major pathway in the transduction cascade of the cellular signal of growth factors to the cell nucleus. The pathway involves kinases at two levels: MAP kinase kinases (MAPKK), and their substrate MAP kinases (MAPK). There are different isoforms in the MAP kinase family. (For a review, see Rony Seger and Edwin G. Krebs, FASEB, Vol. 9, 726, June 1995). The compounds of this invention can inhibit the action of two of these kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAP kinase. MEK is activated by phosphorylation on two serine residues by upstream kinases, such as members of the raf family. When activated, MEK catalyzes phosphorylation on a threonine residue and an ERK tyrosine. Activated ERK then phosphorylates and activates transcription factors in the nucleus, such as fos and j un, or other cellular targets with PXT / SP sequences. It is found that ERK, a p42 MAPK is essential for cell proliferation and differentiation. It has been found that overexpression and / or overactivation of Mek or ERK is associated with several human cancers (eg, Vimala S. Sivaraman, Hsien-yu Wang, Gerard J. Nuovo, and Craig C. Malbon, J. Clin. Invest. Vol. 99, No. 7 of April 1997). It has been shown that inhibition of MEK prevents ERK activation and subsequent activation of the ERK substrate in cells, resulting in the inhibition of cell growth stimulation and reversion of the transformed cell phenotype by ras ( David T. Dudley, Long Pang, Stuart J. Decker, Alexander J. Bridges, and Alan R. Saltiel, PNAS, Vol. 92, 7686, August 1995). Because, as demonstrated, the compounds of this invention can inhibit the coupled action of MEK and ERK, they are useful for the treatment of diseases such as cancer, which are characterized by uncontrolled cell proliferation and which, at less in part, they depend on the MAPK route. The Epithelial Cell Kinase (ECK) is a receptor tyrosine kinase protein (RPTK) that belongs to the family of EPH (Hepatoma that Produces Erythropoietin). Although originally identified as a tyrosine kinase specific to the epithelial lineage, ECK has subsequently shown to be expressed on vascular endothelial cells, smooth muscle cells and fibroblasts. ECK is a type I transmembrane glycoprotein with the extracellular ligand binding domain consisting of a cysteine-rich region followed by three repeats of type III fibronectin. The intracellular domain of ECK possesses a catalytic tyrosine kinase domain that initiates a signal from the transduction cascade that reflects the function of ECK. The ECK binds and is subsequently activated by its counter-receptor, ligand for the Eph-related Kinase (LERK) -l, which is a product of the readily-inducible immediate initial response gene in a form not restricted by lineage with proinflammatory cytokines such such as IL-1 or TNF. Soluble LERK-1 has been shown to stimulate angiogenesis in part by stimulating ECK in a murine model of corneal angiogenesis. Unlike their normal counterparts, tumor cells of several lineages constitutively express LERK-1 and this expression can be up-regulated additionally by hypoxia and proinflammatory cytokines. Many of these tumor cells also express ECK at levels higher than their normal counterparts, thus creating an opportunity for autocrine stimulation via the ECK-LERK-1 interaction. The increased expression of both ECK and LERK-1 has been correlated with the transformation of melanomas from the non-invasive horizontal phase of growth into vertically growing, highly invasive metastatic melanomas. It is believed that the ECKILERK-1 interaction, together, promotes tumor growth via its tumor-promoting and angiogenic effects. Thus, the inhibition of ECK tyrosine kinase activity mediating the signaling cascade induced by its binding and crosslinking to LERK-1 may be therapeutically beneficial in cancer, inflammatory diseases and hyperproliferative disorders. As shown below, the compounds of this invention inhibit the tyrosine kinase activity of ECK and are therefore useful for the treatment of the disorders mentioned above. The growth of most solid tumors depends on angiogenesis that involves the activation, proliferation and migration of vascular endothelial cells and their subsequent differentiation into capillary tubes. The angiogenization of tumors allows access to oxygen and nutrients derived from the blood, it also provides an adequate perfusion. Consequently, the inhibition of angiogenesis is an important therapeutic strategy not only in cancer, but also in a number of chronic diseases such as rheumatoid arthritis, psoriasis, diabetic retinopathy, age-related macular degeneration, and so on. The tumor cells produce a number of angiogenic molecules. The Vascular Endothelial Growth Factor (VEGF) is one of such angiogenic factors. DEGF, a disulfide-linked homodimeric member of the PDGF family, is a specific mitogen of endothelial cells and is known to cause a profound increase in vascular endothelial permeability in affected tissues. VEGF is also a survival factor that prevents the senescence of endothelial cells. Almost all nucleated tissues in the body possess the ability to express VEGF in response to various stimuli including hypoxia, glucose deprivation, advanced glycation products, inflammatory cytokines, etc. The angiogenic effects that promote the growth of VEGF are predominantly mediated via its receptor that contains the insert domain of the signaling receptor kinase (KDR). KDR expression is low in most endothelial cells; however, activation with angiogenic agents results in significant upregulation of KDR on endothelial cells. Most angiogenicized blood vessels express high levels of KDR. KDR is a receptor tyrosine kinase protein with an extracellular VEGF binding domain consisting of 7 immunoglobulin-like domains 7 and a cytoplasmic domain containing the catalytic tyrosine kinase domain spliced by a region of kinase insert. The VEGF binding produces the dimerization of KDR resulting in its autophosphorylation and the initiation of the signaling cascade. The tyrosine kinase activity of KDR is essential for the mediation of its functional effects as a VEGF receptor. The inhibition of functional effects mediated by KDR inhibiting the catalytic activity of KDR is considered an important therapeutic strategy in the treatment of angiogenicized disease states, including cancer. As shown below, the compounds of this invention inhibit the tyrosine kinase activity of KDR and are therefore useful for the treatment of the disease states mentioned above. In addition to the above utilities, some compounds of this invention are useful for the preparation of other compounds of this invention. The compounds of this invention are certain substituted 3-cyano quinolines. Through this patent application, the quinoline ring system will be numbered as indicated in the formulas below; The numbering for the quinazoline ring system is also shown: 3-cyano quinolines having biological activity as inhibitors of the protein tyrosine kinases have not been reported. A 3-cyano quinoline with a substituent of 4- (2-methyl anilino) having inhibitory activity on (H + / K +) - gastric ATPase at high concentrations has been described [Ife RJ, et al., J. Med. Chem. . 35 (18), 34 13 (1992)]. Quinolines exist that do not have the 3-cyano substituent and, unlike the compounds of this invention, are not substituted at position 4 but are reported to be inhibitors of the protein tyrosine kinase [Gazit A., et al., J. Med. Chem. 39 (11), 2170 (1996)]. A series of quinolines having a 3-pyridyl substituent and its substituents at position 4 have been described as inhibitors of the platelet-derived growth factor receptor kinase [Dolle R.E., et al., J. Med. Chem. , 312, 2627 (1994 and Maguire MP, et al., J. Med. Chem. 372, 129 (1994).] Patent applications WO 96/09294 and WO-9813350 disclose protein tyrosine kinase inhibitors including anilino quinolines with a wide variety of substituents at the 5-8 positions but which must also have a hydrogen or fluorine atom at position 3. US Pat. No. 5,480,883 describes quinoline derivatives which are inhibitors of tyrosine kinase proteins, but those derivatives they do not have the unique combination of substituents, including the 3-cyano group, contained in the compounds of the present invention, WO-9802434 and WO-9802438 disclose quinoline derivatives which are tyrosine kinase inhibitors, but those quinolines do not have the important 3-cyano substituent In addition to the quinolines, certain quinazoline derivatives are known which are similar, in some aspects to the compounds of the invention which are inhibitors of the protein t irosine kinases. The application EP-520722 describes 4-anililoquinazolinas containing simple substituents such as chlorine, trifluoromethyl, or nitro groups in positions 5 to 8. The application EP-566226 is similar but with a much greater variety of substituents now allowed in the positions 5 to 8. The application WO-9609294 discloses compounds with similar substituents at positions 5 to 8 and with the substituent at position 4 consisting of some polycyclic cellular systems. Some simple substituted quinazolines are also described in the applications WO-9524190, WO-0521613, and WO-9515758. The applications EP-602851 and WO-9523141 cover similar quinazoline derivatives, where the aryl group attached to the 4-position can vary between heterocyclic ring structures. The application EP-635498 discloses certain quinazoline derivatives having alkenoylamino and alkynylamino groups between the substituents in the 6-position and a halogen atom in the 7-position. The application WO-9519774 describes compounds where one or more of the carbon atoms in positions 5-8 can be replaced with heteroatoms resulting in a large variety of bicyclic systems, where the ring on the left is a 5- and 6-membered heterocyclic ring; In addition, a variety of substituents are allowed in the ring on the left. The application EP-682027-A1 describes certain pyrrolopyrimidine inhibitors of PTK. The application WO-9519970 describes compounds in which the aromatic ring on the left of the basic quinazoline structure has been replaced with a wide variety of different heterocyclic rings, so that the resulting inhibitors are tricyclic. EP-635507 describes quinazolines wherein a further 5 or 6 membered heterocyclic ring with optional substitution is fused in positions 5 and 6. In addition to the patent applications mentioned above, a number of publications describe 4-anilinoquinazolines; 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). There are no publications describing 3-cyano quinolines as inhibitors of PTK.

DESCRIPTION OF THE INVENTION This invention provides a compound of formula 1: wherein: X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyrinidyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkylamino 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 atoms carbon, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino; Z is -NH-, -O-, -S-, or -NR-; R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms; Gi, G2, Ri and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 atoms of carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenyloxy of 3-8 carbon atoms, alkyloxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms carbon, alkenoyloxymethyl of 4-9 carbon atoms, alkynyloxy ethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano , nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-dialkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N, N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, (C (R6) 2) P / R7- (C (R6) 2) P-N? ^ - (CÍRe ^ k-Y- R8Rg-CH-M- (C (R6) 2) k-Y-, (C (R6) 2) P R7- (C (R6) 2) g-Y-. Rr (C (R6) 2) p- - (C (R6) 2) kY- or Het- (C (R6) 2) qW- (C (R6) 2) kY- with the proviso that either of or G2 or both of Gi and G2 must be a radical selected from the group, R8R9-CH- - (C (R6) 2) kY-, R'7- (C (R6) 2) g-Y- • r (C (R6) 2) p-M- (C (6) 2) k-Y-. Het- (C (R6) 2) q-w- (C (R6) 2) k-Y-. or R2-HN- • Y is a divalent radical selected from the group consisting of - (CH2) a-, -O- -N- R « R7 is -NR6R6, -J, -OR6, -N (R6) 3+, or -NR6 (OR6) -; R'7 is -NR6 (OR6), -N (R6) 3+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms , N, N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, '"N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms or N, N- dialkynylamino of 6-12 carbon atoms, with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; M is> NR6, -O-, &nt; N - (C (R6) 2) pNR6R6, or> N- (C (R6) 2) pOR6; W is> NRd, -O- is a bond; Het is a heterocycle selected from the group consisting of morpholino, thiomorpholino , Thiomorpholino S-oxide, S, S-thiomorpholino 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, and wherein the heterocycle is mono- or di-substituted on a carbon or nitrogen with Rs, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -0R6, optionally mono or disubstituted on carbon with monovalent radicals - (C (R6) 2) S0R6 or - (C (Re) 2) SN (Re) 2, or optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -O (C ( R6) 2) sO-; Rd is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; R2 is selected from the group consisting of R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / R (C ( R6) 2) p- N N- (C (Rβ) 2) r. (C (R6) 2) P R7- (C (R6) 2) S-, R7. (C (R6) 2) p- - (C (R6) 2) r- RßR9-CH- - (C (R6) 2) r-. o Het- (C (R6) 2) q-W- (C (R6) 2) f- provided that at least one of the R3 groups is selected from the group . R'7- (C (R6) 2) s-. R7- (C (R6) 2) pM- (C (R6) 2) r- R8R9-CH-M- (C (R6) 2) r-, or Het- (C (R6) 2) qW- (C (R6) 2) r- • R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / R7- (C (R6) 2) pNN- (C (R6) 2) r- / (C (R6) 2) R7- (C (R6) 2 ) s- • R7- (C (R6) 2) pM- (C (R6) 2) r- RBR9-CH- - (C (R6) 2) r - ° Het- (C (R6) 2) qW- (C (R6) 2) r- = Rs, and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; or a pharmaceutically acceptable salt, provided that when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through the saturated carbon atom; and further provided that when Y is -NR6- and R7 is -NR6R6, -N (R6) 3+, or -NR6 (OR6); then g = 2-6; when M is -0- and R7 is -ORe, then p = 1-4; when Y is -NRe-, then k = 2-4; when Y is -0- and M or W is -0-, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is -0- or -NR6-, then k = 2-4. The pharmaceutically acceptable salts are those derived from organic and inorganic acids such as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and also known acceptable acids. The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulfinyl, alkylsulfonyl, aminoalkyl, N-alkylaminoalkyl, N, N-dialkylaminoalkyl, N-alkylaminoalkoxy, N, N-dialkylaminoalkoxy, alkylsulfonamido, carboalkoxy, carboalkyl, carboxyalkyl, Carboalkoxyalkyl, alkanoylamino, N-alkylcarbamoyl, and N, N-dialkylcarbamoyl include linear carbon chains as well as branched carbon chains. The alkenyl portion of the alkenyl, alkenyloxymethyl, alkenyloxy, alkenylsulfonamido substituents include linear carbon chains as well as branched carbon chains and one or more unsaturation sites and all possible configurational isomers. The alkynyl portion of the alkynyl substituents, alkyloxymethyl, alkynylsulfonamido, alkynyloxy include linear carbon chains as well as branched carbon chains and one or more sites of unsaturation. The carboxy is defined as a -C02H radical. Carboalkoxy of 2-7 carbon atoms is defined as a -C02R radical ", where R" is an alkyl radical of 1-6 carbon atoms. The carboxyalkyl is defined as a radical H02C-R '"wherein R"' is a divalent alkyl radical of 1-6 carbon atoms. The carboxyalkyl is defined as a radical R "02C-R" '- where R "' is a divalent alkyl radical and where R" and R "'together have 2-7 carbon atoms The carboalkyl is defined as a radical -COR "wherein R" is an alkyl radical of 1-6 carbon atoms The alkanoyloxy is defined as a -OCOR radical ", where R" is an alkyl radical of 1-6 carbon atoms. "The alkanoyloxymethyl is defined as a radical. radical R "C02CH2-, where R" is an alkyl radical of 1-6 carbon atoms The alkoxymethyl is defined as a radical R "OCH2-, where R" is an alkyl radical of 1-6 carbon atoms. is defined as a radical R "SO-, where R" is an alkyl radical of 1-6 carbon atoms The alkylsulfonyl is defined as a radical R "S02-, where R" is an alkyl radical of 1-6 carbon atoms The alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as a radical R "S02NH-, where R" is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of 2- 6 carbon atoms, or an alkynyl radical of 2-6 carbon atoms, respectively. N-alkylcarbamoyl is defined as a radical R "NHCO-, where R" is an alkyl radical of 1-6 carbon atoms, N, N-dialkylcarbamoyl is defined as a radical R "R'NCO-, where R" is an alkyl radical of 1-6 carbon atoms, R 'is an alkyl radical of 1-6 carbon atoms and R' and R "may be the same or different.When X is substituted, it is preferred that this mono-, di- or trisubstituted, the monosubstituted being most preferred, It is preferred that the substituents R1 and R4, at least one is hydrogen and it is more preferred that both are hydrogen, It is also preferred that X is a phenyl ring, Z is -NH -, and n = 0. Het is a heterocycle, as defined above, which may optionally be mono- or disubstituted with Re on carbon or nitrogen, optionally mono- or disubstituted on carbon with hydroxy, -N (Rβ), or -ORß, optionally mono or disubstituted on carbon with - (C (R6) 2) S0R6 or - (C (R6) 2) SN (Rg) 2 And optionally mono or disustit on a carbon saturated with divalent radicals -0- or -0 (C (R6) 2) «0- (carbonyl or ketal groups, respectively); in some cases when Het is substituted with -0- (carbonyl), the carbonyl group may be hydrated. Het can be attached to W when q = 0 via a carbon atom on the heterocyclic ring, or when Het is a nitrogen-containing heterocycle, which also contains a saturated carbon-nitrogen bond, such a heterocycle can be attached to the carbon, via nitrogen when W is a bond. When q = 0 and Het is a nitrogen-containing heterocycle which also contains an unsaturated carbon-nitrogen bond, that nitrogen atoms of the heterocycle can be attached to the carbon when W is a bond and the resulting heterocycle will have a positive charge. When Het is substituted with R6, such substitution may be on a ring carbon, or in the case of a nitrogen-containing heterocycle, which also contains a saturated carbon-nitrogen, such nitrogen may be substituted with R6 or in the case of a nitrogen-containing heterocycle, which also contains an unsaturated carbon-nitrogen, such nitrogen can be substituted with Rβ in the case that the heterocycle had a positive charge. Preferred heterocycles include pyridine, and morpholine disubstituted at positions 2,6, thiomorpholine disubstituted at positions 2,5, imidazole substituted at position 2, substituted thiazole, thiazolidine, imidazole substituted at the N, 1, - substituted piperazine at the N atom, substituted piperadine at the N, dioxane, 1,3-dioxolane atom, and substituted pyrrolidine at the N atom. The compounds of this invention may contain one or more asymmetric carbon atoms; in such cases, the compounds of this invention include the individual diastereomers, the racemates, and the individual R and S enantiomers thereof. Some of the compounds of this invention may contain one or more double bonds; in such cases, the compounds of this invention include one of the possible configurational isomers as well as mixtures of those isomers. The compounds having the formula 1 and their salts can be prepared by a process which comprises: (a) reacting a compound having the formula where Ri, Gx, G2, R, Z, n and X are as defined above with a dehydrating agent to convert the aminocarbonyl group to a cyano group, or (b) to react a compound having the formula A? -NH-A2 or a salt thereof with a compound having the formula Q-A3 where Q is a leaving group and Ai, A2 and A3 are such that A? -NA2-A3 is a compound conforming to formula 1; or (c) reacting a compound having the formula A4-OH or a salt thereof with a compound having the formula Q-A5 where Q is as defined above and A4 and A5 are such that A4-0-A5 is a compound that conforms to formula 1; or (d) adding an acid to the compound having the formula 1, so that an acid addition salt is prepared.

The preparation of the compounds and intermediates of this invention encompassed by formula 5 is described below in Reaction Scheme 2 where Z and n are as described above and X 'is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, aminomethyl, N- alkylaminomethyl of 2-7 carbon atoms, N, N-dialkylaminomethyl or of 3-7 carbon atoms, mercapto and benzoylamino; RiA R2 ', R3' and R4 'are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-ß carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2- 6 carbon atoms, alkynyloxy of 2-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms carbon, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, trifluoromethyl, cyano, nitro, carboxy, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, alkoxyamino of 1-4 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N, N-dialkylaminoalkyl of 3-14 carbon atoms, phenylamino, benzylamino, N-alkylcarbamoyl of 1-6 carbon atoms, N, N-dialkylcarbamoyl of 2-12 carbon atoms, according to the sequence of the reaction set forth in reaction scheme 1, an ester of acid quin olin-3-carboxylic of Formula 2 is hydrolyzed with base to provide a carboxylic acid of Formula 3. The carboxylic acid group of 3 is converted to an acyl imidazole by heating this with carbonyldiimidazole in an inert solvent such as dimethylformamide (DMF) followed by adding ammonia to the amide 4. Dehydration of the amide functional group with a dehydrating agent such as trifluoroacetic anhydride is pyridine, phosphorus pentoxide in an inert solvent, or the like or gives the 3-cyano quinolines, 5, of this invention. In those cases where any of the intermediates has an asymmetric carbon atom, they can be used as the racemate or as the individual R or S enantiomers, in which case the compounds of this invention will be in the optically active R or S racemic forms , respectively. The quinolin-3-carboxylic acid esters of Formula 2, the quinoline-3-carboxylic acids of Formula 3, and the quinoline-3-carboxylic amides of Formula 4 are necessary to prepare the compounds of this invention and are already known in the art. or can be prepared by methods known in the art as detailed in 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, Drug, 4 (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.; Fiaschi, A. I., Drug, 45 (3), 269, (1990); Marecki, Paul E .; Bambury, Ronald E., J. Pharm. Sci. , 13 (8), 114 (1984); patent application WO 8908105; U.S. Patent 4343804; US Patent 3470186.

REACTION SCHEME 1 The preparation of the compounds of this invention encompassed by Formula 12 are described below in Reaction Scheme 2 where X, Z, n, Ri, G2, Gi and R4 are as described above. The substituted aniline of Formula 6 is heated with or without a solvent, with reagent 7 to give intermediate 8 as a mixture of isomers. Thermolysis of 8 in a high boiling point solvent such as diphenyl ether at 200-350 ° C gives the 3-cyano quinolone of Formula 9; those intermediates can also exist in the tautomeric form 4-hydroxy quinoline. In those cases where R 4 is a hydrogen atom, the intermediates 9 can also be formed as a mixture of the regioisomers. These isomers can be separated by methods well known in the art, including, but not limited to, fractional crystallization and chromatographic methods. The separated isomers can then be converted separately to the compounds of the invention. Alternatively, the isomers can be separated at a later stage of the synthesis. Heating the compounds 9 with or without a solvent with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride gives the 4-chloro-3-cyano quinolines of Formula 10. Condensation of 10 with a nucleophilic diamine reagent, aniline, mercaptan, thiophenol, phenol, or alcohol of Formula 11 gives the intermediates of the 3-cyano quinolines of Formula 12; this condensation can be accelerated by heating the reaction mixture or using basic catalysts such as trialkylamines, sodium hydride in an inert solvent, sodium or potassium alkoxides in alcoholic solvents, and the like. In those cases where the substituents can contribute to an asymmetric carbon atom, the intermediates can be used as a racemate or as individual R or S enantiomers, in which case the compounds of this invention will be in the racemic or optically active R and S forms , respectively. In cases where the substituents may contribute to more than one asymmetric carbon atom, diastereomers may be present; those can be separated by methods well known in the art, including, but not limited to, fractional crystallization and chromatographic methods. In those cases where the Ri, G2, Gi and R portions contain primary or secondary amino groups, the amino groups will first have to be used in protected form prior to the reaction with the reagent 7. Suitable protecting groups include, but are not limited to a, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ). The first protecting group can be removed from the final products of Formula 12 by treatment with an acid such as trifluoroacetic acid, while the latter protecting group can be removed by catalytic hydrogenation. In those cases where the Ri, G2, Gi and R4 portions contain hydroxyl groups, the hydroxyl groups will first have to be used in protected form prior to the reaction with the reagent 7. Suitable protecting groups include, but are not limited to, groups protective t-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.REACTION SCHEME 2 The preparation of intermediate 15 (identical to intermediate 9 of Reaction Scheme 2) can also be carried out as described below in Reaction Scheme 3. Heating the substituted aniline of Formula 13 with dimethylformamide dimethyl acetal with or without a solvent intermediates of Formula 14. The reaction of 14 with the lithium anion of acetonitrile prepared using a base such as N-butyl lithium or the like in an inert solvent gives the 3-cyano quinolines, 15, or the tautomers of 3-cyano- 4-hydroxy quinoline thereof, which can be converted to the compounds of this invention. In those cases where the portions Rx, G2, Gi and R4 contain primary or secondary amino groups, the amino groups will first have to be used in protected form. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The first protecting group can be removed from the final products of Formula 15 by treatment with an acid such as trifluoroacetic acid, while the latter protecting group can be removed by catalytic hydrogenation. In those cases where the portions Rl r G2, Gi and R4 contain hydroxyl groups, the hydroxyl groups will first have to be used in protected form. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final products 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.

REACTION SCHEME 3 The preparation of the compounds of this invention encompassed by Formula 24 are described below in Reaction Scheme 4, where Ri, G2 R4, Z, n and X are as defined. Rio is alkyl of 1-6 carbon atoms (preferably isobutyl). R2 is a radical selected from the group consisting of: R3-S-S- (C (R5) 2) .- where R6, R3, R5, J, s, r, u, and v are as defined. According to the reactions outlined in Reaction Scheme 4, 4-chloro-3-cyano-6-nitroquinoline, 16, can be reacted with an amine or aniline 17 by heating in an inert solvent such as tetrahydrofuran, butanol, or methoxyethanol to give the compounds of Formula 20, wherein Z is -NH-. The reaction of 16 with a mercaptan or thiophenol 18 in an inert solvent can be carried out using a base such as sodium hydride to give those compounds of Formula 20, where Z is -S-. The reaction of 16 with an alcohol or phenol 19 in an inert solvent can be effected using a base such as sodium hydride to give the compounds of Formula 20, where Z is -0-. The compounds of Formula 20 can be reduced to 6-amino-3-cyano-quinoline, 21, using a reducing agent such as sodium hydrosulfite in a two-phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst or by the use of iron in refluxing protic solvents containing acetic acid or ammonium chloride. The acylation of 21 with any of the acid chloride of Formula 22 or a mixture of Formula 23 (which is 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-methyl morpholine gives the compounds of this invention of Formula 24. In those cases where 22 or 23 have an asymmetric carbon atom, they can be used as the racemate or as the individual R or S enantiomers , in which case the compounds of this invention will be in the racemic or optically active forms R and S, respectively. In those cases, where R2 'contains primary or secondary amino groups, the amino groups will first have to be protected before the formation of the anhydride or acid chloride. Suitable protecting groups include, but are not limited to, the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The first protecting group can be removed from the final products of Formula 24 by treatment with an acid such as trifluoroacetic acid, while the latter protective group can be removed by catalytic hydrogenation. In those cases where the R2 'contains hydroxyl groups, the hydroxyl groups will first have to be protected before the formation of the anhydride or acid chloride. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final products 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 those cases, in intermediates 17, 18 or 19 where X contains amino groups or primary or secondary hydroxyl groups, it may be necessary to protect those groups prior to the reaction with 16. The same amino or alcohol protecting groups above may be used and they can be removed from the products 24 as described above.

REACTION SCHEME 4 H2N-. { CH2) "- X (17) Using methods similar to those described above in Reaction Scheme 4, intermediates 25 can be converted to the compounds of this invention, To prepare the compounds of this invention, certain amines are required. Some representative amines are shown below in List A, where R5, p, and r are as defined above. These amines are commercially available, are known in the chemical literature, or can be prepared by simple procedures that are well known in the art. In some cases, those amines can have asymmetric carbon atoms, can be used as the racemate, or can be resolved and used as the individual R or S enantiomers, in which case the compounds of this invention will be in racemic or optically active forms , respectively. Through this application in the Reaction Schemes shown below, those amines, and other similar amines, will be represented by the generic structure of formula: (R ') 2NH, where this formula can represent a primary or secondary amine.

List A Certain alcohols are required to prepare the compounds of this invention. Some representative alcohols are shown below in List B, where R6, p, and r are as defined above. These alcohols are commercially available, are known in the chemical literature, or can be prepared by simple procedures that are well known in the art. In some cases, these alcohols may have asymmetric carbon atoms; they can be used as a racemate, or they can be resolved and used as the individual R or S enantiomers, in which case the compounds of this invention will be in the racemic or optically active forms, respectively. Through this application in the Reaction Schemes shown below, those alcohols, and other similar alcohols, will be represented by the generic structure of formula: R'OH List B R.6 R6-OH μ- (C (R6) 2) -OH R6- - (C (R6) 2) r-OH R6 To prepare some of the compounds of this invention certain mixed anhydrides of Formulas 31, 34 and 38 are required; those are prepared as discussed further in Reaction Scheme 5-6, where R6, Rio, X, Z, n and s are as defined above. J 'is a halogen, chlorine, bromine or iodine atom, or is a tosylate group (p-toluenesulfonate) or mesylate (methanesulfonate). The reaction of 27 with an amine of List A is achieved by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide, or using potassium carbonate or cesium in acetone. The temperature and duration of the heating will depend on the activity of 27; longer reaction times and higher temperatures may be required when it is greater than 1. Treatment of 28 with an alkyl lithium reagent followed by cooling with a dry carbon dioxide atmosphere gives the carboxylic acids of Formula 29. These can be converted to mixed anhydrides of Formula 31 using a reagent such as isobutylchloroformate 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 this invention as described above in Reaction Scheme 4. The reaction of 27 with an alcohol of Schedule B is accomplished using sodium hydride or another non-nucleophilic base such as carbonate. of potassium or cesium in an inert solvent such as tetrahydrofuran, acetone, or N, N-dimethylformamide. In some cases, the alcohol in List B may also be the solvent of the reaction. Treatment of 32 with an alkyl lithium reagent followed by cooling with a dry carbon dioxide atmosphere gives the carboxylic acids of Formula 33. These can be converted to mixed anhydrides of Formula 34 using a reagent such as isobutylchloroformate in a solvent inert such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of this invention as described above in Reaction Scheme 4.

REACTION SCHEME 5 (R ') 2NH J' (C (R6) 2) S Z-Z H (R 2 - (C (R6) 2) = H ROH J '(C (R6) 2) S = H - R'O- (C (R6) 2) S Z-Z H As set forth in Reaction Scheme 6 below, Ri, G2, R4, R6, Rio, X, Z, n and s are as defined above, the alcohols can be protected with a t-butyl dimethylsilyl protecting group by the reaction with the respective silyl chloride in methylene chloride in the presence of triethylamine and 4-N, N-dimethylamino pyridine (DMAP). The resulting protected alcohols, 36, are converted to the acetylene Grignard reagents which, in turn, are maintained under a dry carbon dioxide atmosphere to give the carboxylic acids 37. As described above, they are converted to the anhydrides mixed 38, which upon reaction with the 6-amino-3-cyanoquinoline 39 gives 40. In the final step of the sequence, the silyl protecting group is removed by treating with acid in a protic solvent mixture to give the represented compounds for Formula 41.

REACTION SCHEME 6 . . t-BuSi (CH3) 2-CI HO- (C (R6) 2) S- == - H 12 - t-BuSi (CH3) 2-0- (C (R6) 2) S- == - H CH2Cl2 , (C2Hs 3, 35 DMAP 36 1. THF, MeMgBr) 2) - c J > THF R10O- - * - t-BuSi (CH3) 2-0- (0 ^ Cl 2. CO, OH N-methylmorpholine 37 41 The compounds of this invention are also prepared as shown below in Reaction Scheme 7 where Ri, G2, R4, R6, Rio, X, Z, n and s are as defined above. J 'is a halogen, chlorine, bromine or iodine atom, or is a tosylate or mesylate group. Treatment of 42 with an alkyl lithium reagent at low temperature followed by cooling with a dry carbon dioxide atmosphere gives the carboxylic acids of Formula 47. Those can be converted to mixed anhydrides of Formula 44 using a reagent such as isobutylchloroformate 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 this invention as by the reaction with the 6-amino-3-cyanoquinolines 45 described above in the Reaction Schemes The reaction of 46 with an alcohol of List B is accomplished using sodium hydride or other non-nucleophilic base in an inert solvent such as tetrahydrofuran, or N, N-dimethylformamide to give the compounds of this invention prepared by 47. In some cases, the alcohol of List B may also be the solvent of Reaction 46 with an amine of List A gives the compounds of this invention represented by 48 which is achieved by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide, or using potassium carbonate or cesium in acetone. The temperature and duration of heating will depend on the selectivity of 46, longer reaction times and higher temperatures may be required when this is greater than 1.

REACTION SCHEME 7 1 1 .. TTHHFF ,, nn - BBuuLL¡¡ JO - (CíRßhfc-SH - - - J J --- ((CC (ClR ^), - == - c 42 2 C ° 2 4 «3 OH Using methods similar to those summarized above, 45b can be converted to 47b or 48b. 47b 48b Other "carboxylic acid" chlorides and anhydrides necessary to prepare some of the compounds of this invention are prepared as shown below in Reaction Scheme 8, where R6, R3, Rio, X, Z, J ', n, and s are as defined above, Q 'is an alkyl group of 1-6 carbon atoms, Esters 49, 53 or 57 can be hydrolyzed with a base such as barium hydroxide to give the respective carboxylic acid 50, 54 or 58. That acid can be converted to the respective carboxylic acid chlorides 51 or 56 using oxalyl chloride and catalytic N, N-dimethylformamide in an inert solvent or respective mixed anhydrides 55 or 59 using isobutyl chloroformate and an organic base such as N-N-dimethylformamide. methylmorpholine The leaving group in the compounds represented by Formula 52 can be displaced by the amines of List A or the alcohols of List B using procedures previously described to give the intermediates newspapers 57 and 53, respectively. These carboxylic acid chlorides 51 and 56 and those anhydrides 55 and 59 can be used to prepare some of the compounds of this invention using the methods set forth hereinabove in the Reaction Schemes.

REACTION SCHEME 8 51 J J- (C Ba (OH) ethanol, H20 R '-lc fed) s Ra 0 (COCIV, CH-C.C. DMF / cat. 54 55 56 R, C QQ (R' ^ NH R3__ F < 2Q J ^ - (CfeS) s 3 (F $ N- (C feíS) Ft3 52 57 O Ba (OH) 2 R3 C OH R70- ethanol, H20 (f ^ - - (c yj) / R3 THF, N-methylmorpholine 58 59 Using methods identical to those set forth above in Reaction Scheme ^ 8, it is possible to prepare the analogous carboxylic acid chlorides and anhydrides given below in Schedule C, where R ', R3, p and s are as described above. G is the radical: and A is the radical: -N (R ') 2, -OR', or -J 'where -N (R') 2 is derived from the amines of List A, -OR 'is derived from the alcohols of the List B, and J 'is an outgoing group as defined above. By making use of those chlorides and carboxylic acid anhydrides, following the methods outlined above in the Reaction Schemes, and according to the details described in the examples given below, many of the compounds of this invention can be prepared.

LIST C A- (C (Rs) 2) _) "(C (R3) 2) p The compounds of this invention represented by position Formulas 62-63 can be prepared as shown in Reaction Scheme 9, where Ri, G2, R4 , Rβ, P3, Rio, X, Z, J ', nys are as defined above The reaction of the carboxylic acid chlorides 60 and the 6-amino-3-cyanoquinolines 61 using an organic base in an inert solvent gives the compounds of this invention represented by Formula 62. The reaction of 62 with an alcohol of List B is accomplished using sodium hydride or another non-nucleophilic base such as potassium carbonate or cesium in an inert solvent such as tetrahydrofuran, acetone. , or N, N-dimethylformamide to give the compounds of this invention represented by 63. In some cases, the alcohol of List B may also be the solvent of the reaction.In the reaction of 62 with an amine of List A for give the compounds of this invention represented by 64 is achieved by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide. The temperature and duration of the heating will depend on the reactivity of 62; longer reaction times and higher temperatures may be required when s is greater than 1. In addition, the carboxylic acid chlorides and mixed anhydrides listed in List C may be used to prepare the analogous compounds of this invention.

REACTION SCHEME 9 Applying the methods summarized above, 61b can be converted 63b and 64b via the intermediary 62b.

The reaction of 62 or 62b with a nitrogen-containing heterocyclic HET, which also contains an unsaturated carbon-nitrogen bond, is achieved by refluxing in an inert solvent and gives the compounds of this invention 64c and 64d, respectively, wherein the compound It has a positive charge. The counter-ion J '- can be replaced with any other pharmaceutically acceptable ion using the appropriate ion exchange resin.

HET HET Some of the compounds of this invention can be prepared as set forth below in Reaction Scheme 10 where Ri, G2, R3, R4, Re, Rio, X, Z, J ', n and r are as defined above. Acetylenic alcohols 65 can be coupled to halides, mesylates or tosylates 66 using a base such as sodium hydride in an inert solvent such as tetrahydrofuran. The resulting acetylene 67 is then treated with an alkyl lithium reagent at a low temperature. The maintenance of the reaction under a carbon dioxide atmosphere gives the carboxylic acids 68. These, in turn, are reacted with 6-amino-3-cyanoquinolines, 69, via the mixed anhydrides to give the compounds of this invention represented by the Formula 70. Alternatively, the intermediates 67 can be prepared by starting with an alcohol 71 by first treating it with a base such as sodium hydride in an inert solvent such as tetrahydrofuran and then adding an acetylene 72 having a group. appropriate outgoing In a similar manner, the amino alcohols represented by the Formula: (R6) 2N- (C (Re) 2) r-OH by reacting with 72, and applying the chemistry of Reaction Scheme 10, can be converted to the compounds of this invention represented by the formulas: REACTION SCHEME 10 1. THF NaH HO- (C (R6) 2) r = H R6O- (CíRßh? RJ "65 66 1. THF, n-BuLi 6O- (C (R6) 2) rO- (C (R6) 2) r - = -H - 67 2. CO2 1. THF NaH O- (C (R6) 2) r-OH 2. J '(C (R6) 2) r -ZZ H 71 72 O- (C (R6) 2) r-O- (C (R6) 2) r = -H 67 Applying methods similar to those described above, 69b can be converted to the compounds of this invention represented by 70b. 70b The compounds of this invention represented by Formula 76 and 77 are prepared as shown below in Reaction Scheme 11, where R 1 R 3, R 4, R 6, R 7 and n are as defined above and the amines HN (R ") 2 are selected from the group: Refluxing 73 and 74 in a solvent such as ethanol gives the intermediate 75 which can react with an amine in a refluxing ethane to give the compounds of this invention represented by Formula 76. Treat 75 with an excess of alkoxide. sodium in an inert solvent or a solvent from which the alkoxide is derived from the compounds of this invention of Formula 77.

REACTION SCHEME 11 In a manner similar to that described above, 74b can be converted to 76b or 77b. 74b The compounds of this invention represented by Formula 83 can be prepared as shown in Reaction Scheme 12, where Ri, G2, R4, Re, R3, Rio, X, Z, n and r are as defined above. The reaction of the mercapto carboxylic acids 78 with the reagents 79 gives the compounds represented by the Formula 80. Alternatively, 80 can be prepared from the mercaptan R3SH using mercapto 78, triethylamine and 2-, 2'-dipyridyl disulfide. . The formation of mixed anhydride to give 81 followed by condensation with the 6-amino-3-cyanoquinolines 82 gives the compounds of this invention.

REACTION SCHEME 12 02 H3C-S-SR3 79 HS - (C (6) 2) f- COOH 2-, 20-dipyridyl disulfide, R3SH R3S-S - (C (R6) 2) r- COOH Et3N, THF 78 80 82 THF, pyridine 83 Applying methods similar to those described above 82b can be converted to 83b.

The compounds of this invention prepared by Formulas 86-88 can be prepared as shown in Reaction Scheme 13, where Ri, G2, Ri, R4, Rs, J ', X, Z and n are as defined above. Q 'is alkyl of 1-6 hydrogen atoms, alkoxy d 1-6 hydrogen atoms, hydroxy or hydrogen. The alkylation of 84 with the 6-amino-3-cyanoquinolines 85 can be effected by heating in an inert solvent such as N, N-dimethylformamide using a base such as potassium carbonate to give the compounds of this invention represented by Formula 86 When Q 'is alkoxy, the ester group can be hydrolyzed to an acid using a base such as sodium hydroxide in methanol. In a similar manner, using intermediates 89 and 90, the compounds of this invention represented by Formula 87 and 88 can be prepared, respectively.

REACTION SCHEME 13 86 Applying methods similar to those described above 85b can be converted to 86b-88b. 86b The compounds of this invention represented by Formula 93 can be prepared as shown in Reaction Scheme 14, where Ri, G2, Ri, R4, R5, X, Z and n are as defined above. Reaction of reagent 91 with 6-amino-3-cyanoquinolines 92 is achieved using an excess of an organic base such as triethylamine and an inert solvent such as tetrahydrofuran to give the compounds of this invention represented by Formula 93.

REACTION SCHEME 14 The compounds of this invention represented by Formula 96 can be prepared as shown in Reaction Scheme 15, where Ri, Gi, Ri, R, R5, Re, W, Het, X, Z, k and n are as defined above. by the reaction of Mitsunobu of phenol 94 and an alcohol 95 in an inert solvent. Alternatively, the Mitsunobu reaction can be applied to compound 97 to give 98. This compound can be converted to 96 as described above in Reaction Scheme 4. The heterocycle can be introduced at position 6 using the corresponding compounds where Gi is hydroxy and G2 is located in position 7.

REACTION SCHEME 15 96 There are certain functional group manipulations that are useful for preparing the compounds of this invention that can be applied to various intermediate 3-cyanoquinolines, as well as the final compounds of this invention. These manipulations refer to substituents Ri, Gi, G2 or R4 which are located on the 3-cyanoquinolines shown in the above Reaction Schemes. Some of those functional group manipulations are described below: Where one or more than one of Ri, Gi, G2 or R4 is a nitro group, this can be converted to the corresponding amino group by reduction using a reducing agent such as iron or acetic acid or by catalytic hydrogenation. Where one or more of Ri, Gi, G2 or R4 is an amino group, this can be converted to the corresponding dialkylamino group of 2 to 12 carbon atoms by alkylation with at least two equivalents of an alkyl halide of 1 to 6 carbon atoms. carbon by heating in an inert solvent or by reductive alkylation using an aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium cyanoborohydride. Where one or more of Ri, Gx, G2 or R4 is a methoxy group, this can be converted to the corresponding hydroxy group by reaction with a demethylating agent such as boron tribromide in an inert solvent or by heating with pyridinium chloride with or without solvent Where one or more of Ri, Gi, G2 or R is an amino group, this may be converted to the corresponding alkylsulfonamino, alkenylsulfonamido or alkynylsulfonamido group of 2 to 6 carbon atoms by reaction with an alkylsulfonyl chloride, alkenylsulfonyl chloride, or alkynylsulfonyl chloride, respectively, in an inert solvent using a basic catalyst such as triethylamine or pyridine. Where one or more of Rx, Gi, G2 or R4 is an amino group, this can be converted to the corresponding alkylamino group of 1 to 6 carbon atoms by alkylation with one equivalent of an alkyl halide of 1 to 6 carbon atoms by heating in an inert solvent or by reductive alkylation using an aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium cyanoborohydride in a protic solvent such as water or alcohol, or mixtures thereof. Where one or more of Ri, Gi, G2 or R4 is hydroxy, this may be converted to the corresponding alkanoyloxy group of 1-6 carbon atoms by reaction with an appropriate anhydride or mixed anhydride of an appropriate carboxylic acid in an inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of Rx, Gi, G2 or R4 is hydroxy, this can be converted to the corresponding alkenoyloxy group of 1-6 carbon atoms by reaction with a suitable chloride, anhydride or mixed carboxylic acid anhydride in an inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of Rx, Gx, G2 or R4 is hydroxy, this may be converted to the corresponding alkynoxyloxy group of 1-6 carbon atoms by reaction with an appropriate mixed carboxylic acid chloride, anhydride or anhydride in an inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of Ri, Gi, G2 or R4 is carboxy or a carboalkoxy group of 2-7 carbon atoms, this can be converted to the corresponding hydroxymethyl group by reduction with an appropriate reducing agent such as borane, lithium borohydride, or lithium aluminum hydride in an inert solvent; the hydroxymethyl group, in turn, can be converted to the corresponding halomethyl group which reacts in an inert solvent with a halogenating reagent such as phosphorus tribromide to give a bromomethyl group, or phosphorus pentachloride to give a chloromethyl group. The hydroxymethyl group may be acylated with an appropriate acid chloride, anhydride or anhydride in an inert solvent using pyridine or a trialkylamine as a catalyst to give the compounds of this invention with the corresponding alkanoyloxymethyl group of 2-7 carbon atoms., alkenolioxymethyl group of 2-7 carbon atoms or an alkanoyloxymethyl group of 2-7 carbon atoms. Where one or more of Ri, Gi, G2 or R4 is a halomethyl group, this may be converted to an alkoxymethyl group of 2-7 carbon atoms by displacing the halogen atom with a sodium alkoxide in an inert solvent. Where one or more of Ri, Gi, G2 or R4 is a halomethyl group, this can be converted to an aminomethyl group, N-alkylaminomethyl group of 2-7 carbon atoms or N, N-dialkylaminomethyl group of 3-14 carbon atoms. carbon displacing the halogen atom with ammonia, a primary or secondary amine, respectively, in an inert solvent. In addition to the methods described herein above, there are numerous patent applications that describe methods that are useful for the preparation of the compounds of this invention. Although these methods describe the preparation of certain quinazolines, they are also applicable to the preparation of the corresponding substituted 3-cyanoquinolines. The chemical methods described in the application WO-9633981 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Rx, Gi, G2 or R4 are alkoxyalkylamino groups. The chemical methods described in the application WO-9633980 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Ri, Gi, G2 or R4 are aminoalkylalkoxy groups. The chemical procedures described in the application W0-9633979 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Ri, Gi, G2 or R4 are alkoxyalkylamino groups. The chemical procedures described in the application W0-9633978 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Ri, Gi, G2 or R4 are aminoalkylamino groups. The chemical methods described in the application WO-9633977 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Ri, Gi, G2 or R4 are aminoalkylalkoxy groups. Although the above patent applications describe compounds where the functional groups indicated in position 6 of a quinazoline have been introduced, the same chemistry can be used to introduce the same groups at positions occupied by the substituents Rx, Gi, G2 and R4 of the compounds of this invention. The representative compounds of this invention were evaluated in several standard pharmacological test procedures which showed that the compounds of this invention possess significant activity as inhibitors of protein tyrosine kinases, and are antiproliferative agents. Based on the activity shown in the standard test and pharmacological procedures, the compounds of this invention are therefore useful as antineoplastic agents. The test procedures used and the results obtained are shown below.

Inhibition of Epidermal Growth Factor Receptor Kinase (EGF-R) using Recombinant Enzyme Representative test compounds were evaluated for their ability to inhibit the phosphorylation of the tyrosine residue of a peptide substrate catalyzed by the growth factor receptor kinase enzyme epidermal. The peptide substrate (RR-SRC) has the sequence arg-arg-leu-ile-glu-asp-ala-glu-tyr-ala-ala-arg-gly. The enzyme used in this assay is the His-tagged cytoplasmic domain of EGFR. A recombinant baculovirus (vHcEGFR52) was constructed which contains amino acids 645-1186 which code for the EGFR cDNA preceded by Met-Ala- (His) 6. Sf9 were infected in 100 mm dishes at 10 pfu / cell moi and the cells were harvested 48 hours after infection. A cytoplasmic extract was prepared using 1% Triton X-100 and applied to a Ni-NTA column. After washing the column with 20 mM imidazole, the HcEGFR was eluted with 250 mM imidazole (in 50 mM Na2HP04, pH 8.0, 300 mM NaCl). The collected fractions were dialyzed against 10 mM HEPES, pH 7.0, 50 mM NaCl, 10% glycerol, 1 ug / mL of antipain and leupeptin and Pefabloc SC 0.1 mM. The protein was frozen in dry ice / metal and stored at -70 ° C. The test compounds were prepared in standard solutions of 10 mg / mL in 100% dimethyl sulfoxide (DMSO). Prior to the experiment, standard solutions were diluted to 500 uM with 100% DMSO and then serially diluted to the desired concentration with HEPES buffer (30 mM HEPES, pH 7.4). For the enzymatic reaction, 10 μL of each inhibitor (at various concentrations) was added to each well of a 96-well plate. To this was added 3 μL of enzyme (1:10 dilution in HEPES lOmM, pH 7.4 for a final concentration of 1: 120). This was allowed to settle for 10 minutes on ice and was followed by the addition of 50 μl of peptide (final concentration of 80 μM), 10 μl of 4X Buffer (Table A), 0.25 μL of 33P-ATP and 12 μL of H20. The reaction was allowed to proceed for 90 minutes at room temperature and was followed by spotting the entire volume on pre-cut P81 filter paper. The filter discs were washed 2X with 0.5% phosphoric acid and the radioactivity was measured using a liquid flashing counter.

Table A Reactive Final 100 Rxns 1 M HEPES (pH 7 4) 12.5 mM 50 μL Na3V04 lOmM 50 uM 20 μL MnCl2 1M 10 mM 40 μL ATP lmM 20 uM 80 μL 33P-ATP 2.5uCi 25 μL The inhibition data for the compounds of the invention are shown below in TABLE 1. The IC50 is the concentration of the test compound needed to reduce the total amount of phosphorylated substrate by 50%. The% inhibition of the test compound was determined for at least three different concentrations and the IC50 value was evaluated from the dose-response curve. The% inhibition was evaluated with the following formula: of inhibition = 100 - [CPM (drug) / CPM (control)] X 100 where CP (drug) is in units of counts per minute and is a number that expresses the amount of radioactively labeled ATP (g-33P) incorporated on the RR-SRC peptide substrate by the enzyme after 90 minutes at room temperature in the presence of the test compound according to that measured by the flash count in liquid. The CPM (control) is in units of counts per minute and was a number that expresses the amount of radioactively labeled ATP (g-33P) incorporated in the RR-SRC peptide substrate by the enzyme after 90 minutes at room temperature in the absence of the Test compound according to what measured by the flash count in liquid. The CPM values were corrected by background counts produced by ATP in the absence of the enzymatic reaction. The IC50 values in TABLE 1 are averages of the individual determinations.

TABLE 1 (Recombinant enzyme) Inhibition of the Epidermal Growth Factor Receptor Kinase Compound Cl 5Q (μM) Number of Tests twenty 72 0.006 74 0.01 75 0.0004 5 TABLE 1 (recombinant enzyme) Inhibition of the Epidermal Growth Factor Receptor Kinase (continued) Compound IC50 (μM) Number of Tests 76 0.01 77 0.006 79 0.00036 0. 05 93 1.0 95 0.005 96 0.1 108 0.026 106 0.013 107 0.5 109 0.007 89 0.01 0.005 TABLE 1 (recombinant enzyme) Inhibition of the Epidermal Growth Factor Receptor Kinase (continued) Compound IC50 (μM) Number of Tests 91 0.015 1 119 0.00005 1 103 0.008 2 Inhibition of Epithelial Cell Kinase (ECK) In this standard pharmacological test procedure, a biotinylated peptide substrate is immobilized first on microtiter plates coated with neutravidin. The test drug, Epithelial Cell Kinase (ECK), Mg ++, sodium vanadate (an inhibitor of the protein tyrosine phosphatase), and a buffer to maintain the pH (7.2) are then added to the microtiter wells containing immobilized substrate. Then ATP is added to start phosphorylation. After incubation, the assay plates were washed with a suitable buffer leaving behind the phosphorylated peptide which was exposed to the anti-phosphotyrosine monoclonal antibody conjugated to horseradish peroxidase (HRP). The antibody-treated plates are washed again and the HRP activity in the individual wells is quantified as a reflection of the degree of phosphorylation of the substrate. This non-radioactive format was used to identify inhibitors of ECK tyrosine kinase activity where the IC5o is the concentration of the drug that inhibits substrate phosphorylation by 50%. The results obtained for the representative compounds of this invention are listed in TABLE 2. Multiple entries were tested for a compound given indication multiple times.

Inhibition of the Receptor Containing the Kinase Insert Domain (KDR: the catalytic domain of the VEGF receptor) In this standard pharmacological test procedure, the KDR protein is mixed, in the presence or absence of an inhibitor compound, with a peptide substrate to be phosphorylated (a copolymer of glutamic acid and tyrosine, E: Y :: 4: 1) and other cofactors such as Mg ++ and sodium vanadate (a protein tyrosine phosphatase inhibitor) in an appropriate buffer to maintain pH (7.2.). The ATP and the radioactive indicator (ATP marked with either P- or P33) to initiate phosphorylation. After incubation, the radioactive phosphate associated with the acid insoluble fraction in the test mixture is then quantitated as a reflection of the phosphorylation of the substrate. This radioactive format was used to identify inhibitors of KDR tyrosine kinase activity, where the CI5o is the concentration of drug that inhibits substrate phosphorylation by 50%. The results obtained for the representative compounds of this invention are listed in TABLE 2. Multiple entries were tested for a compound given indication multiple times.

Mitogen Activated Protein Kinase Assay (MAPK) To evaluate MAP inhibitors (mitogen-activated protein kinase) a standard pharmacological test procedure coupled to two components was used, which measures the phosphorylation of a serine / threonine residue in an appropriate sequence in the substrate in the presence and absence of a putative inhibitor. First, recombinant human MEK 1 (MAPKK) was used to activate recombinant human ERK2 (MAPK) and activated MAPK (ERK) was incubated with substrate (MBP peptide or MYC peptide) in the presence of radiolabelled ATP, Mg + 2 and ATP. with 33P. The phosphorylated peptide was captured on a phosphocellulose filter P 81 (filter paper or embedded in a microtiter plate) washed and counted by flashing methods.

Peptide substrates used in the assay are MBP, peptide substrate (APRTPGGRR) or synthetic Myc substrate (KKFELLPTPPLSPSRR'5 TFA) The recombinant enzymes used were prepared as GST fusion proteins of human ERK 2 and human MEK 1. prepared as 10X standards in 10% DMSO and an appropriate aliquot was used to distribute either 10 ug / ml for a single dose of point selection or a final concentration of 100, 10, 1 and 0.1 uM for a dose-response curve. The final concentrations of DMSO were less than or equal to 112tí- The reaction was carried out as follows in 50 mM Tris kinase buffer, pH 7.4 in a reaction volume of 50 ul. The appropriate volume of kinase buffer and inhibitor sample was added to the tube. An appropriate dilution of enzyme was distributed to give 2-5 ug of recombinant MAPK (Erk) per tube. The inhibitor was incubated with MAPK (Erk) for 30 minutes at 0 degrees C. The recombinant Mek (MAPKK) (0.5-2.5 ug) or fully activated Mek (0.05-0.1 units) was added to activate the Erk and incubated for 30 minutes at 30 ° C. Then the substrate and range 33P ATP were added to give a final concentration of MBPP of 0.5-1 mM or Myc 250-500 uM; range P 33 ATP 0.2-0.5 uCi / tube; final ATP concentration of 50 μM. The samples were incubated at 30 ° C for 30 minutes and the reaction sample was stopped by adding 25 μl of 10% TCA cooled on ice. Subsequently, the samples were cooled on ice for 30 minutes, 20 μl of sample was transferred onto phosphocellulose filter paper P 81 or appropriate MTP with filter P 81 included. The filter papers or MTP were washed 2 times with a large volume of acetic acid in 1%, then 2 times with water. The filters or MTP were air-dried briefly before the addition of the flasher and the samples were counted in an appropriate flashing counter set to read the 33P isotope. The samples included a positive control (activated enzyme plus substrate); a non-enzymatic control; a control without substrate; samples with different concentrations of putative inhibitor and samples with reference inhibitors (other active compounds are non-specific inhibitors such as staurosporine or K252 B). The untreated data were captured as cpm. Duplicates of the sample were averaged and corrected for the background count. Data from the mean cpm were tabulated by group and% inhibition by test compound was calculated as (corrected cpm control - corrected cpm sample / control) X 100% inhibition. If several concentrations of inhibitor were tested, the CI5o values (the concentration giving the 50% inhibition) were determined graphically from the dose-response curve for% inhibition or by an appropriate computation program. The results obtained for the representative compounds of this invention are listed in TABLE 2, where there may be separate entries for the same compound; This is an indication that the compound was evaluated more than once.

TABLE 2 Inhibition of the Receptor Containing the Kinase Insert Domain (KDR), Epithelial Cell Kinase (Eck), and Mitogen Activated Protein Kinase (Mek-Er) Example VEGF Eck Mek and Erk% Inhibition of erbB2 μM μM μM 2 μg / mL 72 > 41,724 > 100 96 74 > 42,982 > 100 95 75 > 37,284 100 76 > 40,617 > 100 96 77 42,162 > 100 105 > 21,269 40 53 TABLE 2 (continued) Inhibition of the Receptor Containing the Kinease Insert Domain (KDR), Epithelial Cell Kinase (Eck), and Mitogen Activated Protein Kinase (Mek-Erk) Example VEGF Eck Mek and Erk% Inhibition of erbB2 μM μM μM 2 μg / mL 79 > 38,610 80 82 > 1.8315 > 1,832 30 85 > 21,584 10 87 1. 8 Inhibition of Cancer Cell Growth According to the Measurement by the Number of Cells Human tumor cell lines were cultured in 96-well plates (250 μl / well, 1-6 x 10 4 cells / ml) in RPMI 1640 medium, with a 5% content of FBS (Fetal Bovine Serum). After twenty-four hours of culture, the test compounds were added at five logarithmic concentrations (0.01-100 mg / ml) or lower concentrations for the more potent compounds. After 48 exposure to the test compounds, the cells were fixed with trichloroacetic acid, and stained with Sulforrodamine B. After washing with trichloroacetic acid, the bound dye was solubilized on 10 mM Tris base and the optical density was determined using a plate reader. Under the test conditions the optical density is proportional to the number of cells in the well. The IC50 (concentrations that produce a 50% inhibition of cell growth) were determined from growth inhibition plots. The test procedure is described in detail by Philip Skehan et. to the. J. Na ti. Canc. Inst. , 82, 1107-1112 (1990). These data are shown later in TABLE 3. Information about some of the cell lines used in those test procedures is available from the American Type Tissué Collection; Cell Lines and Hybridomas, Reference Guide 1994, 8th Edition.

Table 3 Inhibition of Cancer Cell Growth Measured by the Number of Cells (IC 50 μg / mL) Example MDAMB435 SW620 A431 SKBR3 3T3 Her2 / 3T3 85 27.6 17.98 4.91 1.74 75 0.2 0.5 0.1 0.04 74 3.9 0.6 0.9 1.0 72 3.5 0.4 0.9 77 0.1 0.1 0.03 0.02 79 0.3 0.1 0.04 0.01 6 0.284 0.239 0.050 0.031 3. 194 > 5 0.369 1.495 1 1.83 1.73 0.232 0.181 2.87 0.375 2. 07 1.53 0.245 0.107 2.04 0.192 0 1.74 1.24 0.234 0.148 2.1 0.329 2 3.32 2.51 0.283 0.188 2.79 0.35 In Vivo Inhibition of Growth of Human Epidermoid Tumors (A431) Female BALB / c nu / nu mice (Charles River, Wilmington, MA) were used in the standard in vivo pharmacological test procedures. Human epidermoid carcinoma cells (American Type Culture Collection, Rockville, Maryland # CRL-155) were grown in vitro as described above. A unit of 5 X 106 cells was injected into the mice. When the tumors reached a mass between 100 and 150 mg, the mice were randomized into treatment groups (day zero). The mice were treated IP or PO once a day either on days 1, 5 and 9 or on days 1 to 10 after treatment with doses of 80, 40 or 20 or 10 mg / kg / dose of the compound to be treated. evaluated in Klucel at 0.2%. The control animals did not receive a drug. The tumor mass was determined every 7 days [(length X width2) / 2] for 28 days after onset. The relative growth of the tumor was determined (average mass of the tumor on days 7, 14, 21, and 28 divided by the average mass of the tumor at day zero) for each treatment group. The% T / C (Tumor / Control) was determined by dividing the relative growth of the tumor of the treated group by the relative growth of the tumor of the placebo group and multiplying by 100. A compound was considered active if the% T / C found was significantly less than 100. The ability of the compound of Example 92 to inhibit the growth of human epidermoid tumors (A431) in vivo is demonstrated below in TABLE 4.

TABLE 4 In Vivo Inhibition of Growth of Human Epidermoid Tumors (A431) in Mice by the Compound of Example 92 a) compound administered on days 1 to 10 PO b) Relative Tumor Growth = Average Tumor Mass at Days 7, 14, 21, 28 / Average Tumor Mass at Day 0 c)% T / C = (Growth Relative Tumor of the Group Treated / Relative Growth of the Tumor of the Placebo Group) X 100 d) Statistical Analysis (Student's T Test) of the Relative Growth of the Tumor. * Indicates statistically significant reduction (p <0.01) in the Tumor Relative Growth of the Treated Group compared to the Control § with Placebo e) S / T = # of Survivor / * of Treaties on Day +28 after the appearance of the tumor.

According to the results indicated by ltj. presented in TABLE 4, the compound of Example 92 is an effective inhibitor of tumor growth in vivo when given orally at 40 mg / Kg. The ability of the compound of Example 89 to inhibit the growth of human epidermoid tumors (A431) 1.5. in vivo is demonstrated below in TABLE 5.

TABLE 5 In Vivo Inhibition of Growth of Human Epidermoid Tumors (A431) in Mice by the Compound of Example 89 twenty TABLE 5 (continued) In Vivo Inhibition of Epidermoid Tumor Growth Human (A431) in Mice by the Compound of Example 89 a) compound administered on days 1 to 10 PO b) Relative Tumor Growth = Average Tumor Mass at Days 7, 14, 21, 28 / Average Tumor Mass at Day 0 c)% T / C = (Growth Relative Tumor of the Group Treated / Relative Growth of the Tumor of the Placebo Group) X 100 d) Statistical Analysis (Student's T Test) of the Relative Growth of the Tumor. * Indicates statistically significant reduction (p <0.01) in the Tumor Relative Growth of the Treated Group compared to the Control with Placebo e) S / T = # of Survivor / * of Treatments on Day +28 after the appearance of the tumor.

As indicated by the results presented in TABLE 5, the compound of Example 89 is an effective inhibitor of tumor growth in vivo when given orally at 40 mg / kg and 10 mg / kg. Based on the results obtained for the representative compounds of this invention, the compounds of this invention are antineoplastic agents which are useful in the treatment, inhibition of the growth of, or eradication of, neoplasms. In particular, the compounds of this invention are useful in the treatment, inhibition of the growth of, or eradication of, neoplasms that express EGFR such as those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary or lung. . In addition, the compounds of this invention are useful to treat, inhibit the growth of, or eradicate neoplasms from the breast that express the receptor protein produced by the erbB2 oncogene (Her2). Based on the results obtained, the compounds of this invention are also useful in the treatment of polycystic kidney disease. The compounds of this invention can be formulated pure or can be combined by one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% suspending agent, syrups containing, for example, from about 10 to 50% sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of a sterile injectable solution or suspension containing from about 0.5 to 5. % of suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. The effective dose of the active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dose of about 0.5 to about 100 mg / kg of body weight, optionally given in divided doses of two to four times a day, or in a form of sustained liberation. It was projected that the total daily dose is from about 1 to 1000 mg, preferably from 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dose regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced according to the requirements of the therapeutic situation. The compounds of this invention can be administered orally as well as by intravenous, intramuscular or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, nonionic surfactants and edible oils such as corn, peanut and sesame oils, since they are appropriate for the nature of the active ingredient and the particular form of administration desired. Adjuvants commonly employed in the preparation of pharmaceutical compositions, such as flavoring agents, coloring agents, preservatives, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA, can be advantageously included. Preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and capsules filled with solid or filled with liquid. Oral administration of the compounds is preferred. In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. The compounds of this invention can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, that preparation contains a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it facilitates the application in existing syringes. It must be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion media containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. For the treatment of cancer, the compounds of this invention can be administered in combination with other antitumor substances or with radiation therapy. These other substances or treatments with radiation can occur at the same time or at different times than the compounds of this invention. These combined therapies can act synergistically and result in improved efficacy. For example, the compounds of this invention can 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 intercalators such as adriamycin or bleoicin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen. The preparation of the representative examples of the compounds of this invention is described below.

Example 1 1.4-Dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile A mixture of 30.2 g (245.2 mmoles) of 3-methoxy aniline and 41.5 g (245.2 mmoles) of ethyl (ethoxymethylene) cyanoacetate was heated in the absence of solvent at 140 ° C for 30 minutes. 1200 ml of Dowtherm was added to the resulting oil. The solution was refluxed, with stirring, under nitrogen for 22 hours. The mixture was cooled to room temperature and 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-oxo-quinoline-3-carbonitrile: mass spectrum (electro-dew, m / e): M + H 200.9.

Example 2 1, 4-Dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile To a suspension of 10 g (49.6 mmol) of 1,4-Dihydro-7-methoxy-6-nitro- 4-Oxo-quinoline-3-carbonitrile in 160 ml of trifluoroacetic anhydride was added 6 g (74.9 mmol) of ammonium nitrate over a period of 3 hours. The mixture was stirred an additional two hours. The excess anhydride was removed under reduced pressure 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 1000 ml of boiling acetic acid and the solution was treated with decolorizing carbon. The mixture was filtered and concentrated to a volume of 300 ml. Cooling of a solid which was collected giving 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile as a brown solid: mass spectrum (electro-dew, m / e ): M + H 246.

Example 3 4-Chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile A mixture of 5.3 g (21.6 mmol) of 1,4-Dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3 -carbonitrile and 9 g (43.2 mmol) of phosphorus pentachloride was heated at 165 ° C for 2 hours. 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 oxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel to give 5.2 g of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile as a brown solid.

Example 4 4- [(3-Bromophenyl) amino] -7-methoxy-6-nitro-quinoline-3-carbonitrile A solution of 5.2 g (19.7 mmoles) of 4-chloro-7-methoxy-6-nitro-quinoline- 3-carbonitrile and 3.7 g (21.7 mmol) of 3-bromoaniline in 130 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was poured into dilute sodium bicarbonate solution. The solid was collected and washed with water and dried in air. The solid was subjected to chromatography on silica gel eluting with chloroform-ethyl acetate 9: 1. The solvent was removed from product fractions to give 1.2 g of 4 - [(3-Bromophenyl) amino] -7-methoxy-6-nitro-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electro-dew, m / e ): M + H 399.0, 402.0.

Example 5 6-Amino-4- [(3-bromophenyl) amino] -7-methoxy-quinoline-3-carbonitrile A mixture of 2.05 g (51.1 mmcles) of 4 - [(3-bromophenyl) amino] -7-methoxy -6-nitro-quinoline-3-carbonitrile, 1.37 g (25.7 mmol) of ammonium chloride, and 0.86 g (15.4 mmol) of pulverized iron was stirred at reflux in 26 ml of water and 26 ml of methanol for 2 hours. The mixture was diluted with ethyl acetate and the hot mixture was filtered. The organic layer was separated from the filtrate and dried over magnesium sulfate. The solvent was removed and the residue was subjected to chromatography on silica gel eluted with mixtures of chloroform and ethyl acetate. The product fractions were combined to give 1.3 g of 6-Amino-4- [(3-bromophenyl) amino] -7-methoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electro-dew, m / e) : M + H 369.1, 371.1.

EXAMPLE 6 Ethyl Ester of 2-Cyano-3- (4-nitrophenylamino) acrylic acid. 4-Nitroaniline (60.0 g, 0.435 mmol) and ethyl (ethoxymethylene) cyanoacetate (73.5 g, 0.435 mmol) were mechanically mixed in a flask. The mixture was heated at 100 ° C for 0.5 h after it had been melted and resolidified. A 114 g portion of the crude product of ethyl formamide was recrystallized to give 44.2 g of yellow crystals: mp 227-228.5 ° C.

Example 7 1, 4-Dihydroquinolin-6-Nitro-4-oxo-3-carbonitrile A 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 to 260 ° C under N2 for 12.5 h. The cooled reaction was poured into 1.5 L of hexane. The product was collected, washed with hexane and hot ethanol dried in vacuo. 18.7 g of brown solid were obtained. An analytical sample was obtained by recrystallization from dimethylformamide / ethanol: mass spectrum (electro-dew, m / e): M + H 216.

Example 8 4-Chloro-6-nitro-quinoline-3-carbonitrile A mixture of 31.3 g (0.147 mmol) of 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile and 160 mL of oxychloride of phosphorus was refluxed for 5.5 h. The phosphorus oxychloride was removed in va cuo and the residue was poured on ice and neutralized with sodium bicarbonate. The product was collected, washed with water and dried in va cuo (50 ° C). 33.5 g of a brown solid were obtained; solid: mass spectrum (electro-vacuum, m / e): M + H 234.

Example 9 4- [(3-Bromophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 17.0 g (73.1 mmol) of 4-Chloro-6-nitro-quinoline-3-carbonitrile and 15.1 g (87.7 g) mmoles) of 3-bromoaniline in 425 mL of ethanol was refluxed for 5 hours. Saturated sodium bicarbonate was added and then all volatile material was removed in vacuo. The residue was suspended with hexane and the product was collected and washed with hexane. The crude product was washed with water and dried in vacuo (60 ° C). 22.5 g of yellow solid were obtained. An analytical sample was obtained by recrystallization from ethyl acetate; mp 258-259 ° C.

Example 10 6-Amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile A mixture of 4.00 g (10.8 mmol) of 4 - [(3-bromophenyl) amino] -6-nitro-quinoline-3 -carbonitrile and 12.2 g (54.2 mmoles) of SnCl2 dihydrate in 160 mL of ethanol was refluxed under N2 for 1.3 h. After cooling to 25 ° C, ice water and sodium bicarbonate were added and the mixture was stirred for 2 h. Extraction with chloroform, treatment with Darco, drying (magnesium sulfate) and removal of the solvent gave 3.9 g of brown crystals: mass spectrum (electro-dew, m / e): M + H 339.

Example 11 4- [(3,4-Dibromophenyl) amino [-6-nitro-quinoline-3-carbonitrile A mixture of 6. 20 g (26.6 mmol) of 4-chloro-6-nitro-quinolin-3- carbonitrile and 8. 00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL was refluxed under N2 for 5 h. Saturated sodium bicarbonate was added and the volatile material was removed. The residue was suspended with hexane, collected, washed, with hexane and water and dried. The insoluble material was repeatedly extracted with boiling ethyl acetate and the solution was then filtered through silica gel. The solvent was removed to give 3.80 g of a green solid: mass spectrum (electro-dew, m / e): m + H 449.

Example 12 6-Amino-4- [(3,4-dibromophenyl) amino] -quinolin-3-carbonitrile A mixture of 4.90g (10.9mmol) of 4 - [(3,4-dibromophenyl) amino] -6-nitro -quinolin-3-carbonitrile and 12.4g (54.7 mmol) of SnCl2 dihydrate in 200 mL of ethanol was refluxed under N2 for 1.5 h. After cooling to 25 ° C, the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. This solution was then extracted with chloroform, treated with Darco, dried (magnesium sulfate) and evaporated. After drying in vacuo (40 ° C), 1.25 g of brown solid was obtained: mass spectrum (electro-dew, m / e): M + H 417, 419, 421.

Example 13 6-Nitro-4- [(3-trifluoromethylphenyl) amino] -quinolin-3-carbonitrile A mixture of 10.6g (45.7mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 8.82g (54.8 mmoles) of 3- (trifluoromethyl) aniline in 270 mL of ethanol was refluxed under N2 for 5 h. The reaction was diluted with ethanol, neutralized with standard sodium bicarbonate and evaporated. The residue was suspended with hexane, collected, washed with hexane and water dried in vacuo (60 ° C) to give 10.9 g of yellow solid. A sample of 2.00g of ethanol was recrystallized to give 1.20g of bright yellow solid; mp 260-261 ° C.

Example 14 6-Amino-4- [(3-trifluoromethylphenyl) amino] -quinolin-3-carbonitrile A suspension of 6.00g (16.8mmol) of 6-nitro-4- [(3-trifluoromethylphenyl) amino] -6-nitro -quinolin-3-carbonitrile and 18.9g (83.3 mmol) of SnCl2 dihydrate in 240 mL of ethanol was refluxed under N2 for lh. After cooling to 25 ° C, the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. The product was extracted with chloroform, treated with Darco, dried (magnesium sulfate) and evaporated. The residue was filtered through silica gel (10% methanol in chloroform), evaporated and dried in vacuo (40 ° C) to give 4.87 g of brown solid: mass spectrum (electro-dew, m / e): M + H 329 Example 15 [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide of 4-bromo-but-2-enoic acid A solution of 1.65 grams (0.01 mol) of 4-bromo acid crotonic (Giza Braun, J. Am. Chem. Soc. 52, 3167 1930) in 15 ml of dichloromethane was treated with 1.74 ml (0.02 mole) of oxalyl chloride and one drop of N, N-dimethylformamide. After one hour the solvents were removed in the rotary evaporator. The 4-bromine crotonyl chloride was taken in 25 ml of tetrahydrofuran, and 3.39 grams of 6-amino-4- (3-bromo-phenylamino) -quinolin-3-carbonitrile in 25 ml of tetrahydrofuran were added dropwise. This was followed by the dropwise addition of 1.92 ml (0.011 moles) of diisopropylethylamine. After the addition of 25 ml of water and 50 ml of ethyl acetate, the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and removed as a solid in vacuo. This solid was digested for one hour with ethyl acetate at reflux and then filtered from ethyl acetate while still hot. In this way, 3.31 grams (68%) of 4-bromo-but-2-enoic acid [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide was obtained.

Example 16 Ethyl Ester of 2-Cyano-3- (2-methyl-4-nitrophenyl) acrylic acid A mixture of 2-methyl-4-nitroaniline (38.0 g, 250 mmol), ethyl (ethoxymethylene) -cyanoacetate (50.8 g, 300 mmoles), and 200 ml of toluene was refluxed for 24 h, cooled, diluted with ether-hexane 1: 1, and filtered. The resulting white solid was washed with hexane: ether and dried to give 63.9 g, mp 180-210 ° C.

Example 17 1,4-Dihydroquinolin-8-methyl-6-nitro-3-carbonitrile A stirring mixture of 64 g (230 mmol) of 2-cyano-3- (2-methyl-4-nitrophenyl) ethyl ester Acrylic and 1.5 L of Dowtherm A was heated at 260 ° C for 12 h, cooled, diluted with hexane and filtered. The yellow solid thus obtained was washed with hexane and dried to give 51.5 g, mp 295-305 ° C.

Example 18 4-Chloro-8-methyl-6-nitro-quinoline-3-carbonitrile A stirring mixture of 1,4-dihydroquinolin-8-methyl-6-nitro-carbonitrile (47 g, 200 mmol), and 200 ml of phosphorus oxychloride was refluxed for 4 hrs. 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 layer was separated and washed with water. The solution was dried and concentrated to a volume of 700 ml. The product was precipitated by the addition of hexane and cooling to 0 ° C. The white solid was filtered and dried to give 41.6 g, mp 210-212 ° C.

Example 19 4- [(3-Bromophenyl) amino] -8-methyl-6-nitro-quinoline-3-carbonitrile A stirring mixture of 4-chloro-8-methyl-6-nitro-quinoline-3-carbonitrile (14.8 g, 60 mmol), 3-bromoaniline (12.4 g, 72 mmol), pyridine hydrochloride (6.93 g, 60 mmol), and 180 ml of ethoxyethanol was refluxed for 1.5 h, cooled, poured into a mixture with stirring water and an amount of sodium carbonate to give a pH of 8-9. The resulting yellow solid was filtered, washed with water, dried, digested in boiling ether, filtered, and dried to give 22.6 g, mp 263-267 ° C.

Example 20 4- [(3-Bromophenyl) -N-acetylamino] -8-methyl-6-nitro-quinoline-3-carbonitrile A stirring mixture of 4 - [(3-bromophenyl) amino] -8-methyl-6 -nitro-quinoline-3-carbonitrile (15.3 g, 40 mmol), 0.37 g (3 mmol) of dimethylamino pyridine, 40 ml of acetic anhydride, and 80 ml of pyridine were refluxed for 3 h and concentrated at 50 ° C under vacuum. The residue was stirred with methylene chloride and 0.1 N HCl. After filtration through Celite, the organic layer was washed with water, dried and concentrated. The residue was subjected to chromatography on silica gel with 1% acetic acid in methylene chloride to give 11.2 g of an amber crystal, NMR (CDCl 3) d 2.29 (N-acetyl group).

Example 21 8-Bromomethyl-4- [(3-bromophenyl) -N-acetylamino] -6-nitroquinoline-3-carbonitrile A suspension with stirring of 4- [(3-bromophenyl) -N-acetylamino] -8- methyl-6-nitro-quinoline-3-carbonitrile (10.6 g, 25 mmol), N-bromosuccinimide (6.68 g, 37.5 mmol), 0.30 g of dibenzoyl peroxide and 200 ml of carbon tetrachloride were refluxed for 2 h , treated with an additional 0.30 g of dibenzoyl peroxide, and refluxed an additional 2.5 h, cooled, diluted with methylene chloride, and stirred with aqueous sodium bisulfite. The organic layer was separated and washed successively with water, sodium bicarbonate solution, and water. The solution was dried and evaporated to give 15 g of a white foam, NMR (CDC13) d 5.19 (DHP, CH2Br).

Example 22 4- [(3-Bromophenyl) amino] -8-dimethylaminomethyl-6-nitro-quinoline-3-carbonitrile To a stirred solution of dimethylamine in THF (2.0 M, 115 ml, 230 mmol) at 0 ° C was added a solution of 8-bromomethyl-4- [(3-bromophenyl) -N-acetylamino] -6-nitro-quinoline-3-carbonitrile (11.6 g, 23 mmol) in 115 ml of THF for 15 m. After heating to 25 ° C the mixture was stirred for 2 h. The THF was evaporated, and the residue was refluxed in 230 ml of methanol with 12.7 g (92 mmol) of potassium carbonate for 1 h. The mixture was cooled, saturated with C02, and concentrated. The residue was partitioned with methylene chloride and water. The organic layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give 6.0 g of yellow solid, mp 223-226 ° C.

Example 23 6-Amino-4- [(3-bromophenyl) amino] -8-dimethylaminomethyl-quinoline-3-carbonitrile A stirring mixture of 4 - [(3-bromiphenyl) amino] -8-dimethylaminomethyl-6-nitro- quinoline-3-carbonitrile (5.98 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atoms), acetic acid (5.67 ml, 99 mmol), and 70 ml of methanol was refluxed for 2 h and then evaporated to remove the methanol. The residue was stirred with water for 10 m, and the orange solid was filtered with 2% acetic acid. The total filtrate was basified to pH 10 with 5N sodium hydroxide. The resulting precipitate was extracted with methylene chloride. The extract was washed with water, dried, and concentrated. The residue was chromatographed on silica gel with ethyl acetate-methanol-triethylamine to give 3.34 g of an amber solid; mass spectrum (electro-vacuum, m / e) M + H 396.2,398.1.

Example 24 6-Amino-4- [(3-iodophenyl) amino] -quinolin-3-carbonitrile A mixture of 6.70 g (16.1 mmol) of 4 - [(3-iodophenyl) amino] -6-nitro-quinoline-3 -carbonitrilq, 300 ml of ethanol and 18.2 g (80.5 mmoles) of SnCl2 dihydrate was heated to reflux under N2. The heat was stirred at 2 hours, ice water was added. Sodium bicarbonate was added until the pH was basic, forming a thick yellow mixture. It was stirred for 2. It was extracted with chloroform, the organic portion was stirred with Darco and filtered through magnesium sulfate. The solvent was removed and dried in vacuo to give 3.48 g of yellow-brown solid: mass spectrum (electron-dark m / e): M + H = 387.0.

Example 25 4- [(3-Iodophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 3.10 ml (25.7 mmoles) of 3-iodoaniline, 200 ml of ethanol and 5.00 g (21.4 mmoles) of 4- chloro-6-nitro-quinoline-3-carbonitrile was heated to reflux under N2 for 3 hours. It was cooled and made basic with a saturated sodium bicarbonate. The solvents were separated and made azeotropes with ethanol. The residue was suspended with hexane and collected. It was dried with air, the solids were washed with water, and dried in vacuo. The solids were dissolved in 400 ml of ethyl acetate, shaken with Darco, and the solvent was filtered and stirred. The solids were dried in vacuo to give 7.38 g of yellow solid: mass spectrum (electron-dark m / e): M + H = 417.0.

EXAMPLE 26 6-Amino-4- [(3-methylphenyl) amino] -quinolin-3-carbonitrile 253 mg of 10% palladium on carbon was added to a bottom flask under N2 and the catalyst was covered with 140 ml of ethane To this were added 2.49 g (8.18 mmoles) of 6-nitro-4- ([3-methylphenyl) amino] -quinolin-3-carbonitrile and 640 μl (20.4 mmoles) of anhydrous hydrazine. The mixture was heated to reflux for 2 hours 15 minutes and filtered hot through celite. The solvent was separated and dried in vacuo to give 2.455 g of yellow solid: mass spectrum (electrorewrapture m / e): M + H = 275.2.

Example 27 6-Nitro-4- [(3-methylphenyl) amino] -quinolin-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml of ethanol and 2.75 ml (25.7 mmoles) of 3-toluidine was heated to reflux for hours. It was cooled and added saturated sodium bicarbonate until the pH was basic. The separated solvents were made azeotropic with ethanol. It was suspended with hexane, collected and dried with air. It was washed with water and dried in va cuo. It was boiled in ethyl acetate, shaken with Darco and filtered. The solvent was separated and dried in vacuo to give 4.82 g of yellow-orange solid: mass spectrum (electron-dark m / e): M + H = 305.2.

Example 28 6-Amino-4- [(3-chlorophenyl) amino] -quinolin-3-carbonitrile A mixture of 6.30 g (19.4 mmol) of 4 - [(3-chlorophenyl) amino] -6-nitro-quinoline-3 -carbonitrile, 300 ml of ethanol and 21.9 g (97 mmol) of SnCl2 dihydrate was heated to reflux under N2. The heat was stirred at 2 hours, ice water was added and it was made basic with sodium bicarbonate. It was stirred for 2 hours and chloroform was extracted. The organic layer was dried with sodium sulfate, filtered, the solvent was removed and the residue was dried in vacuo yielding 5.74 g of solid-yellow-brown: mass spectrum (electron-dark m / e): M + H = 295.1 , 297.1.

Example 29 4- [(3-Chlorophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 10.0 g (42.9 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 260 ml of ethanol and 5.40 ml of 3-chloroaniline was heated to reflux under N2. The heat was stirred at 4 hours, cooled to 25 ° C and saturated sodium bicarbonate was added until the pH was basic. The solvents were separated and azeotroped with ethanol. The residue was suspended with hexane, the solid collected and dried with air. The solids were washed with water and dried in vacuo. They were dissolved in boiling ethyl acetate, shaken with Darco, and filtered. The solvent was removed and the residue was dried in vacuo, yielding 6.5 g of yellow solid: mass spectrum (electron-dark m / e): M + H = 325.0, 327.0.

EXAMPLE 30 6-Amino-4- [(3-methoxyphenyl) amino] -quinolin-3-carbonitrile 325 mg of 10% palladium on carbon was added to a bottom flask under N2 and covered with 165 ml of ethanol. 3.29 g (10.3 mmol) of 4 - [(3-methoxyphenyl) -amino] -6-nitro-quinoline-3-carbonitrile and 800 μl of anhydrous hydrazine were added and the mixture was heated to reflux. After 1 h, it was filtered hot through celite, the solvent was removed and dried in va cuo, yielding 2.876 g of yellow solid: mass spectrum (electron-dark m / e): M + H = 291.2.

EXAMPLE 31 4- [(3-Methoxyphenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml of ethanol , and 3.0 ml (26.0 mmoles) of m-anisidine was heated to reflux under N2. The heat was stirred at a low temperature and made basic with saturated sodium bicarbonate. The solvents were separated and azeotroped with ethanol. It was suspended with hexane and the crystals were collected. It was washed with water, dried in vacuo. 5.94 g of crude product were dissolved in 320 ml of boiling ethyl acetate, shaken with Darco, filtered, the solvent was removed, and dried in vacuo, giving about 5 g of solid-orange: mass spectrum (electro-vacuum m / e): M + H = 291.1.

Example 32 6-Amino-4- [(3-chloro-4-fluorophenyl) amino] -quinolin-3-carbonitrile A mixture of 5,360 g (15.6 mmol) of 4 - [(3-chloro-4-fluorophenyl) amino] -6-Nitro-quinoline-3-carbonitrile, 250 ml of ethanol, 17.67 g (78.2 mmol) of SnCl2 dihydrate was heated to reflux under N2. The heat was stirred at ½ hour and ice water was added. It was made basic with sodium bicarbonate. It was stirred for 2 hours extracted with chloroform. Brine was added to the separatory funnel to help separate the layers. The organic layer was dried with Darco and dried with sodium sulfate. It was filtered, the solvent was separated and dried in vacuo, yielding 4,460 g of yellow-brown solid: mass spectrum (electron-dark m / e): M + H = 312.9, 315.0.

Example 33 4- [(3-Chloro-4-fluorophenyl) lane] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro. quinoline-3-carbonitrile, 200 ml of ethanol and 3.75 g (25.8 mmoles) of 3-chloro-4-fluoroaniline were heated under reflux under N2. The heat was removed at XX > hours and a saturated solution of sodium bicarbonate was added until the mixture was basic. The solvents were separated and azeotroped with ethanol. The residue was suspended with hexane, the solids were collected, washed with water and dried in vacuo. The solids were dissolved in 250 ml of boiling ethyl acetate, shaken with Darco and filtered. The solvent was separated and dried in vacuo, yielding 6.036 g of yellow solid: mass spectrum (electron-dark m / e): M + H = 343.1, 345.1.

EXAMPLE 34 6-Amino-4- [(4-bromophenyl) amino] -quinolin-3-carbonitrile a mixture of 3.10 g (8.40 mmol) of 4 - [(4-bromophenyl) amino] -6-nitro-quinolin-3 -carbonitrile, 155 ml of ethanol, and 9.47 g (42.0 mmoles) of SnCl2 dihydrate were heated to reflux under N2. 4 hours later, the heat was removed and ice water was added. It was made basic with sodium bicarbonate and stirred for 2 hours. With the still basic mixture, it was extracted with chloroform, the organic layer was dried with Darco and stirred with sodium sulfate. It was filtered, the solvent was removed and dried in vacuo, giving 2.265 g of brown-yellow solid: mass spectrum (electron-dark m / e): M * h = 339.0, 341.0.

Example 35 4- [(4-Bromophenyl) amino] -6-butyl-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml of ethanol , and 4.42 g (25.8 mmol) of p-bromoaniline was heated to reflux under N2 for 3 hours. The heat was removed and saturated sodium bicarbonate was added until basic. The solvents were separated and azeotroped with ethanol. The residue was suspended with hexane, the solids were collected, and dried with air. It was washed with water and dried in vacuo. It was eluted in 1.4 liters of ethyl acetate, and without completely dissolving all the solids, it was stirred with Darco, filtered. The solvent was removed and dried in vacuo to give 3.524 g of yellow solid: mass spectrum (electron-dark m / e): M + H = 369, 370.9.

Example 36 6-Amino-4- [(3,4-difluorophenyl) amino] -quinolin-3-carbonitrile A mixture of 4.53 g (13.9 mmol) of 4- [(3,4-difluorophenyl) amino] -6-nitro-quinoline -3-carbonitrile, 200 ml of ethanol and 15.72 g (69.4 mmoles) of SnCl2 dihydrate were heated to reflux under N2. The heat was removed at ½ hour, ice water was added and it was made basic with sodium bicarbonate. It was stirred for 2 hours and extracted with chloroform. The organic layer was shaken with Darco, dried with sodium sulfate and filtered. The solvent was evaporated and dried in vacuo to give 3,660 g of yellow-green solid: mass spectrum (electron-dark m / e): M + H = 297.1.

Example 37 4- [(3,4-Difluorophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 250 ml of ethanol and 2.55 ml (25.8 mmoles) of 3,4-difluoroaniline was heated to reflux under N2. The heat was removed at 3 hours and made basic with saturated sodium bicarbonate. The solvents were separated and azeotroped with ethanol. The residue was suspended with hexane, the solids were collected and air dried. It was washed with water and dried in va cuo. It was dissolved in ethyl acetate, shaken with Darco, filtered, the solvent was separated and dried in vacuo, giving 5.02 g of yellow solid: mass spectrum (electrodewet m / e): M + H = 327.1.

Example 38 6-Amino-4- [(3-chloro-4-thiophenoxyphenyl) amino] -quinolin-3-carbonitrile A mixture of 6,753 g (15.6 mmol) of 4 - [(3-chloro-4-thiophenoxyphenyl) amino] -6-Nitro-quinoline-3-carbonitrile, 250 ml of ethanol, and 17.66 g (78.0 mmol) of SnCl2 dihydrate were heated to reflux under N2. The heat was stirred at 2 hours, a large volume of ice water was added, it was made basic with sodium bicarbonate. It was stirred for 2 hours and with still basic mixture, it was extracted with chloroform. The organic layer was shaken with Darco, dried with sodium sulfate, filtered, the solvent was removed and dried in vacuo to give 5.996 g of yellow solid: mass spectrum (electrodewax m / e): M + H = 403.1, 405.1.

Example 39 4- [(3-Chloro-4-thiophenoxyphenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 250 ml of ethanol and 6.07 g (25.6 mmoles) of 3-chloro-4-thiophenoxyaniline was heated to reflux under N2. The heat was removed at about 8 hours, made basic with saturated sodium bicarbonate, the solvents were separated and azeotroped with ethanol. The residue was suspended with hexane and the solids were collected. It was washed with water and dried in va cuo. It was almost completely dissolved in 400 ml of ethyl acetate, shaken with Darco and filtered. The solvent was removed and eluted in hexane to remove at least the excess aniline. It was dried in va cuo, giving 6.90 g of a red solid: mass spectrum (electron-dark m / e): M + H = 433.1, 435.1.

EXAMPLE 40 6-Amino-4- [(3-cyanophenyl) amino] -quinolin-3-carbonitrile 100 mg of 10% palladium on carbon was added to a bottom flask under N2 and covered with 50 ml of ethanol. 1.00 g (3.17 mmol) of 4 - [(3-cinnaphenyl) amino] -6-nitro-quinoline-3-carbonitrile and 250 μl (7.39 mmol) of anhydrous hydrazine were added and heated to reflux. The heat was stirred at 2 hours and filtered hot through celite. The solvent was removed and dried in vacuo, yielding 887 mg of yellow solid: mass spectrum (electrospray m (e): M + H = 286.2.

Example 41 4- [(3-Cyanophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml of ethanol and 3.04 g (25.8 mmol) of 3-aminobenzonitrile was heated to reflux. The heat was removed at the end and it was made basic with saturated sodium bicarbonate. The solvents were separated and dried with air. The residue was suspended with hexane and the solids were collected. It was washed with water and dried in vacuo. A large volume of ethyl acetate was boiled, the solids were collected and dried in vacuo, giving 5.15 g of yellow-brown solid: mass spectrum (electrorrocio m / e): 316.0.

Example 42 6-Amino-4- [(3-ethylphenyl) amino] -quinolin-3-carbonitrile A mixture of 2.00 g (6.36 mmol) of 4 - [(3-ethylphenyl) amino] -6-nitro-quinolin-3 -carbonitrile, 100 ml of ethanol and 7.19 g (31.8 mmoles) of SnCl 2 dihydrate was heated to reflux under N 2. The heat was stirred at 3 ^ 0 hours and ice water was added. It was made basic with sodium bicarbonate and stirred for 2 hours. It was extracted with chloroform, the organic layer was shaken with Darco, dried with sodium sulfate, filtered, the solvent was removed, and dried in vacuo, yielding 1.737 yellow-brown solid: mass spectrum (electrodewish m / e ): M + H = 285.2.

Example 43 4- [(3-Ethylphenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml of ethanol and 3.82 g (32.6 mmol) of 3-ethynylaniline was heated to low reflux N2 The heat was removed at 3 ^ hours and a solution of saturated sodium bicarbonate was added until it was basic. The solvents were separated and made azeotropic with ethanol. The residue was suspended with hexane and the solids were collected. It was washed with water and dried in va cuo. It was dissolved in ethyl acetate, shaken with Darco, filtered, the solvent was removed and dried in vacuo to give 4.544 g of yellow solid: mass spectrum (electrodewax m / e): M + H = 315.1.

Example 44 4- [(3-Bromo-4-fluorophenyl) amino] -6-nitro-quinoline-3-carbonitrile A mixture of 3.8 g (16.33 rnmoles) of 4-chloro-6-nitro-quinolyl-3-carbonitrile and 3.7 g (20 mmol) of 3-bromo-4-fluoroaniline in 200 mL of ethanol was refluxed for 3 hr. After the solvent was removed, the residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The product was collected as a pale yellow solid, 6.5 g (71%); ESMS m / z 387.3, 389.2, mp 269-270 ° C (dec).

Example 45 6-amino-4- [(3-Bromo-4-fluorophenyl) amino] -quinolin-3-carbonitrile A mixture of 8 g (20.67 mmol) of 4- [(3-chloro-4-fluorophenyl) amino] -6-nitro-quinoline-3-carbonitrile, 4 g (72.35 mmol) of iron powder and 8.9 g (165.36 mmol) of ammonium chloride in 240 mL of methanol and water (ratio 2: 1) was refluxed for 4 hr. The mixture was filtered hot and washed with methanol and water. The product precipitated from the filtrate after cooling. The solid was collected and dried in vacuo to give 5.8 g (79%) of yellowish brown solid; ESMS m / z 356.8, 358.8, mp 210-212 ° C.

EXAMPLE 46 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-3-carbonitrile A mixture of 4.4 g (16.7 mmoles) of 4-chloro-7-methoxy-6-nitro -quinolin-3-carbonitrile and 2.67 g (18.3 mmol) of 3-chloro-4-fluoraniline in 110 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried over sodium sulfate and then the solvent was removed under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of ethyl acetate and methanol to give 3 g of yellow solid: mass spectrum (electro-dew, m / e): 372.9.

Example 47 6-Amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile A mixture of 4.88 g (13 mmol) of 4- [(3-chloro-4-fluorophenyl) ) amino] -7-methoxy-6-nitro-quinoline-3-carbonitrile, 5.2 g (97.5 mmol) of ammonium chloride and 3.3 g (58.5 mmol) of iron were stirred under reflux in 60 ml of water and 60 ml of methanol for 4.5 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtrate was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was subjected to chromatography on silica gel eluting with a mixture of ethyl acetate and methanol to give 3.38 g of yellow solid: mass spectrum (electro-dew, m / e): M + H 343.4.

Example 48 4- (3-Bromo-4-fluoro-phenylamino) -7-methoxy-6-nitro-quinoline-3-carbonitrile A mixture of 3.52 g (9.7 mmoles) of 4-chloro-7-methoxy-6-nitro -quinoline-3-carbonitrile and 2.0 g (10.7 mmoles) of 3-bromo-4-fluoroaniline in 150 ml of methoxyethanol was refluxed under nitrogen for 5.5 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried with sodium sulfate and then the solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give the title compound.

Example 49 6-Amino-4- (3-bromo-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile A mixture of 2.9 g (6.95 mmoles) of 4- [(3-bromo-4-fluorophenyl) ) amino] 7-methoxy-6-nitro-quinoline-3-carbonitrile, 6. 5 g (121.6 mmoles) of ammonium chloride and 4.05 g (73 mmoles) of iron in 50 ml of water and 50 ml of methanol for 6 hours. The sample was diluted with hot ethyl acetate and the hot mixture was filtered. The filtrate was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solvent was removed and the residue was subjected to chromatography on silica gel eluting with a mixture of ethyl acetate and methanol to give 2.11 g of light yellow solid: mass spectrum (electro-dew, m / e) :: M + H 386.7 and 388.8.

Example 50 7-Ethoxy-4-hydroxy-quinoline-3-carbonitrile A mixture of 10 g (73 mmol) of 3-ethoxy aniline and 12.3 g (73 mmol) of ethyl (ethoxymethylene) cyanoacetate was heated in 90 ml of Dowther a 140 ° C for 7 hours. To this mixture was added 250 ml of Dowther. The solution was stirred and refluxed under nitrogen for 12 hours with periodic distillation to remove ethanol. The mixture was collected at room temperature and the solid was collected and washed with hexane. The crude solid was treated with boiling ethanol and then filtered to give 9.86 g of brown solid: mass spectrum (electro-dew, m / e): M + H 214.7.

Example 51 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile To a suspension of 5 g (73 mmol) of 7-Ethoxy-4-hydroxy-quinoline-3-carbonitrile in 75 ml of trifluoroacetic anhydride was added. they added 5.5 g (69 mmoles) of ammonium nitrate over a period of 6 hours at room temperature. The excess anhydride was removed under reduced pressure at 45 ° C. The residue was stirred with 300 ml of water. The solid was collected and treated with boiling ethanol to give 3.68 g of thin solid: mass spectrum (electro-dew, m / e) M + H 259.8.

Example 52 4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile A mixture of 3.45 g (13 mmol) of 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g ( 26 mmoles) 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 in cold, dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.1 g of persimmon solid: mass spectrum (electro-dew, m / e) M + H 277.77.

Example 53 4- (3-Bromo-phenylamino) -7-ethoxy-6-nitro-quinoline-3-carbonitrile A mixture of 2.1 g (7.6 mmoles) of 4-chloro-7-ethoxy-6-nitro-quinoline-3 -carbonitrile and 0.91 ml (8.3 mmoles) of 3-bromoaniline in 100 ml of ethanol was refluxed under nitrogen for 4.5 hours. The reaction mixture was poured into dilute sodium bicarbonate solution. The ethanol was removed under vacuum. The mixture was diluted with ethyl acetate and the organic layer was separated and dried over sodium sulfate. The solution was concentrated and the solid was collected and then washed with hexane. After drying, 2.6 g of yellow solid were obtained: mass spectrum (electro-dew, m / e) M + H 412.8 and 414.9.

Example 54 6-Amino-4- (3-bromo-phenylamino) -7-ethoxy-quinoline-3-carbonitrile A mixture of 2.5 g (6 mmol) of 4- [(3-bromophenyl) amino] -7-ethoxy- 6-nitro-quinoline-3-carbonitrile, 2. 4 g (45 mmol) of ammonium chloride and 1.5 g (27 mmol) of iron were stirred under reflux in 40 ml of water and 40 ml of methanol for 4 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtrate was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solution was concentrated and 1.5 khaki solid was collected: mass spectrum (electro-dew, m / e): M + H 382.8 and 384.8.

Example 55 8-Methoxy-4-hydroxy-6-nitro-quinoline-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 it was heated in 100 ml of Dowther at 120 ° C overnight and at 180 ° C for 20 hours. This mixture was washed with 300 ml of Dowther. The solution was stirred and refluxed under nitrogen for 12 hours' with periodic distillation of the removed ethanol. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude oil was treated with boiling ethanol and then filtered to give 12 g of brown solid: mass spectrum (electro-dew, m / e): M + H 245.8.

Example 56 4-Chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile A mixture of 4 g (16 mmol) of 8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g ( 32 mmoles) of phosphorus pentachloride, and 15 ml of phosphorus oxychloride was refluxed for 2.5 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 dilute cold sodium hydroxide solution. The son was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed yielding 2.05 of brown solid: mass spectrum (electro-dew, m / e) M + H 263.7.

Example 57 6-Nitro-4- (3-bromo-phenylamino) -8-methoxy-quinoline-3-carbonitrile A mixture of 1.9 g (7.6 mmoles) of 4-chloro-8-methoxy-6-nitro-quinoline-3 -carbonitrile and 0.86 ml (8.3 mmoles) of 3-bromoaniline in 95 ml of ethanol was refluxed under nitrogen for 5 hours. The reaction mixture was poured into dilute sodium bicarbonate solution. The ethanol was removed under vacuum. The mixture was distilled with ethyl acetate and the organic layer was separated and dried over sodium chloride. The solution was concentrated and the solid was collected and then washed with hexane. After drying, 2.3 g of yellow solid were obtained: mass spectrum (electro-dew, m / e) M + H 398.8 and 400.8.

Example 58 6-Amino-4- (3-bromo-phenylamino) -8-methoxy-quinoline-3-carbonitrile A mixture of 2.15 g (5 mmol) of 4 - [(3-brornophenyl) amino] -8-methoxy- 6-Nitro-quinoline-3-carbonitrile, 1.95 g (37.5 mmol) of ammonium chloride, and 1.26 g (22.5 mmol) of iron were stirred under reflux in 40 ml of water and 40 ml of methanol for 3 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtrate was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solution was concentrated and 0.43 g of a dark yellow solid was collected; mass spectrum (electro-dew, m / e): M + H 368.9 and 370.9.

Example 59. 4-Chloro-but-2-ianoic acid. Propargyl chloride (2 mL, 26.84 mmol) was dissolved in 40 mL of tetrahydrofuran under nitrogen and cooled to -78 ° C. After the addition of N-butyllithium (5.4 mL, 13.42 mmol, 2.5 M in n-hexane) and stirred for 15 minutes, a flow of dry carbon dioxide was passed through it at -78 ° C for two hours. hours. The reaction solution was filtered and neutralized with 3.5 mL of 10% sulfuric acid. After evaporation of the solution, the residue was extracted with ether. The ether solution was washed with saturated brine solution, and dried over sodium sulfate. After evaporation of the dry ether solution, 0.957 g (60%) of an oily product was obtained: ESMS m / z 116.6 (M-H +).

EXAMPLE 60 4-Dimethylamino-but-2-ynoic acid n-Butyl lithium in hexane (96 mL, 2.5 M in n-hexane) was slowly added to 1-dimethylamino-2-propyne (20 g, 240 mmol) in 100 mL of tetrahydrofuran. under nitrogen. The mixture was stirred for 1 h at -78 ° C, then carbon dioxide was passed through it overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 15.6 g of 4-dimethylamino-but-2-inoic acid: mass spectrum (m / e): M-H 126.

Example 61 Bis- (2-methoxy-ethyl) -prop-2-ynyl-amine Propargyl bromide (17.8g, 150mmol) in a mixture of bis (2-methoxy-ethyl) amine (20g, 150mmol) and cesium carbonate (49g, 150mmol) in 350mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered, 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 to give 20 g of bis- (2-methoxy-ethyl) -prop-2-ynyl-amine: mass spectrum (m / e): M + H 172.

EXAMPLE 62 4- [Bis- (2-methoxy-ethyl) -amino] -but-2-ynoic acid N-butyl lithium in hexane (42mL, .5M in n-hexane) was added slowly to bis- (2- methoxy-ethyl) -prop-2-ynyl-amine (18g, 105 mmol) in 80 mL of tetrahydrofuran under nitrogen.

The mixture was stirred for 1 h at -78 ° C, then carbon dioxide was passed through it overnight.

The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration.

The filtrate was collected and dried in vacuo to give 18 g of 4- [bis- (2-methoxy-ethyl) amino] -but-2-ynoic acid: mass spectrum (m / e): M-H 214.

Example 63 1-Methyl-4-prop-2-ynyl-piperazine Propargyl bromide (23.8 g, 200 mmol) was added dropwise in a mixture of 1-methyl-piperazine (20 g, 200 mmol) and cesium carbonate (65 g, 200 mmol). ) in 350mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered, 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 to give 7.5 g of l-methyl-4-prop-2-ynyl-piperazine: mass spectrum (m / e): M + H 139.

Example 64 4- (4-Methyl-piperazin-1-yl) -but-2-ynyl acid n-Butyl lithium in hexane was added slowly (17.2 mL, 2.5 M in n-hexane) to l-methyl-4-prop-2-ynyl-piperazine (6.0 g, 43.5 mmol) in 40 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at -78 ° C, then carbon dioxide was passed through it overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in ethanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 7 g of 4- (4-methyl-piperazin-1-yl) -but-2-ynoic acid: mass spectrum (m / e): M-H 181.

Example 65 (2-Methoxy-ethyl) -methyl-prop-2-ynyl-amine Propargyl bromide (26.8 g, 225 mmoles) to a mixture of N- (2-methoxyethyl) methyl amine (20 g, 225 mmol) of cesium carbonate (73 g, 225 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The organic salts were then filtered, 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 to give 14 g of (2-methoxy-ethyl) -methyl-prop-2-ynyl-amine: mass spectrum (m / e): M + H 127.

Example 66 4- [(2-Methoxy-ethyl) -methyl-amino] -but-2-ynoic acid n-Butyl lithium in hexane (37.8 L, 2.5 M in n-hexane) to (2-methoxy) was slowly added. ethyl) -methyl-prop-2-ynylamine (12.0 g, 94.5 mmol) in 90 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at -78 ° C, then carbon dioxide was passed through it overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The crude acid was dissolved in ethanol, and the insoluble salt was removed by filtration. The filtrate was collected and dried in vacuo to give 15 g of 4- [(2-methoxy-ethyl) -methyl-amino] -but-2-ynoic acid: mass spectrum (m / e): M-H 170.

EXAMPLE 67 Allyl-methyl-prop-2-ynyl-amine Propargyl bromide (33.4 g, 281 mmol) was added dropwise to a mixture of isopropyl-methyl-amine (20 g, 281 mmol) and cesium carbonate (90 g). , 281 mmoles) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with vinyl acetate. The organic extracts were then evaporated to give 4.6 g of allyl-methyl-propo-2-ynyl-amine: mass spectrum (m / e): M + H 110.

Example 68 4- (Allyl-methyl-amino) -but-2-ynyl acid n-Butyl lithium in hexane (16.4 mL, 2.5 M in n-hexane) was added slowly to allyl-methyl-prop-2-ynyl-amine (4.5 g, 46 mmol) in 50 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at -78 ° C, then dry carbon dioxide was passed through it overnight. The resulting solution was poured out and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure 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 4.1 g of 4- (allyl-methyl-amino) -but-2-ynoic acid: mass spectrum (m / e): M-H 152.

Example 69: 4-Methoxymethoxy-but-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 with stirring, under nitrogen, 10 g of propargyl alcohol was added. during 15 minutes. The mixture was stirred an additional 30 minutes. To the mixture, with stirring, at 0 ° C, 15.8 g of chloromethylmethyl ether was added. Stirring was continued at room temperature overnight. The mixture was filtered and the solvent was removed from the filtrate. He 'residue was distilled (35-38 ° C, 4 mm) giving 8.5 g of a liquid. The distillate was dissolved in 200 mL of ether, the solution was stirred under nitrogen and cooled to -78 ° C as 34. 1 mL of 2.5 molar n-butyl lithium in hexane added for 15 minutes. Stirring was continued for another 1.5 hr. Dry carbon dioxide was allowed to pass over the surface of the stirring reaction mixture as it was heated from -78 ° C to room temperature. The mixture was stirred under a carbon dioxide atmosphere overnight. The mixture was poured into a mixture of 14 mL of hydrochloric acid and 24 mL of water. The organic layer was separated and dried over magnesium sulfate. The solvent was removed and the residue was maintained at 100 ° C at 4 mm for 1 hr giving 10.4 g of 4-methoxymethoxy-but-2-ynoic acid.

EXAMPLE 70 Crotonic 4-Bromo Acid Following the Braun method [Giza braun, J. Am. Che. Soc. 52, 3167 (1930)], 11.76 mL (17.9 grams, 0.1 mol) of methyl 4-bromocrotonate in 32 mL of ethanol and 93 mL of water were cooled to -11 ° C. The reaction was vigorously stirred, and 15.77 g (0.05 mmol) of finely powdered barium hydroxide was added in portions over a period of about 1 hour. Cooling and vigorous stirring continued for approximately 16 hours. The reaction mixture was then extracted with 100 mL of ether. The aqueous layer was treated with 2.67 mL (4.91 g, 0.05 mol) of concentrated sulfuric acid. The resulting mixture was extracted with portions of 3-100 mL of ether. The combined ether extracts were washed with 50 mL of brine, then dried over sodium sulfate. The solution was removed to an oil in vacuo. This oil was removed in approximately 400 mL of boiling heptane, leaving a gum. The heptane solution was separated and boiled until approximately 50 mL remained. Cooling gave 3.46 g of product.

Example 71 4- (2-Methoxy-ethoxy) -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 dropwise. (131.4 mmoles) of 2-methoxyethanol for 15 minutes. After 1 hr, 19.54 g (131.4 mmoles) of 80% propargyl bromide were added dropwise. After stirring for 17 h at room temperature, the mixture was 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 was dissolved in 250 ml of ether and cooled to -78 ° C with stirring under nitrogen. To this solution, 39.95 ml (99.9 mmoles) of 2.5 M n-butyl lithium solution were added per 15 minutes. After 1.5 hr, dry carbon dioxide was bubbled in as the mixture warmed slowly to room temperature. The mixture was kept in a carbon dioxide atmosphere overnight. To the mixture was added 100 ml of 3N hydrochloric acid of solid sodium chloride. The organic layer was separated and dried over magnesium sulfate. The solvent was removed and the residue was kept under vacuum to give 11.4 g of the title compound: mass spectrum (electro-dew, m / e, negative mode): M-H 156.8.

Example 72 4- (2-Methoxy-ethoxy) -but-2-ynoic acid 4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide To a solution of 0.56 g (3.54) mmoles) of 4- (2-methoxy-ethoxy) -but-2-ynoic acid and 0.46 g (3.4 mmoles) of isobutyl chloroformate in 12 mL of tetrahydrofuran were added at 0 ° C with stirring 0.36 g (3.54 mmoles) of N-methylmorpholine. 15 minutes later, 1.0 g (2.95 mmoles) of 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile was added. After stirring 3 hr at 0 ° C and 17 hr at room temperature, the mixture was poured into saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was removed and the residue was evaporated by chromatography on silica gel eluting with mixtures of chloroform-ethyl acetate to give 0.53 g of [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide of acid 4- (2-methoxy-ethoxy) -but-2-ynoic as a yellow powder: mass spectrum (electro-dew, m / e,): M + H 480.9.

Example 73 4- (Methoxymethoxy) -but-2-ynoic acid To a suspension of 8.2 g (205 mmol) of 60% sodium hydride in 271 ml of tetrahydrofuran was added dropwise at 0 ° C with stirring 10.0 g (178.4 g. mmoles) of propargyl alcohol. 30 minutes later, 15.8 g (196.2 mmoles) of chloromethylmethyl ether were added. After stirring over the weekend at room temperature, the mixture was filtered and the solvent was removed. The residue was distilled (35-38 ° C) 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 this solution were added 34.1 ml (85.3 mmoles) of 2.5M n-butyl lithium solution in haxanes, by dripping, for 15 minutes. After 1.5 hr, carbon dioxide was bubbled in as the mixture warmed slowly to room temperature. The mixture was kept in a mixture of carbon dioxide overnight. To the mixture 14 ml of hydrochloric acid in 24 ml of water were added. The organic layer was separated and dried over magnesium sulfate. The solvent was removed and the solvent was kept under vacuum giving 10.4 g of the title compound as a liquid.

Example 74 [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -4-methoxymethoxy-but-2-ynyl acid To a solution of 0.51 g (3.54 mmoles) of 4- ( methoxymethoxy) -but-2-ynyo and 0.46 g (3.4 mmoles) of isobutyl chloroformate in 12 ml of tetrahydrofuran were added at 0 ° C with stirring 0.36 g (3.54 mmoles) of N-methylmorpholine. 15 minutes later, 1.0 g (2.95 mmoles) of 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile was added. After stirring 3 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.66 g of [4- (3-bromo-phenylamino) -3-cyano-quinolin-6-yl] 4-Methoxymethoxy-but-2-ynoic acid amide as a yellow powder: 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile ma: mass spectrum (electro-dew, m / e, ): M + H 465.1, 467.0.

Example 75 N- [4- [(3-Bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (bis- (2-methoxyethyl) amino) -2-butinamide. Isobutyl chloroformate (0.785) was added dropwise. g, 5.75 mmol) in an ice-cooled solution of 4- (bis-methoxyethylamino) -2-butynoic acid (1.9 g, 8.85 mmol) and N-methylmorpholine (0.9386 g, 9.28 mmol) in 50 mL of tetrahydrofuran under N2. After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4- [(3-bromophenyl) -amino] -quinolin-3-carbonitrile in 10 mL of pyridine and the mixture was added dropwise. it was stirred at 0 ° C for 2 hr. The reaction was quenched with ice water, poured into sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. Fractions of product were collected, and dried in vacuo to give 0.82 (35%) of light brown solid; ESMS m / z 536.1, 538.1 (M + H +); mp 98-101 ° C.

Example 76 N- [4- ([3-Bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (N-methoxyethyl-N-methylamino) -2-butinamide. Isobutyl chloroformate (0.785 g) was added dropwise. , 575 mmoles) in an ice-cooled solution of 4- (N-methoxyethyl-N-methylamino) -2-butynoic acid (1.5 g, 8.84 mmol) and N-methylmorpholine (1.36 g, 13.3 mmol) in 60 mL of tetrahydrofuran. under N2. After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile in 15 mL of pyridine was added dropwise and the mixture was added dropwise. stirred at 0 ° C for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. The product fractions were collected, and dried in vacuo to give 0.32 (15%) of a reddish brown solid; ESMS m / z 492.0, 494.0 (m + H +); mp 95 ° C (dec).

Example 77 N- [4- [3-Bromophenyl) amino] -3-cyano-6-quinoline] -4- (N-allyl-N-methylamino) -2-butinamide Isobutyl chloroformate (0.785 g, 5.75 mmole) in an ice-cooled solution of 4- (N-allyl-N-methyl-amino) -2-butynoic acid (1.4 g, 8.84 mmol) and N-methylmorpholine (0.94 g, 9.3 mmol) in 80 mL of tetrahydrofuran under N2 . After stirring for 30 minutes, a solution of 1.5 g (4.42 mmol) of 6-amino-4- [(3-bromophenyl) -amino] -quinolin-3-carbonitriyl in 15 mL of pyridine was added dropwise and the mixture was added dropwise. stirred at 0 ° C for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. Fractions of product were collected, and dried in vacuo to give 0.60 (29%) of brown solid; ESMS m / z 474.4, 476.4 (M + H +); mp 133-135 ° C.

EXAMPLE 78 1-Methyl-1, 2,5,6-tetrahydro-pyridine-3-carboxylic acid [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide A solution of 1 g (2.95 mmoles) of 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile and 1.9 g (14.7 mmoles) of diisopropylethylamine, with stirring in 19 ml of tetrahydrofuran, hydrochloride was added in portions. N-methyl-1, 2, 5, 6-tetrahydronicotinyl chloride solid at 0 ° C. After stirring 1 hr at 0 ° C and 2 hr at room temperature, the mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The solution was dried over magnesium sulfate. The solvent was removed and the residue was recrystallized from methanol-ethyl acetate to give 0.92 g of a yellow powder: mass spectrum (electro-dew, m / e): M + H 462.4, 464.4.

Example 79 [4- (3-Bromophenylamino) -3-cyanoquinolin-6-yl] acid amide 4- ((2S) -2-methoxymethylpyrrolidin-1-yl) but-2-ynoic To an ice-cooled solution of 1.46 g (7.40 mmoles) of 4- ((2S) -2-methoxymethylpyrrolidin-1-yl) but-2-inoic in 85 mL of THF under N2 were added 0.897 g (8.88 moles) of N-methylmorpholine and 0.811 g (5.92 mmoles) of isobutyl chloroformate. After cold stirring for 30 minutes, a solution of 1.00 g (2.96 mmoles) of 6-amino-4- [(3-bromophenyl) amino] quinoline-3-carbonitrile in 8 mL of pyridine was added dropwise. The reaction was heated slowly to 25 ° C for 3 h. The reaction was poured into ice water, saturated NaHCO3 was added and the product was extracted with ethyl acetate. After drying and evaporation of the solvent, the residue was subjected to chromatography on silica gel (10% methanol in ethyl acetate). The yield was 0.560 g of 4- ((2S) -2-methoxymethylpyrrolidin-1-yl) but-2-ynic acid [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] amide as a foam brown: mass spectrum (electro-vacuum, m / e): M + H 518.0, 520.0.

EXAMPLE 80 4- ((2S) -2-Methoxymethylpyrrolidin-1-yl) butynoic acid N-Butyllithium solution in hexane (35.9 mmol) was added over 10 minutes to a solution of 5.49 g (35.9 mmol) of (2S) - 2-methoxymethyl-l-prop-2-vinylpyrrolidine in 100 mL of THF at -78 ° C under N2. After stirring cold for 1 h, CO 2 was bubbled into the solution as it slowly approached 25 ° C. After stirring overnight, 100 mL of water was added, the reaction mixture was extracted with ethyl acetate and the extracts were discarded. The reaction was adjusted to pH 7 with 20% H2SO4 and the solvent was removed. The residue was diluted with methanol and filtered. The filtrate was evaporated and dried in vacuo to give 7.06 g of 4- ((2S) -2-methoxymethylpyrrolidin-1-yl) butynoic acid as a brown foam: mass spectrum (electro-dew, m / e): M + H 198.0 .

Example 81 (2S) -2-Methoxymethyl-1-prop-2-ynylpyrrolidine A mixture of 4.81 g (41.9 mmoles) of S-2- (methoxymethyl) pyrrolidine, 13.7 g (41.9 mmoles) of cesium carbonate and 5.00 g ( 41.9 mmoles) of propargyl bromide in 80 mL of acetone was stirred at 25 ° C overnight. The reaction was filtered and the solvent was removed from the filtrate. The residue was diluted with a small amount of water and saturated NaHCO 3 and extracted with ether. The extract was treated with Darco, dried and evaporated to give 5.93 g of (2S) -2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow-orange oil: mass spectrum (electro-dew, m / e): 153.8.

Example 82 [4- (3-Bromophenylamino) -3-cyanoquinolin-6-yl] Amide of 4- (1, 4-dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ynyoic acid To an ice-cooled solution of 1.75 g (7.78 mmol) of 4- (1,4-dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ynoic acid in 100 mL of THF under N2 0.942 g (9.33 mmoles) of N-methylmorpholine followed by 0.852 g (6.22 mmoles) of isobutyl chloroformate were added. After stirring cold for 30 minutes, a solution of 1.05 g (3.11 mmol) of 6-amino-4- [(3-bromophenyl) amino] -quinolin-3-carbonitrile in 8 mL of pyridine was added dropwise. After stirring cold for 5 h, the reaction was poured into ice water and saturated NaHCO3 was added. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated. Chromatography of the residue on silica gel (20% methanol in ethyl acetate) gave 0.590 g of 4- (1,4-dioxa-8-azaspiro [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] amide acid [4, 5 ] dec-8-yl) but-2-inoic as a brown foam: mass spectrum (electro-dew, m / e): M + H 546.0, 548.1.

Example 83 4- (1,4-Dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ynoic acid n-Butyllithium in hexane (55.8 mmol) 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-ina in 185 mL of THF. -78 ° C under N2. After stirring at -78 ° C for 1 h, C02 was bubbled into the solution as it proceeded slowly at 25 ° C. After stirring overnight, the reaction was diluted with 150 ml of water, extracted with ethyl acetate and the extracts were discarded. The solution was adjusted to pH 6 with 2 M sulfuric acid and evaporated. The residue was suspended with methanol and filtered. The filtrate was evaporated and dried in vacuo to give 4.5 g of 4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) but-2-ynoic acid as a brown amorphous solid: spectrum mass (electro-vacuum, m / e): M + H 225.8.

EXAMPLE 84 3- (1,4-Dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ina A mixture of 10.0 g (69.9 mmol) of 1,4-dioxa-8-azaspiro [ 4, 5] decane, 22.8 g (69.9 mmoles) of cesium carbonate and 8.32 g (69.9 mmoles) of propargyl bromide in 165 mL of acetone was stirred overnight at 25 ° C. The reaction was filtered and the filtrate was evaporated to dryness. A small amount of water and saturated NaHC03 were added to the residue and this was extracted with ether. The ether extracts were treated with Darco, dried and evaporated to give 10.8 g of 3- (1,4-dioxa-8-azaspiro [5] dec-8-yl) but-2-ina as a yellow-orange oil: spectrum mass (electro-vacuum, m / e): M + H 181.8.

Example 85 4- (3-Bromo-phenylamino) -6- (2-ethoxy-3,4-dioxo-cyclobut-1-phenylamino) -quinolin-3-carbonitrile A mixture of 1.00 g (2.95 mol) of 6-amino -4- (3-chloro-phenylamino) -quinolin-3-carbonitrile, 20 mL of ethanol, and 0. 873 mL (5.90 mmol) of 3,4-diethoxy-3-cyclobuten-1, 2-dione was heated to reflux under N2. After 4 hours the heat was removed, cooled to 25 ° C and stirred overnight. The solution was decanted and the solvent was separated. Ether was added to crystallize, the solids were collected and dried. It was boiled in ethyl acetate to remove the initial cyclobutene material. It was dried in va cuo, giving 249 mg of yellow solid: mass spectrum (electro-dew, m / e): M + H = 463. 2.

Example 86 4- (4-Chloro-2-fluoro-phenylamino) -6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 2.0 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 1.46 g of 4-chloro-2-fluoroaniline, 0.925 g of pyridine hydrochloride, and 125 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate at pH 9. The product was collected, washed with water, and dried to give 2.61 g of 4- (4-chloro-2-fluoro-phenylamino) -6,7-dimethoxy-quinoline- 3- carbonitrile as a solid, mp 139-141 ° C; mass spectrum (electro-vacuum, m / e): M + H 357.9.

Example 87 4- (4-Chloro-2-fluoro-phenylamino) -6,7-dihydroxy-quinoline-3-carbonitrile A mixture of 0.358 g of 4- (4-chloro-2-fluoro-phenylamino) -6,7 dimethoxy-quinoline-3-carbonitrile and 3 g of pyridine hydrochloride was stirred under nitrogen at 210-220 ° C for 20 minutes. The mixture was cooled and added to 50 ml of 3% ammonium hydroxide solution. The product was collected, washed with water, and dried to give 0.302 g of 4- (4-chloro-2-fluoro-phenylamino) -6,7-dihydroxy-quinoline-3-carbonitrile as a solid, mp 270-272 °. C; mass spectrum (El, m / e): M + H 329.0363.

Example 88 4- (4-Chloro-2-fluoro-phenylamino) -6-methoxy-7- (2-pyridin-4-yl-ethoxy) -quinolin-3-carbonitrile To a solution of 0.655 g of triphenylphosphine in 20 ml of tetrahydrofuran were added by dripping 0.348 mg of diethyl azodicarboxylate. The solution was stirred for one minute and added to a mixture of 0.330 g of 4- (4-chloro-2-fluoro-phenylamino) -6,7-hydroxy-quinoline-3-carbonitrile and 0.500 g of 2- (4- pyridyl) ethanol in 100 ml of tetrahydrofuran. The mixture was stirred at room temperature for 4 hours, and 10 ml of methanol was added. To a solution of 0.655 g of triphenylphosphine in 20 ml of tetrahydrofuran was added dropwise 0.348 mg of diethyl azodicarboxylate. The solution was stirred for one minute and added to the previous mixture. The mixture was stirred overnight and concentrated in vacuo. The residue was subjected to chromatography on silica gel eluting with 50% methanol in dichloromethane. The solvent was removed from product fractions giving 0.034 g of 4- (4-chloro-2-fluoro-phenylamino) -6-methoxy-7- (2-pyridin-4-yl-ethoxy) -quinolin-3-carbonitrile as a white wax: mass spectrum (El, m / e): M 448.1104. The regiochemistry was unequivocally assigned by NMR analysis (Proton-DQF-COZY, NOESY, ^ H- ^ C.-HMQC,. ^. ^ - "CJ-HMBC, { XH-15N.}. -HMBC.

Example 89 4- [(2-Methoxy-ethyl) -methyl] 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-guinolin-6-yl] -amide hydrochloride] -amino] -but-2-enoic To a solution, with stirring, of 1.2 g (3.5 mmoles) of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinolin-3- carbonitrile and 0.52 g (4.0 mmol) of diisopropylethylamine in 40 ml of tetrahydrofuran at 0 ° C was added a solution of 4-bromine crotonyl chloride in 10 ml of tetrahydrofuran. 45 minutes later, 1.87 were added (21 mmol) of 2-methoxyethyl methyl amine. After lhr at room temperature, the mixture was poured into a sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel. The product was eluted with ethyl acetate-methanol-triethylamine 40: 8: 1 giving 0.87 g of free base. This was dissolved in 20 ml of ethyl acetate and 10 ml of a solution of hydrogen chloride in ether was added thereto. The solid was collected yielding 1.02 g of the title compound as a yellow powder: mass spectrum (electro-dew, m / e): M + H 498.0, (M + 2H) +2 248.5.

Example 90 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-guinolin-6-yl] -amide hydrochloride of (S) -4- (2-methoxymethyl-pyrrolidin- 1-yl) -but-2-enoic Using the method of Example 89, 1.2 g (3.5 mmoles) of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline- were converted 3-carbonitrile and 2.4 g (21 mmol) of (S) - (+) -2- (methoxymethyl) pyrrolidine to 1.5 g of the title compound, obtained as a yellow powder: mass spectrum (electro-dew, m / e): M + H 524.0, (M + 2H) +2 264.4. This reaction can also be carried out with (R) - (-) - 2- (methoxymethyl) pyrrolidine or racemic 2- (methoxymethyl) pyrrolidine giving the R-enantiomer or the racemate, respectively.

Example 91 4- (3-Hydroxymethyl-piperidin-1-yl) 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide acid hydrochloride -but-2-enoic Using the method of Example 89, 1.1 g (3.2 mmoles) of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile were converted and 2.2 g (19.2 mmol) of 3-hydroxymethyl-piperidine to 0.76 g of the title compound, obtained as a yellow powder: mass spectrum (electro-dew, m / e): M + H 524.0, (M + 2H) + 262.3.

Example 92 4- (1,4-dioxa-8-aza-spiro [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide. 4, 5] dec-8-yl) -but-2-enoic Using the method of Example 89, 1.05 g (3.06 mmoles) of 6-amino-4- (3-chloro-4-fluoro-phenylamino) - 7-methoxy-quinoline-3-carbonitrile and 2.6 g (18.4 mmoles) of 1, -dioxa-8-azaspiro [4, 5] decane to 0.62 g of the title compound. The free base was obtained as a yellow foam: mass spectrum (electro-vacuum, m / e): M + H Example 93 4- (2-Hydroxymethyl-piperidin-1-yl) -but [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- (2-hydroxymethyl-piperidin-1-yl) -but -2- enoic Using the method of Example 89, 1.05 g (3.06 mmoles) of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile and 2.1 g were converted. (18.4 mmoles) of 2-hydroxymethyl-piperidine at 0.67 g of the title compound. The free base was obtained as a white matte powder: mass spectrum (electro-dew, m / e): M + H 524.3, (M + 2H) +2 267.7.

Example 94 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo-but-2-enoic acid Using the method of Example 15 , 4-bromo crotonyl chloride and 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinoline-3-carbonitrile were converted to the title compound, which was obtained as a solid It could be purified with boiling methanol.

Example 95 Bromide of 3-. { 3- [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-oxo-quinolin-6-ylcarbamoyl] -alyl} -5-methyl-thiazole-3-io A solution of 0.5 g (1 mmol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] - 4-bromo-but-2-enoic acid amide and 0.6 g (6.1 mmol) of 5-methyl thiazole were refluxed for 4 hr. The mixture was diluted with ethyl acetate and cooled. The solid was collected and recrystallized from methanol-acetone-ethyl acetate to give 0.2 g of the title compound as a yellow powder: mass spectrum (electro-dew, m / e): M + 508.0, 509.9 (M + 2H) +2 254.4, 255.1.

Example 96 Bromide of 3-. { 3- [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7- methoxy-quinolin-6-ylcarbamoyl] -alyl} -4-methyl-thiazole-3-io A solution of 0.7 g (1.4 mmol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] - 4-bromo-but-2-enoic acid amide and 0.85 g (8.6 mmol) of 4-methyl thiazole were refluxed for 17 hr. The mixture was diluted with ethyl acetate and cooled. The solid was collected and recrystallized from methanol-acetone-ethyl acetate to give 0.3 g of the title compound as a yellow powder: mass spectrum (electro-dew, m / e): M + 507.9, 509.8 (M + 2H) +2 254.4, 255.1.

Example 97 Methyl 4-benzyloxy-2- (dimethylaminomethyleneamino) -5-methoxybenzoate A mixture, with stirring, of 70.Og (244 mmoles) of methyl 2-amino-4-benzyloxy-5-methoxybenzoate (Phytochemistry 1976, 15, 1095) and 52 ml of dimethylformamide dimethyl acetal was heated at 100 ° C for 1.5 h, cooled, and evaporated directly under high vacuum to give 81.3 g of a matt white solid, mp 134-140 ° C; NMR (CDC13) d 3.01 (s, Me2N).

Example 98 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile To a solution, with stirring, of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF at -78 ° C was added. they added 3.51 ml of acetonitrile in 20 ml of THF for 10 minutes. After stirring at -78 ° C for 30 minutes, the mixture was treated with 10 g of methyl 4-benzyloxy-2-dimethylaminomethyleneamino) -5-methoxybenzoate in 20 ml of THF for 5 minutes. After 15 minutes at -78 ° C the stirred mixture was heated at 0 ° C for an additional 30 minutes. This was then treated with 5 ml of acetic acid, heated to 25 ° C and stirred for 30 minutes. The mixture was evaporated to dryness, and diluted with aqueous sodium bicarbonate. The resulting matt white solid was filtered, washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile was obtained as a white off-white solid, decomposition > 255 ° C; mass spectrum (electro-dew, m / e) M + H 307.

Example 99 7-Benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile To a suspension, with stirring, of 1 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride were 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 was slowly added thereto until bubbling ceased. After separation of the layers, the organic layer was separated to a small volume, then passed through a plug of magnesol. Elution with 50 ml of methylene chloride, followed by evaporation afforded 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as a pale yellow solid, mp 282-284 ° C; mass spectrum (electro-vacuum, m / e) M + H 325.

Example 100 4-Chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile A suspension, with stirring, of 0.54 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile in 10 ml of chloride of methylene was cooled to 0 ° C. To this was added 10 ml of boron trichloride (1M in methylene chloride). The mixture darkened when it was warmed to room temperature and a solid precipitated. After stirring for 1 hour, no further reaction was observed. The solid (initial material without reacting) was filtered, the remaining solution was cooled to 0 ° C and cooled by the dropwise addition of methanol. After evaporation of the solvent, the residue was dissolved in methylene chloride / methane / acetone. Purification of this residue was carried out using chromatography on silica gel, eluting with a solvent gradient of 1 to 5 percent methanol / methylene chloride, to provide 0.075 g of 4-chloro-7-hydroxy-6- methoxy-quinoline-3-carbonitrile as a yellow solid, decomposition > 245 ° C; mass spectrum (electro-vacuum, m / e) M + H 235.2. Example 101 4-Chloro-6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile A mixture of 0.070 g of 4-chloro-7-hydroxy-6-methoxy-quinolin-3 -carbonitrile, 0.062 g of 3- (4-pyridyl) -1-propanol and 0.235 g of triphenylphosphine in 3 ml of methylene chloride under nitrogen was cooled to 0 ° C. To this was added 0.14 ml of diethyl azodicarboxylate by dripping. 30 minutes later, the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The mixture was concentrated to 1 ml and purified by chromatography on silica gel, eluting with a solvent gradient of 1 to 2 percent methanol / methylene chloride, to provide 0.090 g of 4-chloro-6-methoxy-7-. (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile as a white matte gum.

Example 102 4- (3-hydroxy-4-methyl-phenylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile A mixture of 0.090 of 4-chloro-6- methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile, 0.050 g of 3-hydroxy-4-methylaniline, 0.039 g of pyridine hydrochloride and 3 ml of ethoxyethanol was stirred under nitrogen at room temperature reflux for 20 minutes. The mixture was cooled and filtered. The product was washed with saturated sodium carbonate, water, then dried to give 0.80 g of 4- (3-hydroxy-4-methyl-phenylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) ) -quinolin-3-carbonitrile as a solid, decomposition > 153 ° C, mass spectrum (electro-vacuum, m / e): M + H 440.9.

Example 103 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-dialiamino-but-2-enoic acid A solution of 0.24 g ( 0.5 mmol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo-but-2-enoic acid in 1 ml of N, N-dimethylformamide and 4 ml of tetrahydrofuran was stirred with 0.49 ml (4 mmol) of diallylamine for 3 hr. The reaction was stopped with 10 ml of saturated sodium bicarbonate and 10 ml of ethyl acetate. The insoluble precipitate was collected and washed with water to give 23.7 mg of the title compound (free base); mass spectrum (electro-dew, m / e): M + H 506. 0. The ethyl acetate layer was washed with water. After the solvent was removed, the crude product was purified by preparative TLC (column C18, gradient of 2% acetonitrile containing 0.05% trifluoroacetic acid to 100% acetonitrile containing 0.05% trifluoroacetic acid in 12 minutes) to yield 97.9 mg of the product as the bis-trifluoroacetate salt; mass spectrum (electro-vacuum, m / e): M + H 506.0.

Example 104 [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- [bis- (2-methoxy-ethyl) -amino]] -but-2-enoic In the manner of Example 103, 4- [3- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-acid was converted bromo-but-2-enoic and bis- (2-methoxyethyl) -amine at 52.3 mg of the title compound as the bis-trifluoroacetate salt, mass spectrum (electro-vacuum, m / e): M + H 542.0.

Example 105 4- ([1, 3] dioxolan-2-ylmethyl-methyl-amino) -but-2-enoic acid 3-cyano-7-methoxy-quinolin-6-yl] -amide In the manner of Example 103 , 4-bromo-but-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide was converted ] dioxolan-2-yl-methyl-methyl-amine to 116.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electro-vacuum, m / e): M + H 526.0.

Example 106 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- [bis- (2-hydroxy-ethyl) -amino]] -but-2-enoic In the manner of Example 103, 4- [3- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-acid was converted bromo-but-2-enoic and bis- (2-hydroxy-ethyl) amine at 22.2 mg of the title compound (free base), mass spectrum (electro-dew, m / e): M + H 514.0 and 60.7 mg of the compound of the title as the bis-trifluoroacetate salt); mass spectrum (electro-vacuum, m / e): M + H 514.0.

Example 107 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-thiomorpholin-4-yl-but-2-enoic acid In the manner of Example 103, 4-bromo-but-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide was converted and thiomorpholine at 48.1 mg of the title compound (free base), mass spectrum (electro-dew, m / e): M + H 512.0 and 33.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electro-vacuum, m / e): M + H 512.0.

Example 108 4- [4- (2-hydroxy-ethyl) -piperazine- 4- [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] 1-yl] -but-2-enoic In the manner of Example 103, [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide was converted. of 4-bromo-but-2-enoic acid and 4- (2-hydroxy-ethyl) piperazine to 32.3 mg of the title compound (free base) and the mass spectrum (electro-dew, m / e): M + H 539.1 , 42.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electro-vacuum, m / e): M + H 539.1.

Example 109 4- (1, 4, 7-trioxa-10-aza- 4- [3- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] cyclodec-10-yl) -but-2-enoic In the manner of Example 103, [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl was converted] -amide of 4-bromo-but-2-enoic acid and 1,4-, 7-trioxa-10-azacyclododecane to 37.5 mg of the title compound (free base) and the mass spectrum (electroremoval, m / e): M + H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electro-dew, m / e): M + H 584.1.

Example 110 4- (Methoxy-methyl-amino) -but-2-enoic acid 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide A mixture of 1 g of 4-bromo-but-2-enoic acid (4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide mmoles, 1 equivalent), 1.2 g of N, O-dimethylhydroxylamine hydrochloride (12.25 mmoles, 9 equivalents), and 1.5 g of sodium bicarbonate (18.38 mmoles, 9 equivalents) in DMF (10 ml) was stirred at room temperature for 24 hours. hours. Ethyl acetate was added to the reaction mixture, and the crude product was filtered. After flash chromatography (ethyl acetate: methanol: triethylamine 40: 4: 1), 0.486 g of the title compound were isolated (yield 50.7%); mp 210-217 ° C.

Example 111 4- (4-Hydroxy-piperidin-1-yl) -but 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide -2-enoic A mixture of 250 mg (0.51 mmol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo acid -but-2-enoic, and 103.2 mg (1.02 mmol) of 4-hydroxypiperidine in 2.25 ml of dimethylformamide was stirred at room temperature for 3 hours. Saturated sodium bicarbonate was added and the filtrate was filtered and washed with hexane to give the first crop of product. The filtrate was extracted with ethyl acetate and the organic layer purified by preparative TLC to give the second crop. The two crops were combined to give 105.8 mg (41%) of brown solid: mp > 215 ° C.

Example 112 [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- [1,4 '] bipepyridinyl-1-yl- but-2-enoic A mixture of 250 mg (0.51 mmoles) of 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide bromo-but-2-enoic, and 172 mg (1.02 mmol) of 4-piperidinopiperidine in 5.0 ml of dimethylformamide was stirred at room temperature for 4 hours and at 60 ° C for 1 hour. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 100 mg (40%) of yellow solid: mp 140-144 ° C.

EXAMPLE 113 4-Thiazolidin-3-yl-but-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide A mixture 250 mg (0.51 mmoles) of 4-bromo-but-2-enoic acid [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide , and 80μL (1.02 mmoles) of thiazolidine in 2.25 ml of dimethylformamide was stirred at room temperature for 19.5 hours. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 95.6 mg (38%) of yellow solid: mp 135-138 ° C.

Example 114 4- (2,6-dimethyl-piperidin-1-yl) 4- (2, 6-dimethyl-piperidin-1-yl) 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide) -but-2-enoic A mixture of 250 mg (0.51 mol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-acid -bromo-but-2-enoic, and 137 μL (1.02 mmol) of cis-2,6-dimethylpiperidine in 2.25 ml of dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure to yield 170.4 mg (64%) of brown solid: mp 120-122 ° C.

Example 115 4- [bis- (2-hydroxy-propyl) -amino] 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] -but-2-enoic A mixture of 250 mg (0.51 mmoles) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-acid -bromo-but-2-enoic, and 136 mg (1.02 mmol) of 1,1 '-iminodi-2-propanol in 2.25 ml of dimethylformamide was stirred at room temperature for 3 hours and at 60 ° C for 2 hours. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. 240.1 mg (87%) of brown solid was produced: mp 122-125 ° C.

Example 116 4- (3-Hydroxy-pyrrolidin-1-yl) -but 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide -2- enoic A mixture of 250 mg (0.51 mmol) of [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo acid -but-2-enoic, and 85 μL (1.02 mmol) of R - (+) - pyrrolidinol in 5.0 ml of dimethylformamide was stirred at room temperature for 2 hours and at 60 ° C for 1 hour. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, and purified by preparative TLC. 84.2 mg (33%) of yellow solid were produced: mp 215-220 ° C.

Example 117 4- [(2-Hydroxy-ethyl) -amino] -but [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] -2-enoic [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo-but-2-enoic acid was dissolved with stirring (250mg, 51mmol) and 2- (methylamino) -ethanol (97mg, 1.02mmol), under nitrogen, in 9 ml anhydrous dimethylformamide. 48 hours later, the mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to give a gum. This was subjected to chromatography on silica gel, and eluted with 40/4/1 (ethyl acetate / methanol / triethylamine) yielding 183 mg (74%) of the purified product as a yellow solid: mp 210-214 ° C.

EXAMPLE 118 4- (2,5-dimethyl-pyrrolidin-1-yl) 4- (2, 5-dimethyl-pyrrolidin-1-yl) 4- [2,5-dimethyl-pyrrolidin-1-yl] 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] but-2-enoic In the same manner as in Example 117, [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide was reacted 4-bromo-but-2-enoic acid (.51 mmole) with 2,5-dimethylpyrrolidine (1.02 mmole, 101 mg) in dimethylformamide. The crude product was also purified via chromatography as in Example 117, leaving 214mg (82%) of the yellow product: mp 110-113 ° C.

Example 119 4- (4,4-Dihydroxy-pi? Eridin-1-yl) 4- (4,4-dihydroxy-pi? Eridin-1-yl) 4- [4 (4-dihydroxy-pi? Eridin-1-yl) 4- [4 (4-chloro-phenyl-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide} ) -but-2-enoic After the procedure of Example 117, [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4 -bromo-but-2-enoic (.51 mmole) in dimethylformamide with 4-piperidone monohydrate hydrochloride (470 mg, 3.06 mmol), and sodium bicarbonate (386 mg, 4.59 mmol) for 24 hours. The crude product was purified in the same manner as in Example 117 and 119 mg (72%) of the product was produced as a yellow solid: mp 225-30 ° C.

EXAMPLE 120 6- (4-Chlorobutylamino) -4- (3-chloro-4-fluorophenylamino) -7-methoxy-3-quinolinecarbonitrile To a solution of 1.12 g of 4-chlorobutanol and 5.3 ml of 3M sulfuric acid in 11 ml of Tetrahydrofuran, at 0 ° C, was added a solution of 2.0 g of 6-amino-4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-3-quinolinecarbonitrile in 40 ml of dimethylformamide. To this, 0.4 g of sodium borohydride was added in portions. After 1 hr, another 1.0 g of aldehyde, 10 ml of dimethylformamide, and 5 ml of 3M sulfuric acid were added followed by the 0.8 parts addition of sodium borohydride. 2 hours later, the mixture was poured into water and the pH was adjusted to 9. The mixture was extracted with ethyl acetate several times. The organic solution was dried over magnesium sulfate and the solvent was removed, giving the title compound as an oil which was used without further purification.

Example 121 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6- (4-morpholin-4-yl-butylamino) -quinolin-3-carbonitrile Example 122 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6-pyrrolidin-1-yl-quinoline-3-carbonitrile A mixture of 2.5 g of 6- (4-chlorobutylamino) -4- ( 3- chloro-4-fluorophenylamino) -7-methoxy-3-quinolinecarbonitrile, 7.54 g of morpholine and 0.17 g of sodium iodide in 30 ml of dimethylformamide was stirred at 750 ° C for 7 hrs. The mixture was poured into dilute sodium bicarbonate and the solid was collected. This material was dissolved in ethyl acetate. The solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel using ethyl acetate-methanol-triethylamine mixtures. A more polar component (0.54 g) was 4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-6- (4-morpholin-4-yl-butylamino) -quinolin-3-carbonitrile; a less polar component (0.28 g) is the compound of this invention, 4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-6-pyrrolidin-1-yl-quinoline-3-carbonitrile, obtained as a yellow solid: mass spectrum (electro-dew, m / e): M + H 397.4.

Example 124 4- (3-Chloro-4-fluoroanilino) -7-methoxy-6- (lH-pyrrol-1-yl) -3-quinolinecarbonitrile A suspension of dimethylformamide (4.4 ml) of 6- amino-4- [( 3-chloro-4-fluoroanilino) -7-methoxy-3-quinolinecarbonitrile (0.2 g, 0.5839 mmol), 2,5-dimethoxytetrahydrofuran (0.1 ml, 0.77 mmol) and 4-chloropyridinium chloride (0.05 g, 0.333 mmol) heated at 108 ° C overnight. The reaction solution was mixed with saturated sodium bicarbonate solution, brine and ethyl acetate. The ethyl acetate layer was separated, filtered through silica gel, dried to give 119 mg of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6- (lH-pyrrol-1-yl) -3-quinolinecarbonitrile as a cream-colored solid, mp 192.5-193.5 ° C: high resolution mass spectroscopy (electro-dark, m / e): M + H 393.0913.

Example 124 6- [(2-Chloroethyl) amino] -4- (3-chloro-4-fluoroanilino) -7-methoxy-3-quinolinecarbonitrile To a solution of 1 g of 6-amino-4- [(3-chloro -4-fluoroanilino) -7-methoxy-3-quinolinecarbonitrile (2.92 mmol) in 20 ml of dimethylformamide at 0 ° C, a solution of 50% aqueous chloroformadehyde (0.75 ml, 5.84 mmole) and 3M sulfuric acid (2.92) was added. ml, 8.76 mmoles) in 5.3 ml of tetrahydrofuran, followed by the addition in portions of 1.1 g of sodium borohydride powder (29.68 mmoles). After the mixture was stirred overnight at room temperature, the precipitated product was collected and partitioned between ethyl acetate and ION sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed to give 0.7648 g of yellow solid. After recrystallization from acetonitrile, 0.5831 g of crystals in the form of bright needles were obtained; mp 207.2-207.8 ° C; high resolution mass spectroscopy (El, m / e): 404,060. The filtrate was treated with ION sodium hydroxide and ethyl acetate, and worked as above to give an additional 0.38 g of crude product.

EXAMPLE 125 6- (1-Aziridinyl) -4- (3-chloro-4-fluoroanilino) -7-methoxy-3-quinolinecarbonyl group To a solution of 0.202 g (0.5 mmol) of 6 - [(2-chloroethyl) amino] ] -4- (3-chloro-4-fluoroanilino) -7-methoxy-3-quinolinecarbonitrile in 4 ml of dimethylformamide, added 0.075 g of sodium iodide (0.5 mpiol) and 0.069 g of potassium carbonate (0.5 mmol). After the reaction solution was heated to 75 ° C overnight, it was decanted into a saturated solution of cold sodium bicarbonate. The organic layer was separated and dried over sodium sulfate. The solvent was removed to yield 0.19 g of a light brown solid. The clear product was washed with hexane to give 0.1 g of a yellow solid, mp 197-199 ° C; high resolution mass spectrometry (El, m / e): M 368.0888.

Example 126 1- (Dimethylaminomethyleneamino) -3-chlorobenzene A mixture of 3-chloroaniline (63.8 g, 0.50 mol) and dimethylformamide dimethyl acetal (106 ml, 0.75 mol) was heated at 100 ° C for 2 h and evaporated at 60 ° to 0.5 mm Hg. to give 91.8 g of amber oil; em 183.0 (M + H) +.

Example 127 1- (Dimethylaminomethyleneamino) -3-chloro-4-nitrobenzene To a solution, with stirring, of 1- (dimethylaminomethyleneamino) -3-chlorobenzene (67.5 g, 0.37 mol) in 148 ml of HOAc was added 70% nitric acid. % (70 ml, 1.11 mmoles) for 15 m with cooling to 10 °. To the resulting solution was added AC2O (222 ml, 2.58 moles) for 30m with cooling to maintain at 15-20 °. The solution was heated at 65 ° for 20 m. The resulting exothermic reaction was moderate with cold water at 65-68 ° for 45 m and then the reaction was heated at 65 ° for 90 m. The reaction mixture was heated to 10 °, stirred with DCM, and cooled with ice and 10 N NaOH (850 ml). The organic layer was separated, washed thoroughly with water, dried, filtered through Magnesol, and concentrated to give 62.2 g of a solid, rubbery, red. Flash chromatography of residue on silica gel with DCM-EtOAc-MeOH 20: 4: 1 gave an amber solid, mp 78-90 °; em 228.1 (M + H) +.

Example 128 Acid (E / Z) -2-Cyano-3- (3-chloro-4-nitrophenylamino) acrylic, ethyl ester To a mixture, with stirring, of 1- (dimethylaminomethyleneamino) -3-chloro-4-nitrobenzene ( 7.9 g, 35 mmol) and 17.4 ml of HOAc at 25 ° C were added ethyl cyanoacetate (5.2 g, 46 mmol). The resulting mixture was refluxed for 1.5 h, cooled, stirred in water for 45 m. The resulting amber solid was filtered, washed with water followed by 5: 1 hexane-EtOAc, and dried; mp 195-205 °; em 294.1 (M + H) +.

Example 129 1-Dihydroquinoline-7-chloro-6-nitro-4-oxo-3-carbonitrile A mixture, with stirring of (E / Z) -2-cyano-3- (3-chloro-4-nitrophenylamino) Acrylic, ethyl ester (2.36 g, 8.0 mmol) and 240 ml of Dowtherm A was heated at 260 ° C for 2 h, cooled, diluted with hexane, and filtered. The brown solid thus obtained was digested with boiling EtOAc, filtered and dried to give 1.47 g, mp 320-330 ° (dec); em 248.1 (M-H) +.

EXAMPLE 130 4,7-Dichloro-6-nitro-3-quinolinecarbonitrile A stirred mixture of 1,4-dihydroquinoline-7-chloro-6-nitro-4-oxo-3-carbonitrile (14.7 g, 58.9 mmol) and 59 ml of phosphorus oxychloride was refluxed for 3 h. The phosphorus oxychloride was removed in vacuo, and the residue was stirred with methyl chloride at 0 ° C and treated with a suspension of ice and potassium carbonate. The mixture was filtered through Celite, and the organic layer of the filtrate was separated, washed with water, dried and concentrated to give 10.7 g of brown solid. Recrystallization from hexane-DCM io the title compound, mp 143-153 ° C; em 266.7 (M-H) +.

Example 131 4- (3-Chloro-4-fluoroanilino) -7-chloro-6-nitro-3-quinolinecarbonitrile A mixture, with stirring, of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile (10.7 g, mmoles), 3-chloro-4-fluoroaniline (7.0 g, 48 mmol), pyridine hydrochloride (4.6 g, 40 mmol), and 200 ml of 2-propanol was heated to reflux temperature and maintained for 1 h. The 2-propanol was evaporated, and the residue was stirred in water with potassium bicarbonate (pH ~ 8). The resulting solid was filtered, washed with water and hexane-DCM 5: 1, and dried. Recrystallization from EtOH gave 11.3 g of yellow solid, mp 259-263 °; em 3771.1 (M + H) +.

Example 132 4- (3-Chloro-4-fluoroanilino) -7- (4-methyl-1-piperazinyl) -6- nitro-3-quinolinecarbonitrile A mixture, with stirring, of 4- (3-chloro-4-fluoroanilino) ) -7-chloro-6-nitro-3-quinolinecarbonitrile (1.88 g, 5.0 mmol), N-netylpiperazine (5 mL, 45 mmol), and 10 mL of toluene was refluxed for 45 minutes, evaporated to remove volatile matter , and stirred in water with potassium carbonate (2.75 g). The resulting solid was filtered, washed with water, and dried to give 2.26 g. A solution of acetone was passed over a pad of silica gel; elution with acetone-MeOH-TEA 50: 2: 1 and evaporation gave a red solid, mp 240-246 °; in 441.2 (M + H) +, 221.2 (M + 2H) +2.

Example 133 6-Amino-4- (3-Chloro-4-fluoroanilino) -7- (4-methyl-1-piperazinyl) -3-quinolinecarbonitrile, In the same manner as in Example 23 the 4- (3-chloro 4-fluoroanilino) -7- (4-methyl-1-piperazinyl) -β-nitro-3-quinolinecarbonitrile was reduced with iron powder and acetic acid in MeOH to give the title compound as an amorphous solid; em 411.2 (M + H) +, 206.2 (M + 2H) +2.

Example 134 N- [4- (3-Chloro-4-fluoroanilino) -3-cyano-7- (4-methyl-1-piperazinyl) -6-quinolinyl] -2-butinamide To a stirred solution of 2-acid butinoic acid (0.25 g, 3.0 mmol) in 1.5 ml in DCM at 0 ° DCC (0.21 g, 1.0 mmol) was added. 15 minutes later the mixture was heated to 25 °, re-cooled to 0 °, and treated with 6-amino-4- (3-chloro-4-fluoroanilino) -7- (4-methyl-1-piperazinyl) -3-quinolinecarbonitrile (0.21 g, 0.50 mmol) followed by a rinse with 0.5 ml of DCM. The resulting mixture was stirred at 25 ° for 18 h and filtered to remove dicyclohexyl urea. The filtrate was partitioned with water which contained potassium carbonate (0.4 g, 3 mmol). The organic layer was washed with water, dried and concentrated. The residue was passed with a DCM solution on a pad of silica gel. The product was eluted with 50: 2: 1 acetone-MeOH-TEA and concentrated to give 0.165 g of amorphous solid; em 477.2 (M + H) +, 239.1 (M + 2H) +2.

Example 135 3-Chloro-N- [4- (3-chloro-4-fluoroanilino) -3-cyano-7- (4-morpholinyl) -6-quinolinyl] propionamide To a solution, with stirring of 3-chloropropionic acid ( 0.65 g, 6.0 mmol) in 3 ml of 0 ° DCM was added DCC (0.41 g, 2.0 mmol). 15 minutes later the mixture was heated to 25 °, re-cooled to 0 °, and treated with 6-amino-4- (3-chloro-4-fluoroanilino) -7- (4-morpholinyl) -3-quinoline-carbonitrile (0.40 g, 1.0 mmol) followed by a rinse with 1 ml of DCM. The resulting mixture was stirred at 25 ° for 20 h, diluted with DCM, and stirred with aqueous sodium bicarbonate. The mixture was filtered to remove diclohexyl urea. The organic layer of the filtrate was washed with water, dried and concentrated. The residue was passed to a solution in DCM on a pad of silica gel. The product was eluted with DCM-EtOAc-MeOH-TEA 25: 25: 2: 1 and concentrated to give 0.38 g of amorphous solid; em 488.1 (M + H) +.

Example 136 N- [4- (3-chloro-4-fluoroanilino) -3-cyano-7- (4-morpholin) -6-quinolin] acrylamide To a solution, with stirring, of 3-chloro-N- [4 - (3-chloro-4-fluoroanilino) -3-cyano-7- (4-morpholinyl) -6-quinolinyl] propanamide (0.30 g, 0.61 mmol) in 1.2 ml of THF at 0 ° was added 1.2 ml of KOtBu / tBuOH 1.0 M per drip for 1 minute. After 2 h at 0 ° the reaction was stopped with solid C02 and partitioned with DCM-water. The organic layer was washed with water, dried and evaporated, yielding 0.28 g of the title compound as a white amorphous solid; em 452.2 (M + H) +. By using the methods described in the Examples 1-136 above the methods described in patent applications WO-9843960 and WO-9909016, the compounds of this invention listed in Table 6 were prepared.

Table 6 137 [4- (3-Bromo-phenylamino) -3- amorphous 538.0 (M + H) Table 6 (continued) Table 6 (continued) Table 6 (continued) 147 4- (2-Bromo-4-chloro- 165-167 533.1 (M + H) phenylamino) -7- [2- (4-hydroxy-267.1 (M + 2H) +2 Table 6 (continued) 151 Ethyl ester of l- acid. { 3- [3-95-101 587.2 (M + H) cyano-4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy] -propyl} - piperidine-4-carboxylic \ ~ + "and -i 152 7- [3- (4-acetyl-l-115-11.558.2 (M + H) piperazinyl) propoxy] -4- [(2,4-dichloro-5-methoxyphenyl) amino) -6-methoxy-quinoline -3- carbonitrile A -r-- t ~ A 153 4- (3-chloro-4-fluoroanilino) -413.2 (M + H) 7-methoxy-6 (4-morpholinyl) -3-quinolinecarbonitrile 154 7- [3- (4-Benzyl-piperazine-l-140-142 606.2 (M + H) yl) -propoxy] -4- (2, -dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline -3- carbonitrile Table 6 (continued) 155 4- (2,4-Dichloro-5-methoxy-161-164 491.1 (M + H) phenylamino) -7- [3- (2-hydroxyethylamino) -propoxy] -6-methoxy-quinoline-3 carbonitrile 156 4- (2,4-Dichloro-5-methoxy-) 162-165 519.2 (M + H) phenylamino) -7-. { 3- [Ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -6-methoxy-quinoline-3-carbonitrile h- _, t ~ H 157 7-. { 3- [Bis- (2-methoxy-ethyl) -122-113 563-1 (M + H) amino] -propoxy} -4- (2,4-dichloro-5-methoxy-phenylamino) 6-methoxy-quinoline-3-carbonitrile A (- -r- \ - H 158 7-. { 3- [Bis- (2-hydroxy-ethyl) -156-159-535.1 (M + H) amino] -propoxy} -4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile Table 6 (continued) Compound Example p.f. CC spectrum) masses 159 4- (3-chloro-4-fluoroanilino) - 235-239 428.1 (M + H) 7- (4-morpholinyl) -6-nitro-3-quinolinecarbonitrile Table 6 (continued) Table 6 (continued) Table 6 (continued) Table 6 (continued) 174 4- (2,4-dichloro-5-25-228 484.1 (M + H) Table 6 (continued) Table 6 (continued) 182 4- (2,4-dichloro-5-229-230 439.1 (M + H + methoxyanilino) -6-methoxy-7- (lH-pyrrol-l-yl) -3-quinolinecarbonitrile r- 183 4- (4-bromo-2-fluoroanilino; 180-182 483.0 (M + H) 6-methoxy-7- [2- (1 H-1,2,3-triazol-1-yl) ethoxy] -3- quinolincarbonitrile r- - ri- 184 4- (4-bromo-2-fluoroanilino) 93-103 483.0 (M + H) 6-methoxy-7- [2- (1 H-1,2,3-triazol-2-yl) ethoxy] -3- quinolinecarbonitrile 185 -. 185 - (2,4-dichloro-5- 210-214 500.1 (M + H) methoxyanilino) -6-methoxy-7- [3- (lH-tetraazol-1-yl) propoxy] -3-quinolinecarbonitrile Table 6 ( continuation) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula 1, characterized in that it has the structure: wherein: X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyrinidyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring can be mono-, di- or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, carbon, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms , alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl , thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 atoms carbon, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino; Z is -NH-, -O-, -S-, or -NR-; R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms; Gi, G2, Ri and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 atoms of carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenyloxy of 3-8 carbon atoms, alkyloxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms carbon, alkenoyloxymethyl of 4-9 carbon atoms, alkyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1 -6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, diakylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N, N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, (C (R6) 2) P / \ 'Rr (C (R6) 2) p-N N- (C (R6) 2) k-Y-. RβR9-CH-M- (C (R6) 2) k-Y- (C (R6) 2) p R7- (C (R6) 2) "- Y-. Rr (C (R6) 2) pM- (C (R6) 2) kY- or Het- (C (R6) 2) qW- (C (R6) 2) kY- with the proviso that either Gi or G2 or both of Gi and G2 must be a radical selected from the group. RßR9-CH-M- (C (R6) 2) k-Y-. R'7- (C (R6) 2) g-Y-. R (C (R6) 2) P-M- (C (R6) 2) -Y-. Het- (C (R6) 2) q-W- (C (R6) 2) k-Y-, H O R2-N- » And it's a divalent radical selected from the group consisting of - (CH2) a-, -O-, and -N- R6 R7 is -NR6R6, -J, -0R6, -N (R6) 3 or -NR6 (OR6); R'7 is -NRd (OR6), -N (R6) 3+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms , N, N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms or N, N-dialkynylamino of 6-12 carbon atoms, with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; M is > NR6, -O-, > N- (C (R6) 2) PNR6R6, or > N- (C (R6) 2) pOR6; c * W is > NR6, -O- or is a link; Het is a heterocycle selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino 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, and; wherein the heterocycle is mono- or di-substituted on a carbon or nitrogen with R6, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -ORe, optionally mono or disubstituted on carbon with monovalent radicals - (C (R6) 2) sORβ - (C (R6) 2) SN (Rβ) 2, or optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -O (C (R6) 2) SW-; R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7-carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms , phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; R2 is selected from the group consisting of R R33 S ° R3-S-S- (C (R3) 2) r-. { , aH ^ JT N-Rß R3 Re Y R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / R7- (C (R6) 2) P-N ^ / N- (C (R6) 2) r-. (C (R6) 2) P R7- (C (R6) 2) s-. R7- (C (R6) 2) p- - (C (R6) 2) R8R9-CH-M- (C (F-6) 2) r- .0 Het- (C (R6) 2) q-W- (C (R6) 2) r: with the proviso that at least one of the groups R3 is selected from the group (C (R6) 2) P ~ / \ RHC (R6) 2) P-N N- (C (Rβ) 2) r. (C (R6) 2) p R'7- (C (R6) 2) S-. R7- (C (R6) 2) pM- (C (R6) 2) r- RβR9-CH-M- (C (R6) 2) r- or Het- (C (R6) 2) qW- (C (R6) 2), -: R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, R7- (C (Re) 2) s- • R7- (C (Re) 2) pM- (C (R6) 2) r- RβR9-CH-M- (C (R6) 2) r- .0 Hßl - (C (Rβ) 2? TfW- (C (Rβ) 2) r; Rβ, and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; p = 2-4; q = 0-4, r = 1-4, s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; or a pharmaceutically acceptable salt, provided that when R6 is alkenyl of 2-7 carbon atoms and alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through the saturated carbon atom; and further provided that when Y is -NR6- and R7 is -NR6Rd, -N (R6) 3+, or -NR6 (OR6); then g = 2-6; when M is -O- and R7 is -ORß, then p = 1-4; when Y is -NR6-, then k = 2-4; when Y is -O- and M or W is -O-, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is -O- or -NR6-, then k = 2-4.

2. The compound according to claim 1, characterized in that Z is -NH- and n = 0 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, characterized in that X is optionally substituted phenyl or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, characterized in that Ri and R4 are hydrogen or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, characterized in that it is: a) [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl] -amide of 1-methyl-1, 2 acid, 5,6-tetrahydro-pyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof; b) N- [4- [(3-bromophenyl) amino] -3-cyano-6-quinolinyl) -4- (N-al 1-N-methylamino) -2-butinamide or a pharmaceutically acceptable salt of the same; c) N- (4- [(3-Bromophenyl) amino) -3-cyano-6-quinolinyl) -4- (N-methoxyethyl-N-methylamino) -2-butinamide or a pharmaceutically acceptable salt thereof; d) N- [4- [(3-Bromophenyl) amino] -3-cyano-6-quinolinyl] -4- (bis- (2-methoxy-ethyl) amino) -2-butinamide or a pharmaceutically acceptable salt of the same; e) [4- (3-Bromo-phenylamino) -3-cyano-quinolin-6-yl) -amide of 4-methoxymethoxy-but-2-ynoic acid or a pharmaceutically acceptable salt thereof; f) 4- (4-Chloro-2-fluoro-phenylamino) -6-methoxy-7- (2-pyridin-4-yl-ethoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; g) 4- (2-methoxy-ethoxy) -but-2-ynoic acid 4- (3-Bromo-phenylamino) -3-cyanoquinolin-6-yl] -amide or a pharmaceutically acceptable salt thereof; h) 4- ((2S) -2-methoxymethylpyrrolidin-1-yl) but-2-ynoic acid [4- (3-bromophenylamino) -3-cyanoquinolin-6-yl] amide or a pharmaceutically acceptable salt thereof; i) [4- (3-Bromophenylamino) -3-cyanoquinolin-6-yl] -amide of 4- (1, 4-dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ynoic acid or a pharmaceutically acceptable salt thereof; j) 4- (3-Bromo-phenylamino) -6- (2-ethoxy-3,4-dioxo-cyclobut-1-enylamino) quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; k) [4- ((2-methoxy-ethyl) -methyl-amino] 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] -but-2-enoic or a pharmaceutically acceptable salt thereof; 1) (4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl) -amide of (S) -4- (2-methoxymethyl-pyrrolidin-1) hydrochloride -yl) -but-2-enoic or a pharmaceutically acceptable salt thereof; m) 4- (3-Hydroxymethyl-piperidin-1-yl) -but-2 [4- (3-chloro-4-fluorophenylamino) -3-cyano-7- methoxy-quinolin-6-yl) -amide] -enoic acid or a pharmaceutically acceptable salt thereof; n) 4- (1,4-dioxa-8-aza-spiro [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl) -amide. 4.5] dec-8-yl) -but-2-enoic or a pharmaceutically acceptable salt thereof; o) 4- (2-hydroxymethyl-piperidin-1-yl) -but-2 [4- (3-chloro-4-fluorophenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] -enoic acid or a pharmaceutically acceptable salt thereof; p) [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-bromo-but-2-enoic acid or a pharmaceutically acceptable salt of the same; q) 4- (3-Hydroxy-4-methyl-phenylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; r) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-diallylamino-but-2-enoic acid or a pharmaceutically acceptable salt thereof; s) 4- [bis- (2-methoxy-ethyl) -amino] [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide] -but-2-enoic or a pharmaceutically acceptable salt thereof; t) 4- ([1, 3] dioxolan-2-ylmethyl-methyl-amino) -but-2-enoic acid 3-cyano-7-methoxy-quinolin-6-yl] -amide or a pharmaceutically acceptable salt thereof the same; u) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7- methoxy-quinolin-6-yl) -amide of 4- [bis- (2-hydroxy-ethyl) -amino]] -but-2-enoic or a pharmaceutically acceptable salt thereof; v) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-thiormorpholin-4-yl-but-2-enoic acid or a pharmaceutically acceptable salt thereof; w) 4- (4- (2-hydroxy-ethyl) -piperazine 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl) -amide 1-yl) -but-2-enoic or a pharmaceutically acceptable salt thereof; x) 4- (1, 4, 7-trioxa-10-aza-) 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide cyclododec-10-yl) -but-2-enoic or a pharmaceutically acceptable salt thereof; y) 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- (methoxy-methyl-amino) -but-2-enoic acid or a pharmaceutically acceptable salt thereof; z) 4- (4-hydroxy-piperidin- / 1-yl) - [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- (4-hydroxy-piperidin- / 1-yl) - but-2-enoic or a pharmaceutically acceptable salt thereof; aa) [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7- methoxy-quinolin-6-yl] -amide of 4- [1,4 '] bipiperidinyl-1'-yl- but-2-enoic or a pharmaceutically acceptable salt thereof; bb) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4-thiazolidin-3-yl-but-2-enoic acid or a pharmaceutically acceptable salt thereof; ce) Bromide of 3-. { 3- [4- (3-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-ylcarbamoyl) -alyl} -4-methyl-thiazol-3-io or a pharmaceutically acceptable salt thereof; dd) 4- (2,6-Dimethyl-piperidin-1-yl) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide) -but-2-enoic or a pharmaceutically acceptable salt thereof; ee) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of 4- [bis- (2-hydroxy-propyl) -amino]] -but-2-enoic or a pharmaceutically acceptable salt thereof; ff) 4- (3-hydroxy-pyrrolidin-1-yl) -but- [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl-amide of 4- (3-hydroxy-pyrrolidin-1-yl) -but- 2-enoic or a pharmaceutically acceptable salt thereof; pyrrolidin-1-yl) -but-2-enoic or a pharmaceutically acceptable salt thereof; gg) [4- ((2-hydroxy-ethyl) -methyl-amino] 4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7- methoxy-quinolin-6-yl] -amide] -but-2-enoic or a pharmaceutically acceptable salt thereof; hh) 4- (2,5-dimethyl-pyrrolidin-1-yl) [4- (3-chloro-4-fluoro-phenylamino) -3-cyano-7- methoxy-quinolin-6-yl] -amide -but-2-enoic or a pharmaceutically acceptable salt thereof; ii) [4- (4-Chloro-4-fluoro-phenylamino) -3-cyano-7-methoxy-quinolin-6-yl] -amide of the acid, 4- (4,4-dihydroxy-piperidin-1-yl) ) -but-2-enoic or a pharmaceutically acceptable salt thereof; jj) 4- (3-Chloro-4-fluoro-phenylamino) -7-methoxy-6-pyrrolidin-1-yl-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; kk) 4- (3-Chloro-4-fluroanilino) -7-methoxy-6- (1H-pyrrol-1-yl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; 11) 6- (1-Aziridinyl) -4- (3-chloro-4-fluoroanilino) -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; mm) [4- (3-Bromo-phenylamino) -3-cyano-7-ethoxy-quinolin-6-yl] -amide of 4- [(2-methoxy-ethyl) -methyl-amino] -but-2 -amide. -enoic or a pharmaceutically acceptable salt thereof; nn) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7- (3- (-hydroxy-piperidin-1-yl) propoxy] -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt of the same, oo) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7-. { 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl) -propoxy} -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; pp) 4- (2-Bromo-4-chloro-phenylamino) -7-. { 2- [(2-hydroxy-ethyl) -methyl-amino] -ethoxy} -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; qq) 4- (2, -Dichloro-5-methoxy-phenylamino) -7-. { 3- ^ [(2-hydroxy-ethyl) -methyl-amino] -propoxy} -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; rr) 4- (2, -Dichloro-5-methoxy-phenylamino) -6-methoxy-7- (3-thiomorpholin-4-yl-propoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ss) 4- (2,4-Dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methoxy-ethylamino) -propoxy] -quinino-3-carbonitrile or a pharmaceutically acceptable salt thereof; tt) 4- (2,4-Dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperidin-1-yl) -propoxy] -quinolin-3-carbonitrile or a salt pharmaceutically acceptable thereof; uu) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7- [3- (2,6-dimethy1-morpholin-4-y1) propoxy] -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; vv) 4- (2-Bromo-4-chloro-phenylamino) -7-. { 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy} -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ww) 4- (2-Bromo-4-chloro-phenylamino) -1- [2- (4-hydroxy-piperidin-1-yl) -ethoxy] 6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt of the same; xx) 4- (2-Bromo-4-chloro-phenylamino) -6-methoxy-7- (2-thiomorpholin-4-yl-ethoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; and y) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7- [3- (2, 5-diimethyl-pyrrolidin-1-yl) -propoxy] -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; zz) 4- (2, -Dichloro-5-methoxy-phenylamino) -7- [3- (3-hydroxy-propylamino) -propoxy) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; aaa) Ethyl ester of l- acid. { 3- [3-cyano-4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy] -propyl) -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof; bbb) 7- (3- (4-acetyl-1-piperazinyl) propoxy] 4- [(2,4-dichloro-5-methoxyphenyl) amino] -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ecc) 4- (3-chloro-4-fluoroanilino) -7-methoxy-6 (4-morpholinyl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ddd) 7- [3- (4-Benzyl-piperazin-1-yl) -propoxy] -4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile or a salt pharmaceutically acceptable thereof; eee) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7- [3- (2-hydroxy-ethylamino) -propoxy] -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; fff) 4- (2,4-Dichloro-5-methoxy-phenylamino) -7-. { 3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ggg) 7-. { 3- [Bis- (2-methoxy-ethyl) -amino] -propoxy} 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; hhh) 7-. { 3- (Bis- (2-hydroxy-ethyl) -amino] -propoxy.} -4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically salt acceptable thereof, iii) 4- (3-chloro-4-fluoroanilino) -7- (4-morpholinyl) -6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; jjj) N- (4- (3-chloro-fluoroanilino) -3-cyano-7- (4-morpholinyl) -6-quinolinyl] -2-butinamide or a pharmaceutically acceptable salt thereof; kkk) 6-amino -4- (3-chloro-4-fluoroanilino) -7- (4-morpholinyl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; 111) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- (3 { [2- (4-morpholinyl) ethyl] amino) propoxy) -3-quinolinecarbonitrile or a pharmaceutically salt acceptable thereof; mmm) 7-. { 3- [(2-anilinoethyl) amino] propoxy} -4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnn) N- [4- (3-chloro-4-fluoroanilino) -3-cyano-7- (4-morpholinyl) -6-quinolinyl) acrylamide or a pharmaceutically acceptable salt thereof; ooo) 4- (3-chloro-4-fluoroanilino) -7-. { 4- [2- (dimethylamino) ethyl] -1-piperazinyl} -6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; PPP) 6-amino-4- (3-chloro-4-fluoroanilino) -1-. { 4- [2- (dimethylamino) ethyl] -1-piperazinyl} -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; qqq) N- (4- (3-chloro-4-fluoroanilino) -3-cyano-7-. {4- [2- (dimethylamino) ethyl] -1-piperazinyl} - 6-quinolinyl) acrylamide or a pharmaceutically acceptable salt thereof; rrr) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- (. {2- [4- (2-methoxyethyl) -1-piperazinyl] ethyl} amino) -3- quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; sss) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [3- (2H-1,2,3-triazol-2-yl) propoxy) -3-quinolinecarbonitrile or a pharmaceutically salt acceptable thereof; ttt) 4- (2, -dichloro-5-methoxyanilino) -6-methoxy-7- [3- (1H-1, 2, 3-triazol-1-yl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; uuu) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- (3-thienyl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; vvv) 4- [(E) -2- (2-quinolinyl) ethenyl) aniline or a pharmaceutically acceptable salt thereof; www) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7-. { [2- (2H-1, 2,3-triazol-2-yl) ethyl] amino) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; xxx) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7-. { [2- (lH-1, 2,3-triazol-1-yl) ethyl] amino} -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; yyy) 4 - (2,4-dichloro-5-methoxyanilino) -7- (3-thienyl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; zzz) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- (3- (IH-1,2,4-triazol-1-yl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically salt acceptable therefrom; aaaa) 4- (2,4-dichloro-5-methoxyanilino) -7- [3- (1H-imidazol-1-yl) propoxy] -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof same; bbbb) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [3- (1H-pyrazol-1-yl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; cccc) N- (3-cyano-4- (2,4-dichloro-5-methoxy-anilino) -6-methoxy-7-quinolinyl] -N- [4- (4-ethyl-l-piperazinyl) butyl] acetamide or a pharmaceutically acceptable salt thereof; dddd) N- (3-cyano-4- (2,4-dichloro-5-methoxy-anilino) -6-methoxy-7-quinolinyl] -N- (3- ( 4-ethyl-l-piperazinyl) propyl) acetamide or a pharmaceutically acceptable salt thereof, eeee) 4- (2, -dichloro-5-methoxyanilino) -6-methoxy-7-. { 3- [4- (2-methoxyethyl) -1-piperazinyl] propoxy} -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ffff) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- (lH-pyrrol-1-yl) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; gggg) 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; hhhh) 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [2- (2H-1, 2, 3-triazoI-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; iiii) - (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [3- (lH-tetraazol-1-yl) propoxy] -3-quinoline-carbonitrile or a pharmaceutically acceptable salt thereof; j j j j) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [3- (2H-tetraazol-2-yl) propoxy) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; kkkk) 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; 1111) 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [2- (2H-1, 2, 3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; or mmmm) 4- (2,4-dichloro-5-methoxyanilino) -7-. { 3- [[2- (dimethylamino) ethyl] (methyl) amino] propoxy} -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof.

6. The use of a compound of formula 1 for the manufacture of a medicament for treating, inhibiting the growth of, or eradicating a neoplasm in a mammal. wherein: X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyrinidyl, pyrimidinyl or phenyl ring may be mono-, di- or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkylamino 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 atoms carbon, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino; Z is -NH-, -O-, -S-, or -NR-; R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms; Gi, G2, Ri and R are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 atoms of carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenyloxy of 3-8 carbon atoms, alkyloxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms carbon, alkenoyloxymethyl of 4-9 carbon atoms, alkynyloxymethyl • of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano , nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl or of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N- < alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N, N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, (C (R6) 2) P / Rt- (C (R6) 2) p- N ^ N- (C (R6) 2) kY- RβR9-CH-M- (C (R6) 2) kY-, (C (Rβ) 2) p R7- (C (R6) 2) g-Y-. RHCÍRekJp-M-íCíRßkk-Y-. or, Het- (C (R6) 2) q-W- (C (R6) 2) k-Y- with the proviso that either Gi or G2 or both of Gi and G2 must be a radical selected from the group RßR9-CH-M- (C (R6) 2) k-Y-. R'7- (C (R6) 2) g-Y-. R7- (C (R6) 2) p-M- (C (R6) 2) k-Y-. Het- (C (R6) 2) q-W- (C (R6) 2) k-Y-, H R, -N- And it's a divalent radical selected from the group consisting of - (CH2) a- -N- Rr R7 is -NR6R6, -J, -0R6, -N (R6) 3+, or -NR6 (OR6); R'7 is -NR6 (OR6), -N (R6) 3+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms , N, N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms or N, N-dialkynylamino of 6-12 carbon atoms, with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; M is > NR6, -O-, > N- (C (R6) 2) PNR6R6, or > N- (C (R6) 2) POR6; W is > NR6, -O-, or is a link; Het is a heterocycle selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino 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, and; wherein the heterocycle is mono- or di-substituted on a carbon or nitrogen with Re, optionally mono- or disubstituted on a carbon with hydroxy, -N (R6) 2, or -ORe, optionally mono- or di-substituted on carbon with monovalent radicals - (C (R6) 2) sORe or - (C (R6) 2) sN (Re) 2, or optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -O (C (R6) 2) sO_; R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; R2 is selected from the group consisting of R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / \ Rr (C (R6) 2) p-N N- (C (R6) 2) r-, (C (R6) 2) P R7- (C (R6) 2) S- • R7- (C (R6) 2) pM- (C (R6) 2) r- R8R9-CH- - (C (R6) 2) f- or Het- (C (R6) 2) qW- (C (R6) 2) r-: provided that at least one of the R3 groups is selected from the group (C (R6) 2) P / \ Rr (C (R6) 2) pN ^ U-C R6) 2) f ', (C (R6) 2) P R'7- (C (R6) 2) s -. R

7. (C (R6) 2) p-M- (C (R6) 2) r- R8R9-CH- - (C (R6) 2) r- or Het- (C (R6) 2) q-W- (C (R6) 2) r-. R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, RβR9-CH-M- (C (R6) 2) r. . or HeHCíR ^ -W-ÍÍÍÍ);,) -: Rβ, and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; p = 2-4 q = 0-4. r = 1-4 s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; or a pharmaceutically acceptable salt, provided that when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through the saturated carbon atom; and further provided that when Y is -NR6- and R7 is -NR6R6, -N (R6) 3+, or -NR6 (OR6); then g = 2-6; when M is -O- and R7 is -0R6, then p = 1-4; when Y is -NR6-, then k = 2-4; when Y is -O- and M or W is -O-, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is -O- or -NR6-, then k = 2-4. The use according to claim 6, characterized in that the neoplasm is selected from the group consisting of neoplasms of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary and lung. 8- The use of a compound of formula 1 for the manufacture of a medicament for treating, inhibiting the progress of, or eradicating polycystic kidney disease in a mammal. wherein: X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyrinidyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may be mono-, di- or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino , alkanoylamino of 1-6 carbon atoms, alkenoylal of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1 -5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino; Z is -NH-, -0-, -S-, or -NR-; R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms; Gi, G2, Ri and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 atoms of carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenyloxy of 3-8 carbon atoms, alkyloxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms carbon, alkenoxyloxymethyl of 4-9 carbon atoms, alkynyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1 -6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl d and 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl . N, N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N, N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, . R8R9-CH-M- (C (R6) 2) k-Y-. R7- (C (R6) 2) gY- • Rr (C (R6) 2) PM- (C (R6) 2) kY-. «Het- (C (R6) 2) qW- (C (R6) 2 ) kY- with the proviso that either Gi or G2 or both of Gi and G2 must be a radical selected from the group (C (R6) 2) P / R7- (C (R6) 2) P-N- (C (Rβ) 2) k-Y- R8R9-CH- - (C (R6) 2) k-Y-. (C (R6) 2) P R "7- (C (R6) 2) gY-, R7- (C (R6) 2) PM- (C (R6) 2) kY .. Het- (C (R6) 2) qW- (C (R6) ) 2) kY-, H 0 R2-N-; And it is a divalent radical selected from the group consisting of ~ (CH2) a -o- -N- e R7 is -NR6R6, -J, -0R6, -N (R6) 3+, or -NR6 (OR6); R'7 is -NR6 (OR6), -N (R6) 3+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms , N, N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms or N, N-dialkynylamino of 6-12 carbon atoms, with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; M is > NR6, -O-, > N- (C (R6) 2) PNR6R6, or > N- (C (R6) 2) pOR6; W is > NR6, -O- or is a link; Het is a heterocycle selected from the group consisting of morpholino, thiomorpholino, S-oxide of thiomorpholino, S, S-thiomorpholino 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, N tetrahydropyran, and n; wherein the heterocycle is mono- or di-substituted on a carbon or nitrogen with R6, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -0R6, optionally mono or disubstituted on carbon with radicals monovalent - (C (R6) 2) sORβ or - (C (Rβ) 2) SN (Re) 2, or optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -0 (C (Re) 2) s0-; R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; R2 is selected from the group consisting of R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / R7- (C (R6) 2) P-N U- (C (R6) 2) r. (C (R6) 2) P R7- (C (R6) 2) S-. R7- (C (Rβ) 2) p-M- (C (Rβ) 2) r R8R9-CH-M- (C (R6) 2) r- .0 Het- (C (R6) 2) q-W- (C (R6) 2): provided that at least one of the R3 groups is selected from the group R'7- (C (Re) 2) s-. R7- (C (Re) 2) p-M- (C (Re) 2) r R8R9-CH-M- (C (R6) 2) r-, 0 Het-iCÍRgJj qW-ÍCÍRßíaJ • R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl , carboalkyl of 2-7 carbon atoms, (C (R6) 2) P / R7- (C (R6) 2) P-N N- (C (R6) 2) r-. (C (R6) 2) P R7- (C (R6) 2) s-. R7- (C (R6) 2) P-M- (C (R6) 2) r- R8R9-CH-M- (C (R6) 2) r- or Het- (C (R6) 2) q-W- (C (R6) 2) r-: R8, and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; or a pharmaceutically acceptable salt, provided that when Rβ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through the saturated carbon atom; and further provided that when Y is -NR6-and R7 is -NR6Rβ, -N (R6) 3+, or -NR6 (OR6); then g = 2-6; when M is -O- and R7 is -0R6, then p = 1-4; when Y is -NR6-, then k = 2-4; when Y is -O- and M or W is -O-, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is -O- or -NRβ-, then k = 2-4. 9. A pharmaceutical composition, characterized in that it comprises a compound of formula 1 having the structure where: X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyrinidyl, pyrimidinyl or phenyl ring, wherein the pyridyl, pyrimidinyl or phenyl ring may be mono-, 4-di- or tri- substituted > with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl , alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 -7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 atoms of carbon, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylam 3-9 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino; Z is -NH-, -O-, -S-, or -NR-; R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms; Gi, G2, Ri and R are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 atoms of carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenyloxy of 3-8 carbon atoms, alkynyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 atoms of carbon carbon, alkenoyloxymethyl of 4-9 carbon atoms, alkyloxymethyl > of 4-9 carbon atoms, alkoxymethyl 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms carbon, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino of 4 to 12 carbon atoms, N, N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, (C (R6) 2) P / \ Rr (C (R6) 2) p - ^ - (CÍRekk-Y-. RßR9-CH- - (C (R6) 2) kY-. (C (R6) 2) p R7- (C (R6) 2) g-Y-. Rr (C (R6) 2) PM- (C (R6) 2) kY- or Het- (C (R6) 2) qW- (C (R6) 2) kY- with the proviso that either Gx or G2 or both of Gi and G2 must be a radical selected from the group (C (R6) 2) p / \ Rr (C (R6) 2) pN N -I ^ R ^ Y- f R8R9-CH-M- (C (R6) 2) kY- (C (Re) 2) P R'7- (C (R6) 2) g-Y-, Rr (C (R6) 2) p-M- (C (R6) 2) k.?. , Het- (C (R6) 2) q-W- (C (F-6) 2) k-Y. H R2-N- And it's a divalent radical selected from the group consisting of ~ (CH2) a-. -O- R »fi6 R7 is -NR6R6, -J, -OR6, -N (R6) 3+, or -NR6 (OR6); R'7 is -NR6 (OR6), -N (R6) 3+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms , N, N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, '. N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms' or N, N-dialkynylamino of 6-12 carbon atoms, with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through of a saturated carbon atom; M is > NR6, -O-, > N- (C (R6) 2) pNR6R6, or > N- (C (R6) 2) pOR6; W is > NR6, -O- or is a link; Het is a heterocycle selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino 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, and H; wherein the heterocycle is mono- or di-substituted on a carbon or nitrogen with R6, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -ORe, optionally mono or disubstituted on carbon with monovalent radicals - (C (R6) 2) S0R6 or - (C (R6) 2) S (Re) 2, optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -0 (C (Rβ) 2) s0-; R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; R2 is selected from the group consisting of R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (C (R6) 2) p /? R (C ( R6) 2) -N N-íCÍRßJa) -, (C (R6) 2) P 7- (C (Re) 2) s-. R7- (C (R6) 2) P-M- (C (R6) 2) r- R8R9-CH-M- (C (R6) 2) r- or Het- (C (R6) 2) qW- (C (R6) 2) r- - with the proviso that at least one of the R3 groups is selected from the group (C (R6) 2) P / \ R (C (R6) 2) p-NN / N- (C (R6) 2) r-, (C (R6) 2) p R'7- (C (R6) 2) S-. R7- (C (R6) 2) P-M- (C (R6) 2) r- R8R9-CH-M- (C (R6) 2) r-, or Het- (C (R6) 2) q-W- (C (R6) 2) r- '• R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, R7- (C (R6) 2) s-. R7- (C (Re) 2) p-M- (C (R6) 2) r- R8R9-CH-M- (C (R6) 2) r. ° HßHCtR? Dq-W-tCÍRßJa), R8, and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; or a pharmaceutically acceptable salt, provided that when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through the saturated carbon atom; and further provided that when Y is -NR6- and R7 is -NR6R6, -N (R6) 3+, or -NR6 (0R6); then g = 2-6; when M is -O- and R7 is -0R6, then p = 1-4; when Y is -NR6-, then k = 2-4; when Y is -O- and M or W is -0-, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is -O- or -NR6-, then k = 2-4. 10. A process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it comprises (a) reacting a compound having the formula where Ri, Gi, G2, R4, Z, n and X are as defined above with a dehydrating agent to convert the aminocarbonyl group to a cyano group, or (b) react a compound having the formula A? -NH-A2 or a salt thereof with a compound having the formula QA ^ where Q is a leaving group and Ai, A2 and A3 are such that A? -NA2-A3 is a compound conforming to formula 1; or (c) reacting a compound having the formula A4-OH or a salt thereof with a compound having the formula Q-A5 where Q is as defined above and A4 and A5 are such that A4-0-A5 is a compound that conforms to formula 1; or (d) adding an acid to the compound having the formula 1, so that an acid addition salt is prepared. 3-CYANOQUINOLINES SUBSTITUTED AS PROTEIN INHIBITORS TYROSINE KINASES SUMMARY OF THE INVENTION This invention provides compounds of formula (1), where Ri, Gx, G2, R4, Z, X and n are as defined herein, or a pharmaceutically acceptable salt thereof, which are useful as antineoplastic agents in the treatment of polycystic kidney disease.