MXPA01003230A - 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 the treatment 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 that 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: 127995. 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 make 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., An ti cancer Res. , 7, 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. Wat. 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 receiver. 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 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 (1995); Nauta J., et al., Pedia tric Research 31 (6), 755 (1995); Gattone V.H., et al., Developmen tal. Biol ogy, 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 cell signal transduction cascade of growth factors to the cell nucleus. Via 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 Ed in 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 way of the MAPK. 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 specific tyrosine kinase of the epithelial lineage, ECK has subsequently shown to be expressed on vascular endothelial cells, smooth muscle cells and fibroblasts. ECK is a transmembrane glycoprotein of type I 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 autochthonous stimulation via the ECK.LERK-1 interaction. The increase in the expression of both ECK and LERK-1 has been correlated with the transformation of melanomas from the noninvasive horizontal phase of growth into metastatic melanomas that grow vertically, very invasive. It is believed that the ECK-LERK-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 the 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 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 mediated predominantly 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: 1 1 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), 3413 (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 tyrosine kinase protein [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. 312, 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 positions 5-8 but which must also have a hydrogen or fluorine atom at position 3. US Patent 5,480,883 discloses 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 that 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 shot sina 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 describes 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 quinazole 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 the positions 5-8 can be replaced with heteroatoms resulting in a wide 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 chemozoline 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 at positions 5 and 6. In addition to the patent applications mentioned above, a number of publications describe 4-anilinoqumazolines; 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: where: X is a ring system of aryl or bicyclic heteroaryl of 8 to 12 atoms where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S with the proviso that the bicyclic heteroaryl ring does not contain OO bonds , SS or SO and where the bicyclic aryl ring or bicyclic heteroaryl may optionally be mono-, di-, tri-, or tetra substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino; or X is a radical that has the formula: where A is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, or di-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 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 3-10 carbon atoms, mercapto, and benzoylamino; T is bonded to a carbon of A and is: -NH (CH2) m-, -0 (CH2) m-, -S (CH2) m-, -NR (CH2) m-, - (CH2) m- - (CH2) mNH-, - (CH2) m0-, - (CH2) mS- or - (CH2) mNR-; L is an unsubstituted phenyl ring or a phenyl ring 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 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 carbon atoms, N, N-dialkylaminoalkoxy of 3 -10 carbon atoms, mercapto, and benzoylamino; provided that L can be an unsubstituted phenyl ring only when m > 0 and T is not -CH2NH- or -CH20-; or L is a 5- or 6-membered heteroaryl ring, wherein the heteroaryl ring contains from 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain 0-0, SS or SO, and where the heteroaryl ring is mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 carbon, 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-, -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, alkynyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 atoms of carbon carbon, alkenoxyloxymethyl 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, 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 / R ( C (R6) 2) p-N N- (C (R6) 2) kY- _ R8R9-CH- - (C (R6) 2) kY-. (C (R6) 2) P R7- (C (R6) 2) 9-Y- • R- (C (R6) 2) pM- (C (R6) 2) kY-, or Het- (C (R6) 2) qW- (C ( R6) 2) kY- or R1 and R4 are as defined above and Gi or G; or both are R2-NH-; or if any of the substituents Ri, G2, G3 or R4 are located contiguous to carbon atoms then they can be taken together as the divalent radical -O-C (Re) 2-0-; And it's a divalent radical selected from the group consisting of - (CH2) a, -O-, and - Nr-; R7 is -NR6R6, -OR6, -J, / -N (R6) 3+, or -NR6 (OR6); M is > NRe, -O-, > N- (C (R6) 2) PNR6R6. or > N- (C (R6) 2) POR6; W is > NRß, -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, N tetrahydropyran, and H where Het is mono- or di-substituted on a carbon or nitrogen with Rβ, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -ORd, optionally mono or disubstituted on carbon with monovalent radicals - (C (Rd) 2) sORe or - (C (Re) 2) SN (Re) 2. and optionally mono or disubstituted on a carbon saturated with divalent radicals -O- or -O ( C (Re) 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; with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; 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, R7- (C (R6) 2) S- • R7. (C (R6) 2) p-M- (C (R6) 2) r- R8R9-CH- - (C (R6) 2) r-. 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, (C (R6) 2) P Rr (C (R6) 2) pN ^ / 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-M- (C (R6) 2) r .o- Het- (C (R6) 2), - W - (C (R6) 2) r-: Rß. and R9 are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; 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; is 0-3; 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 -0R6, then p = 1-4; when Y is -NR6-, 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. Preferred bicyclic aryl or bicyclic heteroaryl ring systems include naphthalene, 1, 2, 3, 4-tetrahydronaphthalene, indane, 1-oxo-indane, 1,2,3,4-tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-l, 3-dihydro-isobenzofuran, benzothiaphene, 1, 1- dioxo-benzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo-2,3-dihydro-lH-isoindole, benzotriazole, lH-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzooxazole, purine, phthalimide, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido [2, 3-b] pyridine, pyrido- [3, -b] pyrazine, pyrido [3, 2-c] pyridazine, pyrido [3,4- b] pyridine, lH-pyrazole [3, -d] pyrimidine, 1-benzodioxane, pteridine, 2 (1H) -quinolone, 1 (2H) -isoquinolone, 2-oxo-2,3-dihydro-benzthiazole, 1, 2-methylenedioxybenzene, 2-oxindole, 1,4-benzisoxacin, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoacin, phthalazine, 1, 4- dioxo-l, 2, 3, 4-tetrahydro-phthalazine, 2-oxo-l, 2-dihydro-quinoline, 2,3-dioxo-l, 4-dihydro-2H-benzo [d] [1, 3] oxacin , 2, 5-dioxo- 2, 3, 4, 5-tetrahydro-lH-benzo [e] [1,4] diacepine, or cinnoline. When L is a 5- or 6-membered heteroaryl ring, preferred heteroaryl rings include pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole or 1,2,4-triazole. Either or both rings of the bicyclic aryl or bicyclic heteroaryl group can be completely unsaturated, partially saturated or fully saturated. An oxo substituent on the bicyclic aryl or bicyclic heteroaryl portion means that one of the carbon atoms has a carbonyl group. A thio substituent on the bicyclic aryl portion or bicyclic heteroaryl means that one of the carbon atoms has a thiocarbonyl group. When L is a 5- or 6-membered heteroaryl ring, it may be completely unsaturated, partially saturated or completely saturated. The heteroaryl ring can be bonded to A via carbon or nitrogen. An oxo substituent on the heteroaryl ring means that one of the carbon atoms has a carbonyl group. A thio substituent on the heteroaryl ring means that one of the carbon atoms has a thiocarbonyl group. The alkyl portion of the alkyl, Alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulphinyl, alkylsulphonyl, alkylsulfonamido, carboalkoxy, carboalkyl, carboxyalkyl, alkanoylamino, N-alkylcarbamoyl, and N, N-dialkylcarbamoyl, N-alkylaminoalkoxy, N, N-dialkylaminoalkoxy include carbon chains linear as well as branched carbon chains. The alkenyl portion of the alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido include linear carbon chains as well as branched carbon chains and one or more sites of unsaturation and all possible configurational isomers. The alkynyl portion of the alkynyl, alkyloxyloxymethyl, alkynylsulfonamido, alkynyloxy substituents 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 "C02CH-, where R" is an alkyl radical having 1-6 carbon atoms. The alkoxymethyl is defined as R "OCH 2, where R" is an alkyl radical of 1-6 carbon atoms radical. The alkylsulphinyl 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. carbon. 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 "NHC0-, where R" is an alkyl radical of 1-6 carbon atoms, N, N-dialkylcarbamoyl is defined as a radical R "R'NC0-, 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, with monosubstituted being most preferred. it is preferred that Rl and R4 substituents, at least one is hydrogen and it is most preferred that both be 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 by R on carbon or nitrogen, optionally mono- or disubstituted on carbon with hydroxy, -N (R6) 2? , -ORß, optionally mono or disubstituted on carbon with - (C (R6) 2) sORβ or - (C (R6) 2) SN (R?) 2, and optionally mono or disusti on carbon saturated with divalent radicals -O- or -O (C (R6) 2) sO- (carbonyl and ketal groups, respectively); in some cases when Het is substituted with -O- (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, 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, morpholine disubstituted in the 2,6-positions, thiomorpholine disubstituted in the 2,5-positions, imidazole substituted in the 2-position, substituted thiazole, substituted imidazole in the substituted N, 1,4-piperazine atom in the N atom, substituted piperadine in the N atom, and substituted pyrrolidine in 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, 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 Q-A3 where Q is a leaving group and Ai, A2 and A3 are such that A1-NA2-A3 is a compound conforming to formula 1; [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 A-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 the formula 5 is described below in Reaction Scheme 1 where Z, X, n, Ri, R2. G2, Gi and R4 are as described above. According to the sequence of the reaction set forth in reaction scheme 1, a quinoline-3-carboxylic acid ester 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 the addition of ammonia to give the amide 4. The dehydration of the amide functional group with a dehydrating agent such as the trifluoroacetic anhydride is pyridine, pentoxide. phosphorus 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 racemic forms or R and S optically active, respectively. The quinoline-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 as are known in the art. or can be prepared by methods known in the art as set forth in detail 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, Fárma co, 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. , 13 (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, Rl7 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, intermediates 9 can also be formed as a mixture of two 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. The condensation of 10 with a reactive nucleophilic diamine, 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 portions Rx, G2, Gi and R4 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 portions Rlr G2, Gi and R4 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, protecting groups 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 of the 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 Ri, G2, Gi and R < They 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 Rí 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: 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-methylmorpholine gives the compounds with 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 the compounds of this invention will be in the racemic or optically active R and S forms, 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 HjN-tCHjk-X (17) Using methods similar to those described above in Reaction Scheme 4, intermediates 25 can be converted to the compounds of this invention, 26.

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 Rd, 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 (_.}. ~ 0H * 6NQ> -OH R (~ ° H / - ° H R6N ^) - O? C -OH 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 below in Reaction Scheme 5-6, where R, 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 s 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 9. 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 = H (R') 2N- (C (Rβ) 2) s = H to R'OH As set forth in Reaction Scheme 6 below, Ri, G2, R4, Rβ, 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 acetylenic 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 HO- CO ^ - H -B Si (OH)? - C,, BuSW CH2Cl2, (C2Hs) 3. ^ 2 l ^ 2Js - H 35 DMAP 36 The compounds of this invention are also prepared as shown below in Reaction Scheme 7 where Ri, G2, R / Rβ, 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 alkyllithium 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 achieved using sodium hydride or another 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 In some cases, the alcohol in Schedule B may also be the reaction solvent. 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 the 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 47 Using methods similar to those summarized above, 45b can be converted to 47b or 48b.

Other chlorides and carboxylic acid 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 earlier. OJ 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-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 intermediates 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 R •? - ( 52 57.O R70- Ba (OH) _, R3 C QH C 1 ethanol, H2O (b "N- - (c (eri) s 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 Rβ, R, 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 carboxylic acid chlorides and 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 The compounds of this invention represented by position Formulas 62-63 can be prepared as shown in Reaction Scheme 9, where Ri, G2, R, R3, R3, 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 achieved 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 can also be the solvent of the reaction. In the reaction of 62 with an amine of List A to 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 outlined above, 61b can be converted 63b and 64b via the intermediary 62b. 63b 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, R, R6. 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. Maintaining 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 (Rβ) 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 2. R6O- (C (R6) 2) rJ "65 66 1. THF n-Buü R6O- (C (R6) 2) rO- (C ( R6) 2) r == - H 67 2. CO2 1. THF, NaH R6O- (C (R6) 2) r-OH 2. J '(C (R6) 2) r- -H 71 72 R60- (C (R6) 2) r-O- (C (R6) 2) r == - H 67 By 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 Ri, R3, R4, R6, R7 and n are as defined above and the HN amines (R ") 2 are selected from the group: HH Refluxing 73 and 74 in a solvent such as ethanol gives the intermediate 75 which can react with an amine in a refluxing ethanol to give the compounds of this invention represented by Formula 76. Treat 75 with an excess of alkoxide of 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 10 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, R, Rßr 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 the mercapto acid 78, triethylamine and 2,2'-dipyridyl disulfide. The formation of anhydride mixed 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-S 3 79 HS - (C (Rß) 2) r- COOH 2-, 20-dipyridyl disulfide, R3SH R3S-S - (CíRß l - COOH E? 3N, THF 78 80 83 Applying methods similar to those described above 82b can be converted to 83b. 82b 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, R5, 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 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, R, 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 R? r Gl r Ri, R 4, Rs. 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, Gi, G2 or R4 is a methoxy group, this may 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 R4 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 R i Gi, G 2 or R 4 is hydroxy, this may be converted to the corresponding alkanoyloxy group of 1-6 carbon atoms by reaction with a suitable 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 Ri, Gi, G2 or R4 is hydroxy, this can be converted to the corresponding alkenoyloxy 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, 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 Rx, Gx, 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 can be acylated with an appropriate acid chloride, anhydride or mixed 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, alkenethyloxymethyl group of 2-7 carbon atoms or an alkanoyloxymethyl group of 2-7 carbon atoms. Where one or more of Ri, Gx, 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 procedures described in the application WO-9633981 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 O-9633980 can be used to prepare the 3-cyanoquinoline intermediates used in this invention where Ri, Gi, G 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 Rx, Gi, G or R4 are alkoxyalkylamino groups. The chemical procedures described in the application WO-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 procedures described in the application W0-9633977 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 the 6-position of a quinazoline have been introduced, the same chemistry can be used to introduce the same groups in positions occupied by the substituents Ri, Gi, G2 and R 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 the 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 test procedure 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 plates at a moi of 10 pfu / cell 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 20 mM coh imidazole column, 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 / methanol and stored at -70 ° C. The test compounds were prepared in standard solutions of 10 mg / mL in 100% dimethylsulfoxide (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 Reactivo Final 100 Rxns HEPES 1 M (pH 7 4) 12. 5 mM 50 μL MnCl2 10 mM IMM 40 μL AT P lmM 20 uM 80 μL 0 33P-ATP 2. 5uCi 25 μL The inhibition data for the compounds of the invention are shown below in TABLE 1. The IC5o 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% C inhibition was evaluated with the following formula: of inhibition = 100 - [CPM (drug) / CP (control)] X 100 where CPM (drug) is in units of counts per J minute and is a number that expresses the amount of radioactively labeled ATP (? -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 (? -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 is 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. Where it was possible to determine the IC 50 value, this was reported in TABLE 1, otherwise the% inhibition at a concentration of 0.5 μM of the test compound is shown in TABLE 1. Multiple entries for the same compound indicate that It was tested multiple times.

TABLE 1: Inhibition of EGF-R Kinase (Recombinant Enzyme) Example ci50 (μM)% Inhibition _ 0.5 μM 173 0.5 TABLE 1: Inhibition of EGF-R Kinase (Recombinant Enzyme) (continued) Example ci50 (μM)% Inhibition @ 0.5 μM 172 0.09 176 0.01 96 > 10 97 > 10 101 > 1 27 111 > 1 10 148 > 1 11 115 > 0.5 49 167 > 1 126 .45 168 > 1 127 > 1 25 144 > 1 14 149 > 1 TABLE 1: Inhibition of EGF-R Kinase (Recombinant Enzyme) (continued) Example ci50 (μM)% Inhibition @ 0.5 μM 156 > 1 34 141 > 1 5.5 142 > 1 24 130 > 1 5 129 > 1 6.7 131 > 1 0 150 0015 150 004 151 > 1 34 152 > 1 24 132 > 1 0 133 > 1 0 134 > 1 35 135 > 1 0 TABLE 1: Inhibition of EGF-R Kinase (Recombinant Enzyme) (continued) Example ci50 (μM)% Inhibition @ 0.5 μM 153 > 1 14 136 > 1 33 137 .15 Inhibition of Epithelial Cell Kinase (ECK) In this standard pharmacological test procedure, a biotinylated peptide substrate is immobilized first on microtitre 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 IC50 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 an indication of compound tested 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 (an inhibitor of the protein tyrosine phosphatase) in a buffer suitable for maintaining the pH (7.2.). The ATP and the radioactive indicator (ATP marked with either P32- 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 IC50 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 the inhibitors of MAP (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 from human ERK 2 and human MEK 1. were 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 1. . 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 ° C. 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 inhibitor runs 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 compounds representative of S 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 Domain of the Kinease Insert (KDR), Epithelial Cell Kinase (Eck), and Protein Kinase Activated by Mitogen (Mek-Erk) Example KDR Eck Mek-Erk μM μM μM 96 8.0214 > 53,476 2 < 1 0. 8 0 97 > 2.5610 > 2,561 55 98 52.9872 > 2.64! 2.5 > 2.6494 < 1 5 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 KDR Eck Mek-Erk μM μM μM 0. 4 < 0.1 99 21.4247 < 1 < 1 0. 08 0. 05 0. 08 0. 3 0. 07 0. 08 < 1 0.2 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 KDR Eck Mek-Erk μM μM μM 0. 3 < 1 0. 2 < 1 0. 2 0. fifteen 0. 25 0. 25 0. fifteen 0. 8 < 1 < 1 TABLE 2 (continued) Inhibition of the Receptor Containing the Kinase Insert Domain (KDR), Epithelial Cell Kinase (Eck), and Mitogen Activated Protein Kinase (Mek-Erk) Example KDR Eck Mek-Erk μM μM μM 0. 2 0. 2 0. 3 0. 4 1. 1 0. 4 0. 25 0. 4 0. 05 0. 299 0. 04 0. 1 TABLE 2 (continued) Inhibition of the Receptor Containing the Kinase Insert Domain (KDR), Epithelial Cell Kinase (Eck), and Mitogen Activated Protein Kinase (Mek-Erk) Example KDR Eck Mek-Erk μM μM μM 0. 1 0. 2 0. 4 < 0.001 0. 06 0. 06 0. 09 < 0.001 0. 09 0. 4 100 > 72.2892 > 48,193 > 100 3. 5 TABLE 2 (continued) Inhibition of the Receptor Containing the Kinease Insertion Domain (KDR), Epithelial Cell Kinase (Eck), and Mitogen Activated Protein Kinase (Mek-Erk) Example KDR Eck Mek-Erk μM μM μM > 100 101 5.3706 > 53,706 0.8 < 1 0. 001 < 0.001 102 14.1123 > 56,449 10 0. 5 0. # 2 0. 8 0. 3 151 28.9550 > 28,955 20 152 > 0.0000 > 27,825 > 100 153 > 28.0594 > 28,059 > 100 154 12.8256 0.770 0.5 > 2.5651 < 0.1 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 KDR Eck Mek-Erk μM μM μM 155 4 156 > 79.7071 > 26,569 35 171 < 1 < 0.001 0. 0025 < 0.001 66 > 2.5391 0.762 67 24.8472 0.025 2. 4847 > 2,485 68 4.4995 > 22,497 < 1 Inhibition of Cancer Cell Growth as Measured 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 RPMl 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 in 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 Tissue 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) Ex MDA-MB- A431 SK-BR3 A2780 DDP S 620 3T3 3T3 / c- 435 erhb2 99 0.020 0.025 0.016 0.032 0.036 0.033 100 0.067 0.369 0.429 0.270 0.249 0.325 101 0.073 0.216 0.18 0.231 0.313 0.326 101 0.365 0.123 0.0374 0.286 1.53 0.933 102 0.490 1.309 0.780 1.491 3.054 2.1! 103 0.309 1.611 0.767 2.391 2.690 2.637 104 0.021 0.049 0.034 0.044 0.107 0.207 105 0.235 0.270 0.281 0. 411 0. 853 0. 375 106 2,045 1,961 > 5 > 5 > 5 > 5 107 > 5 > 5 > 5 > 5 > 5 > 5 108 0.352 0.342 0.294 < .0005 0.525 0.0198 109 > 5 > 5 > 5,922 > 5 4.616 Table 3 (continued) Inhibition of Cancer Cell Growth Measured by the Number of Cells (IC50 μg / mL) Ex MDA-MB- A431 SK-BR3 A2780 DDP S 620 3T3 3T3 / c- 435 erbb2 110 0.0280 0.0244 0.0281 0.0181 0.0923 0.0311 111 3.404 > 5 > 5 1,565 > 5 3.301 112 0.0033 0.257 0.336 0.146 0.392 0.251 115 0.0359 0.0368 0.0220 0.0212 0.344 0.0267 126 2,626 0,786 2,094 4,313 3,219 4,801 127 > 5 > 5 > 5 > 5 > 5 > 5 Living Jn Inhibition of Human Colon Carcinoma S 620 Growth The representative compounds of this invention (listed below) were evaluated in a standard in vivo pharmacological test procedure which measured their ability to inhibit the growth of human squamous cell tumors. SW620 cells from human colon carcinoma (American Type Culture Collection, Rockville, Maryland # CRL-227) were grown in vi tro as described above. Female mice were used BALB / c nu / nu Í (Charles River, Wilmington, MA) in this standard in vivo pharmacological test procedure. A unit of 7 X 106 cells was injected into the mice. When the tumors reached a mass between 80 and 120 mg, the mice were randomized into treatment groups (day zero). The mice were treated IP once a day on days 1 to 20 after being placed at doses of 30, 10, 3 or 1 mg / kg / dose of the compound to be evaluated in 0.2% Klucel. The control animals received vehicle only. The tumor mass was determined every 7 days [(length X width2) / 2] for 28 days after the start of treatment. 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 on day zero) for each treatment group. The statistical analysis (Student's t test) of the log of the relative growth of the tumor compares the treated group against the control. A value of p (p <; 0.05) indicates a statistically significant reduction in the relative growth of the tumor of the treated group compared to the vehicle control. The compounds of Example 99 were evaluated for their ability to inhibit the growth of human colon carcinoma in vivo using the standard pharmacological test procedure described above. The results obtained are shown in Table 4.

TABLE 4 In Vivo Inhibition of Colon Carcinoma Growth Human S 620 (9791CD-186) in Mice by. Compound of Example 99. Relative Growth of the Tumor a) Compound administered in days 1 to 20 IP b) Relative Tumor Growth = Average Tumor Mass at Days 7, 14, 21 / Average Tumor Mass on Day 0 c)% T / C = (Relative Growth) of the Tumor of the Treated Group / Relative Growth of the Tumor of the Placebo Group) X 100 d) Statistical analysis (Student's T Test) of the Log of Relative Tumor Growth. A value of p (p = 0.05) indicates a statistically significant reduction in the Tumor Relative Growth of the Treated Group, compared with the Control with Placebo. e) S / T = No. of Survivors / No. Treated on Day +21 after the appearance of the tumor.

As shown in Table 4, the compound of Example 99 inhibited tumor growth; for example at 30 mg / kg (administered ip during devices 1-20), tumor growth was inhibited by 56% on day 7, 67% on day 14, and 60% on day 21. 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 for treating, inhibiting the growth of, or eradicating neoplasms of 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 such forms 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 from 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 pharmaceutically acceptable solid or liquid 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 the intravenous routes, intramuscular or subcutaneous. 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. To the resulting oil was added 1200 ml of Do therm. 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 (electroretrocity, 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 mmoles) 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 (electroretrocity, 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 giving 5.2 g of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile as a brown solid.

Example 4 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 dimethylformamide was recrystallized to give 44.2 g of yellow crystals: mp 227-228.5 ° C.

Example 5 1,4-Dihydroquinolin-6-Nitro-4-oxo-3-carbonitrile A suspension of 25. Og (95.8 mmol) of 2-Cyano-3- (4-nitrophenylamino) acrylic acid ethyl ester in 1.0 L of Do therm 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 va cuo. 18.7 g of brown solid were obtained. An analytical sample was obtained by recrystallization from dimethylformamide / ethanol: mass spectrum (electroretrocity, m / e): M + H 216.

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

Example 7 Ethyl Ester of 2-Cyano-3- (2-methyl-4-nitorphenyl) 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 8 1,4-Dihydroquinoline-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 gray solid thus obtained was washed with hexane and dried to give 51.5 g, mp 295-305 ° C.

Example 9 4-Chloro-8-methyl-6-nitro-quinoline-3-carbonitrile A mixture, with stirring, of 1,4-dihydroquinoline-8-methyl-6-nitro-carbonitrile (47 g, 200 mmol), and 200 ml of phosphorus oxychloride was refluxed for 4 h. 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 10 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 cooled to 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 (electrorrocio, m / e): M + H 214.7.

EXAMPLE 11 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile To a suspension of 5 g (23 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 brown solid: mass spectrum (electro-iron, m / e) M + H 259.8.

Example 12 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 with dilute cold sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed yielding 2.1 g of persimmon solid: mass spectrum (electroretrocity, m / e) M + H 277.7.

Example 13 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. To this mixture was added 300 ml of Dowther. The solution was stirred and refluxed under nitrogen for 12 hours with periodic distillation of the ethanol removed. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude solid was treated with boiling ethanol and then filtered to give 12 g of brown solid: mass spectrum (electroretrocity, m / e): M + H 245.8.

Example 14 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 solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed yielding 2.05 g of brown solid: mass spectrum (electroretrocity, m / e) M + H 263.7.

Example 15 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 16 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 dry 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 by 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 17 Bis- (2-methoxy-ethyl) -prop-2-ynyl-amine Propargyl bromide (17.8 g, 150 mmol) was added dropwise to a mixture of bis (2-methoxy-ethyl) amine (20 g, 150 mmol). ) 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 18 4- [Bis- (2-methoxy-ethyl) -amino] -but-2-ynoic acid N-butyl lithium in hexane (42mL, 2.5M in n-hexane) was added slowly to bis- (2-methoxy) -ethyl) -prop-2-inyl-amine (18g, 105mmol) in 80 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 h at -78 ° C, then dry 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 by 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 19 1-Methyl-4-prop-2-ynyl-piperazine Propargyl bromide (23.8 g, 200 mmol) was added dropwise into 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 20 4- (4-Methyl-piperazin-1-yl) -but-2-ynoic acid n-Butyl lithium in hexane (17.2 mL, 2.5 M in n-hexane) was slowly added to l-methyl-4-prop -2-inyl-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 dry 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 by 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 21 (2-Methoxy-ethyl) -methyl-prop-2-ynyl-amine Propargyl bromide (26.8 g, 225 mmol) was added dropwise to a mixture of N- (2-methoxyethyl) methyl amine (20 g, 225 mmoles) and cesium carbonate (73 g, 225 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 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 22 4- [(2-Methoxy-ethyl) -methyl-amino] -but-2-ynoic acid N-butyl lithium in hexane (37.8 mL, 2.5 M in n-hexane) was added slowly to (2-methoxy). ethyl) -methyl-prop-2-ynyl-amine (12.0 g, 94.5 mmol) in 90 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 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 by filtration. The filtrate was collected and dried in vacuo to give 15 g of 4- [(2-methoxy-ethyl) -methylamino] -but-2-ynoic acid: mass spectrum (m / e): M-H 170.

EXAMPLE 23 Allyl-methyl-prop-2-ynyl-amine Propargyl bromide (33.4 g, 281 mmole) was added to a mixture of isopropyl-methyl-amine (20 g, 281 mmol) and cesium carbonate (90 g, 281 mmol) 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 ethyl 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 24 4- (Allyl-methyl-amino) -but-2-ynoic 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 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 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 25 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 water were added dropwise. propargyl alcohol for 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. The 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 over 15 minutes. Stirring was continued for another 1.5 hr. Dry carbon dioxide was allowed to pass over the surface of the reaction mixture with stirring while it was heated to -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 26 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 stirred vigorously, and 15.77 g (0.05 mmol) of finely powdered barium hydroxide was added portionwise 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 va cuo. 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 27 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 dropwise 10 g. (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 (electroretrocity, m / e, negative mode): M-H 156.8.

Example 28 4- (Methoxymethoxy) -but-2-ynoic acid To a suspension of 8.2 g (205 mmol) of 60% sodium hydride in 271 ml of tetrahydrofuran 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 | 4mm) 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 was added 34.1 ml (85.3 mmoles) of 2.5M n-butyl lithium solution in hexanes, 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 29 4- ((2S) -2-Methoxymethylpyrrolidin-1-yl) butynoic acid solution of N-butyllithium 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 in 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 suspended 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 (electropartum, m / e): M + H 198.0 .

Example 30 (2S) -2-Methoxymethyl-1-prop-2-ynylpyrrolidine A mixture of 4.82 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 (electropartic, m / e): 153.8.

Example 31 4- (1,4-Dioxa-8-azaspiro [, 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 mmoles) of 3- (1,4-dioxa-8-azaspiro [4, 5] dec-8-yl) but-2-ina in 185 mL of THF at -78 ° C under N2. After stirring at -78 ° C for 1 h, CO 2 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 (electrorrocio, m / e): M + H 225.8.

Example 32 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 of masses (electrorrocio, m / e): M + H 181.8.

EXAMPLE 33 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 34 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 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-dimethylaminomethylamino) -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-tolerance, m / e) M + H 307.

Example 35 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 evaporated 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 (electrorrocio, m / e) M + H 325.

EXAMPLE 36 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 (IM 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 unreacted material) 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 / methanol / acetone. Purification of this residue was carried out using silica gel chromatography, 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 (electrorrocio, m / e) M + H 235.2.

EXAMPLE 37 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 silica gel chromatography, 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 38 4-Chloro-7-methoxy-quinoline-3-carbonitrile A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile and 8.3 g (40 mmol) ) of phosphorus pentachloride was heated at 165 ° C for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was mixed with brine and dilute sodium hydroxide solution and extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered through a pad of silica gel to give 3.7 g of 4-chloro-7-methoxy-quinoline-3-carbonitrile as a white solid: mass spectrum (electroretrocity, m / e ) M + H 218.9.

Example 39 3-Carbetoxy-4-hydroxy-, 7-dimethoxyquinoline A mixture of 30.6 g of 4-aminoveratrol and 43.2 g of ethyl ethoxymethylenemalonate was heated at 100 ° C for 2 hours and at 165 ° C for 0.75 h. The intermediate thus obtained was dissolved in 600 ml of diphenyl ether, and the resulting solution was heated at reflux temperature for 2 h, cooled, and diluted with hexane. The resulting solid was filtered, washed with hexane followed by ether, and dried to give the title compound as a brown solid, mp 275-285 ° C.

Example 40 3-Carbetoxy-4-chloro-6,7-dimethoxy-quinoline A mixture of 28.8 g of 3-carbethoxy-4-hydroxy-6,7-dimethoxy-quinoline and 16.6 ml of phosphorus oxychloride was stirred at 110 ° C for 30 minutes , it was cooled to 0 ° C and treated with a mixture of ice and ammonium hydroxide. The resulting gray solid was filtered, washed with water and ether, and dried, mp 147-150 ° C.

EXAMPLE 41 Ethyl 2-cyano-3- (3, 4-dimethoxyphenylamino) acrylate A mixture of 7.66 g of 4-aminovaratrol, 8.49 g of ethyl ethoxymethyleneacetate, and 20 ml of toluene was heated at 100 ° C for 90 minutes. The toluene was evaporated to give a solid, mp 150-155 ° C.

Example 42 1,4-Dihydro-6,7-dimethoxy-4-oxo-quinoline-3-carbonitrile A mixture of 40 g of ethyl 2-cyano-3- (3,4-dimethoxyphenylamino) acrylate and 1.2 L of Dowthern ® A was refluxed for 10 h, cooled, and partitioned with hexane. The resulting solid was filtered, washed with hexane, followed by dichloromethane, and dried; mp 330-350 ° C (decomposition).

Example 43 4-Chloro-6,7-dimethoxy-quinoline-3-carbonitrile A mixture, with stirring, of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-quinoline-3-carbonitrile and ml of phosphorus oxychloride was refluxed for 2 hours, cooled, and evaporated free of volatile matter. The residue was stirred at 0 ° C with dichloromethane-water as solid sodium carbonate was added until the aqueous layer had a pH of 8. The organic layer was separated, washed with water, dried and concentrated. Recrystallization of dichloromethane gave a solid, mp 220-223 ° C.

Example 44 Methyl 2- (dimethylaminomethyleneamino) benzoate To a solution, with stirring, of 7.56 g of methyl anthranilate in 50 ml of dimethylformamide at 0 ° C was added 5.6 ml of phosphorus oxychloride for 15 m. The mixture was heated to 55 for 45 m, cooled to 0, and diluted with dichloromethane. The mixture was gassed at 0 ° C by the slow addition of cold INN NaOH to pH 9. The dichloromethane layer was separated, washed with water, dried and concentrated to an oil.

Example 45 1,4-Dihydro-4-oxo-quinoline-3-carbonitrile A mixture, with stirring, of 1.03 g of ethyl 2- (dimethylaminomethyleneamino) benzoate, 0.54 g of sodium methoxide, 1.04 ml of acetonitrile, and ml of toluene was refluxed for 18 h. The mixture was cooled, treated with water, and brought to pH 3 by the addition of dilute HCl. The resulting solid was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from tanol to give a solid, mp 290-300 ° C.

Example 46 4- (3-Chloro-propoxy) -5-methoxy-benzoic acid methyl ester A mixture of 102.4 g (411.7 mmoles) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmoles) of methyl ester 4-hydroxy-5-methoxy-benzoic acid, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricaprylammonium chloride in 900 ml of acetone were stirred rapidly under reflux for 18 hr. The mixture was filtered and the solvent was removed to give 106 g of the title compound after recrystallization of a chloroform-hexane mixture.

Example 47 4- (2-Chloro-ethoxy) -5-methoxy-benzoic acid methyl ester Using a method identical to that of Example 46, 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 were converted g of 2-chloroethyl p-toluene sulfonate, 77.7 g of potassium carbonate and 1.7 g (4.1 mmol) of methyl-tricaprylammonium chloride at 91.6 of the title compound: mass spectrum (electropartum, m / e): M + H 245.0.

Example 48 4- (3-Chloro-propoxy) -5-methoxy-2-nitrobenzoic acid methyl ester To a solution of 100 g (386.5 mmoles) of 4- (3-chloro-propoxy) methyl ester - 5-methoxy-benzoic acid in 300 ml of acetic acid was added dropwise to 100 ml of 70% nitric acid. The mixture was heated at 50 ° C for 1 hr and then poured into ice water. The mixture was extracted with chloroform. The organic solution was washed with dilute sodium hydroxide and then dried over magnesium sulfate. The solvent was removed. Ether was added and the mixture was stirred until a solid was deposited. The solid was collected by filtration giving 98 g of 4- (3-chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester as white crystals: mass spectrum (electroretrocity, m / e): M + H 303.8; 2M + NH2 623.9.

Example 49 4- (2-Chloro-ethoxy) -5-methoxy-2-nitrobenzoic acid methyl ester Using an identical method as in Example 48, 85 g of 4- (3-chloro) methyl ester were nitrated. -ethoxy) -5-methoxy-2 ^ benzoic to give 72 g of the title compound: mass spectrum (electro-tolerance, m / e): 2M + NH2 595. 89 Example 50 2-Amino-4- (3-chloro-propoxy) -5-methoxy-benzoic acid methyl ester A mixture of 91 g of (299.6 mmol) of 4- (3-chloro-propoxy) methyl ester - 5-methoxy-2-nitro-benzoic and 55.2 g (988.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 60.1 g of ammonium chloride, 500 ml of water, and 1300 ml of methanol for 5.5 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solvent was removed and the residue mixed with 300 ml of 2: 1 ether-hexane. After standing, 73.9 g of the title compound were obtained as a pink solid: mass spectrum (electroretrocity, m / e): 2M + HC1 + H 511.0; M + H 273.8.

Example 51 2-Amino-4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester A mixture of 68.2 g (235.4 mmoles) of 4- (2-chloro-ethoxy) -5 methyl ester -methoxy-2-nitro-benzoic acid and 52.6 g (941.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 62.9 g of ammonium chloride, 393 ml of water, and 1021 ml of methanol for 15 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solution was concentrated to 200 ml and diluted with 250 ml of hot hexane. After standing 47.7 g of the title compound were obtained as a solid: mass spectrum (electroretrocity, m / e): M + H 259.8.

Example 52 7- (2-Chloro-ethoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile A mixture of 25 g (96.3 mmol) of 4- (2-chloro-ethoxy) -5 methyl ester -methoxy-benzoic acid and 17.2 g (144.4 mmol) of dimethylformamide dimethylacetal were heated at reflux for 1.5 hr. The excess reagents were removed under reduced pressure leaving 30.3 of residue, which were dissolved in 350 ml of tetrahydrofuran. In a separate flask, to a solution, with stirring of 80.9 ml of n-butyl lithium 2.5M in hexane in 300 ml of tetrahydrofuran at -78 ° C, 8.3 g (202.1 mmoles) of acetonitrile were added dropwise during 40 minutes. 30 minutes later, the above amidine solution was added dropwise for 45 minutes at -78 ° C. 1 hr later, 27.5 ml of acetic acid were added and the mixture was allowed to warm to room temperature. The solvent removed and water was added. The solid was collected by filtration and washed with water and ether. After drying in va cuo, 18.5 g of the title compound was obtained as a brown powder: mass spectrum (electroretrocity, m / e) M + H 278.8.

Example 53 7- (3-Chloro-propoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile Using the method of Example 52 and starting with 6.01 g of the corresponding amine, 1.58 g of acetonitrile, and 15.25 ml of n-butyl lithium solution, 3.7 g of the title compound was obtained as a brown powder: mass spectrum (electro-tolerance, m / e) M + H 292.8; 2M + H 584.2.

Example 54 7- (3-Chloro-propoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile A mixture of 3.5 g (12 mmol) of 7- (3-chloro-propoxy) -4-hydroxy-6 -methoxy-quinoline-3-carbonitrile and 28 ml of phosphorus chloride were refluxed for 1.5 hr. The excess reagent was removed under reduced pressure. The residue was mixed with dilute sodium hydroxide cooled with ice and ethyl acetate. The mixture was extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and filtered through a short column of silica gel. The solvents were removed giving 3.2 g of the title compound as a pink solid which was used with further purification.

Example 55 7- (2-Chloro-ethoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile A mixture of 8 g (28.7 mmol) of 7- ('2-chloro-ethoxy) -4-hydroxy- 6-methoxy-quinoline-3-carbonitrile and 18.2 g (143.5 mmol) of oxalyl chloride in 80 ml of methylene chloride containing 0.26 g of dimethylformamide were stirred under reflux for 2.5 hr. The solvent was removed. The residue was mixed with dilute sodium hydroxide cooled and extracted several times with ethyl acetate and tetrahydrofuran. The combined extracts were dried over magnesium sulfate and the solution was passed through a column of short silica gel. The solvents were removed giving 6.0 g of the title compound as a white matte solid which was used without further purification.

Example 56 4-Chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile A mixture of 7.95 g (32.6 mmoles) of 6-ethoxy-7- (methoxy) -4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 mL of phosphorus oxychloride was refluxed for 3h 40 min.

The phosphorus oxychloride was removed in vacuo and the residue was suspended with ice water. Solid NaHCO3 was added (pH8) and the product was collected by filtration, washed well with water and dried in vacuo (40 ° C). The yield was 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile as a brown solid: mass spectrum (electroretrocity, m / e): M + H 262.8, 264.8.

Example 57 6-Ethoxy-7-methoxy-4-oxo-l, 4-dihydroquinoline-3-carbonitrile A solution of 10.2 g (45.3 mmol) of methyl 2-amino-5-ethoxy-4-methoxy benzoate and 10.8 g (90.7 mmol) of dimethylformamide dimethyl acetal in 50 mL of dimethylformamide was refluxed for 3 h. The volatile material was removed and the residue made azeotropic with toluene and dried in vacuo to give formamidine as a purple syrup. N-Butyllithium (100 mmol) in hexane was diluted with 60 mL of tetrahydrofuran at -78 ° C. A solution of 4.18 g was added (102 mmoles) of acetonitrile in 80 ml of tetrahydrofuran for 15 minutes and the solution was stirred for 20 minutes. The crude formamidine was dissolved in 80 mL of tetrahydrofuran and added dropwise to the cold solution for 0.5 h. After stirring for 2 h, the reaction was cooled or stopped at -78 ° C with 13 mL of acetic acid. This was allowed to warm to room temperature and the volatile material was removed in va cuo. The residue was suspended with water and the crude product was collected by filtration, washed with water and dried. This material was then washed with chloroform and dried to give 7.95 g of 6-ethoxy-7-methoxy-4-oxo-l, 4-dihydroquinoline-3-carbonitrile as yellow crystals: mass spectrum (electroretrocity, m / e) : MH 243.2.

Example 58 Methyl 2-Amino-5-ethoxy-4-methoxybenzoate A mixture of 17.0 g (66.7 mmoles) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmoles) of pulverized iron and 17.7 g. g (334 mmol) of ammonium chloride in 95 mL of water and 245 mL of methanol was refluxed for 4.5 h. 13.1 g of additional iron were added followed by reflux for 2.5 h. Then 13.1 g of additional iron and 17.7 g of additional ammonium chloride were added and the mixture was refluxed for 12 h. The reaction was filtered through Celite and the methanol was removed from the filtrate. The filtrate was extracted with chloroform and the extracts were treated with Darco, evaporated and dried in va cuo (50 ° C). The yield was 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate as brown crystals: mass spectrum (electroretrocity, m / e): M + H 225.9.

Example 59 Methyl 5-ethoxy-4-methoxy-2-nitrobenzoate A mixture of 15.0 g (74.1 mmoles) of methyl 3-ethoxy-4-methoxybenzoate in 45 mL of acetic acid was treated with 15 mL of concentrated nitric acid, drip, for 12 min. The reaction was maintained at 55 ° C for 45 min, cooled to 25 ° C and poured into ice water. The product was extracted into methylene chloride and the extracts were washed with water and dilute sodium hydroxide, dried and evaporated. The yield was 17.8 of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate as yellow crystals: mass spectrum (electroretrocity, m / e): M + H 256.0.

EXAMPLE 60 Methyl 3-Ethoxy-4-methoxybenzoate A mixture of 24.3 g (143 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhydrous potassium carbonate and 31.4 g (201 mmol) of ethyl iodide in 500 mL of dimethylformamide was stirred at 100 ° C for 5.5 h. An additional amount of ethyl iodide (31.4 g) and potassium carbonate (18.4 g) was added and heating continued for a further 2 h. The reaction was filtered and the volatile material was removed from the filtrate in va cuo. The residue was suspended with water and filtered to collect the product, which was washed with water and dried. Recrystallization of heptane removed 15.6 g of methyl 3-ethoxy-4-methoxybenzoate as white crystals: mass spectrum (electroretrocity, m / e): M + H 210.9.

Example 61 Methyl 3-hydroxy-4-methoxybenzoate A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 mL of concentrated sulfuric acid in 600 mL of methanol was refluxed overnight. The majority of the solvent was removed and the remaining solution was poured into 600 mL of water containing 25 g of sodium bicarbonate. The product was extracted in ether, treated with Darco, dried and evaporated. The yield was 31.8 g of methyl 3-hydroxy-4-methoxybenzoate as pale yellow crystals.

EXAMPLE 62 N '- [2-Carbetoxy-4,5-bis (2-methoxyethoxy) phenyl] -N, N-dimethylformamide To a solution, with stirring, of 15.7 g (50 mmol) of 2-amino-4, 5 ethyl bis (2-methoxyethoxy) benzoate (WO-96130347) in 50 ml of DMF at 0 ° C was added phosphorus oxychloride (5.6 ml, 60 mmol) for 15 m. The resulting solution was heated at 55 ° C for 45 m, cooled, diluted with methylene chloride and treated at 0 ° C with 200 ml of sodium hydroxide N / l for 2 m. The organic layer was separated and washed at 0 ° C with water. The solution was dried and evaporated with the added toluene to give 18.4 g of amber oil; NMR (CDC13) d 3.02 (s, Me2N).

Example 63 1,4-Dihydroquinolin-5,6-bis (2-methoxyethoxy) -3-carbonitrile To a solution, with stirring, of n-butyllithium (44 ml of 2.5 M in hexane, 110 mmol) in 65 ml of THF at -78 ° C was added a solution of acetonitrile (5.85 ml, 112 mmol) in 110 ml of THF for 10 minutes. After stirring at -78 ° C for 15 minutes, the mixture was treated with solution of N '- [2-carbethoxy-4,5-bis (2-methoxyethoxy) phenyl] -N, N-dimethylformamide in 75 ml of THF during 20 minutes. After 30 minutes at -78 ° C the stirred mixture was treated with acetic acid (14.3 ml, 250 mmol). The mixture was heated to 25 ° C and stirred for 2 h. The mixture was evaporated to dryness, and diluted with water. The resulting white solid was filtered, washed with water, dried to give 10.7 g; mass spectrum (electrorrocio, m / e) M + H 319.2 Example 64 4-Chloro-5,6-bis (2-methoxyethoxy) -quinolin-3-carbonyl trile A mixture, with stirring, of 1,4-dihydroquinolin-5,6-bis (2-methoxyethoxy) -3-carbonitrile (9.68 g, 30.4 mmol) of phosphorus oxychloride was refluxed for 1. 5 h. The resulting solution was concentrated under vacuum, and the residue was stirred with methylene chloride at 0 ° C as ice water and sodium carbonate was added until the pH of the mixture was 8-9. The organic layer was separated, washed with water, dried and concentrated to give a brown solid; mass spectrum (electroretrocity, m / e) M + H 337.1, 339.1.

Example 65 Methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) benzoate A mixture, with stirring of methyl isovalinate (22.6 g, 124 mmol), N- (3-chloropropyl) -morpholine (25.4 g, 155 mmol) potassium carbonate (18.8 g, 136 mmol) tetrabutylammonium iodide (0.92 g, - 2.5 mmol) and 248 ml of 2-butanone was refluxed for 20 h. The 2-butanone was evaporated, and the residue was stirred with water at 0 ° C. The resulting white solid was filtered, washed successively with water and hexane, and dried; mp 90-94 ° C.

Example 66 Methyl 4-methoxy-5- (3-morpholin-4-yl-propoxy) -2-nitrobenzoate To a solution, with stirring of 4-methoxy-3- (3-morpholin-4-yl-propoxy) benzoate of methyl (30.9 g, 100 mmol) in 100 ml of acetic acid at 25 ° C was added 50 ml of 70% nitric acid for 30 m. The solution was heated to 45 ° C, at which point the reaction started and remained on its own at that temperature. After a total of 1.5 h at 45-50 ° C the mixture was cooled to 0 ° C, treated with ice water and 240 g (1.75 mol) of potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give a yellow solid, mp 78-82 ° C.

Example 67 Methyl 2-amino-4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate A solution of 4-methoxy-5- (3-morpholin-4-yl-propoxy)) -2- Methyl nitrobenzoate (32.5 g, 91.7 mmol) in 110 ml of methanol and 220 ml of ethyl acetate was hydrogenated at 55 psi (379.2 kPa) in the presence of 2.0 g of 10% Pd on carbon catalyst at 25 ° C. After 4 h the mixture was filtered, and the filtrate was evaporated to dryness. The residue was recrystallized from acetone-hexane to give a brown solid, mp 78-82 ° C.

Example 68 Ethyl 2- (dimethylaminomethyleneamino) -4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate A mixture of 2-amino-4-methoxy-5- (3-morpholin-4-yl- methyl propoxy) benzoate 6.49 g, 20 mmol) and dimethylformamide dimethyl acetal (4.25 ml, 30 mmol) was heated at 100 ° C for 1.5 h. All volatile materials were evaporated directly at 70 ° C to give a syrup; mass spectrum (electrorrocio, m / e) M + H 380.5.

Example 69 1,4-Dihydroquinolin-7-methoxy-6- (3-morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile To a solution, with stirring of n-butyllithium (17.6 ml of 2.5 M in hexane, 44 mmol) in 26 ml of THF at -78 ° C was added a solution of acetonitrile (1.85 ml, 45 mmol) in 44 ml of THF for 10 m. After stirring at -78 ° C for m, the mixture was treated with a solution of ethyl 2- (dimethylaminomethylamino) -4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate (7.6 g, 20 mmol) in 30 ml of THF during m After 90 m at -78 ° C the mixture was treated with carbon dioxide while heating slowly until ° C and then evaporated to dryness. The residue was partitioned with n-butanol (200 ml) and half-saturated NaCl solution (40 ml). The organic layer was separated, washed with saturated NaCl solution, and evaporated to dryness. The resulting solid was triturated successfully with boiling acetone and methane, filtered, and dried to give a brown solid, mp 255-260 ° C.

Example 70 4-Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile A mixture, with stirring, of 1-dihydroquinolin-7-methoxy-6- (3- morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile (4.75 g, 13.8 mmol), 0.10 ml of DMF, and 55 ml of thionyl chloride was refluxed for 3 h. The volatile matter was removed by evaporating at 30 ° C, and the residue was stirred at 0 ° C with a mixture of methylene chloride and water containing potassium carbonate to give a pH of 9-10. The organic layer was separated, washed with water, dried and concentrated to give a brown solid; mass spectrum (electro-tolerance, m / e) M + H 362.4, 364.4.

Example 71 4-Chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile 122 mg (0.50 mmol) of 7-ethoxy-1,4-dihydro-6-methoxy-4-oxo-quinoline-3 were mixed. carbonitrile and 2.0 ml of methylene chloride under N2 and kept at a temperature close to 25 ° C. 218 μl (2.5 mmoles) of oxalyl chloride and 10 μl (0.125 mmoles) of DMF were added. It was stirred overnight, diluted with chloroform and stirred in saturated sodium bicarbonate until gasified. The layers were separated and the organic products were dried with magnesium sulfate, the solvent was removed and dried in va cuo, giving 117 mg of brown solid: mass spectrum (electroretrocity, m / e): M + H 262.8, 264.8.

Example 72 7-Ethoxy-1,4-dihydro-6-methoxy-4-oxo-quinoline-3-carbonitrile 54.0 ml (135.mmoles) of n-butyl lithium were added to 150 ml of THF and cooled to -78 ° C under N2. 7.05 ml (135 mmoles) of acetonitrile in 200 ml of THF were added dropwise over 20 minutes. The mixture was stirred for 15 minutes and a solution of 17.99 g (64.2 mmol) of methyl 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate in 150 ml of THF was added dropwise over 20 minutes. It was allowed to stir for 0.5 hours at -78 ° C. 11.0 ml (193 mmol) of acetic acid were added and gradually heated to 25 ° C. After 2.5 hours, the solvent was removed, the residue was suspended with water, the solids were collected and dried in vacuo, yielding 13,025 g of yellow solid: mass spectrum (electroretrocity, m / e): M + H 245.2.

Example 73 Methyl 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate A mixture of 15,056 g (66.9 mmol) of methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 ml (100 mmol) of N , N-dimethylformamide dimethylacetal was heated at 100 ° C under N2. After 4.5 hours, 4.7 ml (33.3 mmoles) plus DMF / DMA were added and the heat was removed at 5 hours. The solvent was separated, made azeotrope with toluene, and dried in va cuo, giving 18,211 g of gray-brown solid: mass spectrum (electroretrocity, m / e): M + H 281.3.

Example 74 Methyl 2-amino-4-ethoxy-5-methoxybenzoate A mixture of 24,110 g (94.5 mmol) of methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) of iron powder, 25.28 g (472 mmol) of ammonium chloride, 135 ml of water, and 350 ml of methanol were heated to reflux under N2. At both 3 and 5.5 hours the same amount of iron and ammonium chloride was added. The heat was stirred at 6.5 hours, ethyl acetate and saturated sodium bicarbonate were added, filtered through celite and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, dried with magnesium sulfate, the solvent was removed and dried in vacuo, yielding 17.594 g of pink solid: mass spectrum (electroretrocity, m / e): M + H = 226.2.

Example 75 Methyl 4-ethoxy-5-methoxy-2-nitrobenzoate 5.00 g (23.7 mmol) of methyl 4-ethoxy-3-methoxybenzoate were dissolved in 25 ml of acetic acid under N2 and 6.1 ml (95.1) were added dropwise. mmoles) of 69% nitric acid for 30 minutes. They were heated at 50 ° C for 1.5 hours and poured over an ice bath. They were extracted with chloroform, dilute sodium hydroxide solution was washed and filtered through magnesium sulfate. The solvent was removed and dried in vacuo to give 5.268 g of white off-white solid: mass spectrum (electro-iron, m / e): M + H 225.8.

EXAMPLE 76 Methyl 4-ethoxy-3-methoxybenzoate A mixture of 25.0 g (137 mmol) of methyl vanillate, 38.87 g (274 mmol) of potassium carbonate, 500 ml of DMF, and 16.5 ml (206 mmol) of ethyl iodide was heated to 100 ° C under N2. After 2.5 hours, the solids were cooled and removed. The solvent was removed, and partitioned between water and methylene chloride. The solvent was removed and dried in vacuo to give 25.85 g of white solid, mass spectrum (El, m / e): M = 210.0.

Example 77 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. at 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 of the ethanol removed. The mixture was cooled to 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 (electrorrocio, m / e): M + H 214.7.

Example 78 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile To a suspension of 5 g (23 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 reduced 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 fine solid; mass spectrum (electrorrocio, m / e) M + H 259.8.

Example 79 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 (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 with dilute cold sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed yielding 2.1 g of persimmon solid: mass spectrum (electroretrocity, m / e) M + H 277.7.

Example 80 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 (ethoxymethylene) cyanoacetate ethyl was heated in 100 ml of Dowther at 120 ° C overnight and at 180 ° C for 20 hours. To this mixture was added 300 ml of Dowther. The solution was stirred and refluxed under nitrogen for 12 hours with periodic distillation of the ethanol removed. The mixture was cooled to room temperature and the solid was collected and washed with hexane. The crude solid was treated with boiling ethanol and then filtered to give 12 g of brown solid: mass spectrum (electroretrocity, m / e): M + H 245.8.

Example 81 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 solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed yielding 2.05 g of brown solid: mass spectrum (electroretrocity, m / e) M + H 263.7.

EXAMPLE 82 4-Hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile A mixture of 4.82 g of methyl 3, 5-trimethoxyanthranilate in 20 ml of N, N-dimethylformamide dimethyl acetal was refluxed for 18 hours. hours and concentrated in va cuo. The crude amidine product was used in the next step without further purification. To 25 ml of tetrahydrofuran at -78 ° C was added 17.6 ml of n-butyllithium 2.5M in hexane. Then 2.35 ml of acetonitrile in 45 ml of tetrahydrofuran were added dropwise. The mixture was stirred at -78 ° C for 15 minutes. A solution of the crude amidine in 30 ml of tetrahydrofuran was then added dropwise. The mixture was stirred at -78 ° C for 30 minutes, then 5.7 ml of acetic acid was added. The mixture was warmed to room temperature, and 100 ml of water was added. The product was collected, washed with water, and dried to give 4.14 g of 4-hydroxy-6,7, 8-trimethoxy-quinolin-3-cranonitrile as a solid, mp 280 ° C (decomposition); mass spectrum (electropartic, m / e): M + H 261.2 Example 83 4-Chloro-6, 7, 8-trimethoxy-quinoline-3-carbonitrile A mixture, with stirring, of 1.30 g of 4-hydroxy-6, 7, 8-trimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorus oxychloride, and 1 drop of N, N-dimethylformamide was refluxed for 10 minutes and evaporated free of volatile matter. The residue was stirred with 20 ml of 5% methyl alcohol in ethyl acetate. The product was collected and dried to give 1.12 g of 4-chloro-6,7, 8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 161-163 ° C; mass spectrum (El, m / e): M 278.0452.

EXAMPLE 84 2- (Dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester A mixture of 3.46 g of 2-amino-3,6-dimethoxybenzoic acid (Manouchehr Azadi-Ardakani and Timothy W. Wallace, Tetrahedron, Vol. 44, No. 18, pp. 5439 to 5952, 1988) in 20 ml of N, N-dimethylformamide dimethyl acetal was refluxed for 18 hours and concentrated in vacuo. To the residue was added 180 ml of ethyl acetate. The mixture was filtered, and 200 ml of hexane was added to the filtrate. The mixture was then concentrated to 100 ml. The product was collected and dried to give 3.25 g of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester as a solid, mp 81-83 ° C; mass spectrum (El, m / e): M 266.1263.

Example 85 4-Hydroxy-5, 8-dimethoxy-quinoline-3-carbonitrile To 12.5 1 of tetrahydrofuran at -78 ° C was added 8.8 ml of n-butyllithium 2.5M in hexane. Then 1.18 ml of acetonitrile in 25 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78 ° C for 15 minutes. Then a solution of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ether in 62 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78 ° C for 10 minutes, then warmed to room temperature in 15 minutes. Acetic acid (3 ml) was added, followed by 200 ml of water. The product was collected, washed with water, and dried to give 1.57 of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 300-305 ° C; mass spectrum (El, m / e): M 230.0685.

Example 86 4-Chloro-5, 8-dimethoxy-quinoline-3-carbonitrile A mixture, with stirring, of 1.30 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorus oxychloride, and 2 drops of N, N-dimethylformamide was refluxed for 10 minutes and evaporated free of volatile matter. The residue was stirred with 50 ml of water. The product was collected and dried to give 1.74 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 165-167 ° C; mass spectrum (El, m / e): M 248.0346.

Example 87 Methyl 2- (dimethylaminoethyleneamino) -4,5-diethoxybenzoate To a solution, with stirring, of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 ml of DMF at 0 ° C. phosphorus oxychloride (2.24 ml, 24 mmol) was added for 15 m. The mixture was heated to 55 ° C and stirred for 45 m. The resulting solution was diluted with methylene chloride, cooled to 0 ° C, and treated with 80 ml of sodium hydroxide N / l precooled for 5 m. The organic layer was separated and washed at 0 ° C with water. The solution was dried and concentrated to give an amber oil; NMR (CDC13) d 3.00 (s, Me2N).

EXAMPLE 88 1,4-Dihydroquinolin-6,7-diethoxy-4-oxo-3-carbonitrile To a solution, with stirring of n-butyllithium (17.6 ml of 2.5 M in hexane, 44 mmole) in 25 ml of THF a- At 78 ° C, a solution of acetonitrile (2.35 ml, 45 mmol) in 44 ml-of THF for 10 m was added. After stirring at -78 ° C for 15 m, the mixture was treated with a solution of ethyl 2- (dimethylaminomethyleneamino) -4,5-diethoxybenzoate (5.83 g, 19.8 mmol) in 30 ml of THF for 30 m. After 30 m at -78 ° C the mixture was treated with 5.5 ml (100 mmol) of acetic acid and evaporated to dryness. The residue was stirred in water, and the resulting precipitate was filtered, washed with water and dried to give 4.01 g of white off-white solid; NMR (DMSO-d6) d 8.58 (s, 2-H).

Example 89 4-Chloro-6,7-diethoxy-quinoline-3-carbonitrile In the manner described in Example 64, the treatment of 1,4-d-hydroquinoline-6,7-diethoxy-4-oxo-3-carbonitrile with phosphorus oxychloride gave the title compound as a pink solid, proliferation 170-175 ° C.

EXAMPLE 90 2- (Dimethylamino-methyleneamino) -3-methoxy-benzoic acid methyl ester A reaction mixture of 5.0 g (29.9 mmol) of 2-amino-3-methoxy-benzoic acid in 25.0 mL of DMF-DMA was heated at 100-105 ° C for 2.5 hr, and then the solvent was removed to give a viscous red-purple oil. After standing in a refrigerator, the oil solidified to give 5.8 of the product compared a red-purple solid with a yield of 82.8%, mass spectrum (electroretrocity, m / e): M + H 236.9.

Example 91 1, 4-Dihydro-8-methoxy-4-oxo-quinoline-3-carbonitrile To 35.0 ml of THF were added 26.6mL (66.4 min) of n-BuLi solution for 5 minutes at -78 [deg.] C. To the solution - with stirring, a solution of 3.55 mL (67.9 mmoles) of CH3CN in 65 mL of THF was added for 10 minutes, at which time the solution was converted to a white suspension, and then stirring continued for 15 minutes at -78 ° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2- (dimethylaminomethyleneamino) -3-methoxy-benzoic acid methyl ester in 45 mL of THF for 30 minutes, and then continued stirring for 30 minutes at -78. ° C, during which time the mixture gradually became clear. The solution was cooled with 8.5 mL of HOAc. The resulting sticky suspension was stirred and heated to room temperature. After the majority of the solvent was evaporated, the residue was diluted with cold water. The separated solid was collected by filtration and washed with water. After drying in vacuo, this gave 3.8 g of the product as a matt white solid with a yield of 77.6%, mp 270 ° C (decomposition), mass spectrum (electro-tolerance, m / e): M + H 201.1.

EXAMPLE 92 4-Chloro-8-methoxy-quinoline-3-carbonitrile A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carbonitrile and 40 mL of oxychloride of - Phosphorus and 5 drops of DMF was refluxed for 0.5 hours. The mixture was evaporated to dryness and diluted with hexane. The solid was collected and mixed with dilute cold sodium carbonate solution and extracted several times with ethyl acetate. The organic layer was dried over sodium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 3.8"g of 4-chloro-8-methoxy-quinoline-3-carbonitrile as a matt white solid with a yield of 91%, mass spectrum (electroretrocity, m / e): M + H '219.1 .

Example 93 4-Chloro-7-methoxy-quinoline-3-carbonitrile In the manner of Example 64 the treatment of 1,4-dihydroquinolin-7-methoxy-4-oxo-3-carbonitrile with phosphorus oxychloride gave the title compound as a brown solid: mass spectrum (electrorrocio, m / e) M + H 219.2, 221.2.

Example 94 7-Benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile To a solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF at -78 ° C was added 3.51 ml of acetonitrile in 20 ml of THF for 10 min. After stirring at -78 ° C for 30 minutes, the mixture was treated with 10 g of L17741-150 (B. Floyd) in 20 ml of THF for 5 min. After 15 minutes at -78 ° C the mixture, with stirring, 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 matte solid, decomposition a >255 ° C; mass spectrum (electro-tolerance, m / e) M + H 307.

Example 95 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 (2M 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 it stopped bubbling. After separation of the layers, the organic layer was evaporated to a small volume, then passed through a magnesium plug. 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-tolerance, m / e) M + H 325.

Example 96 4- (2,3-Dihydro-lH-indol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile To a solution of 400 mg (1.4 mM) of 4-chloro-6,7- diethyl-quinoline-3-carbonitrile in 258 g (1.88 mM) of the 6-Aminoindoline dihydrochloride salt in 10 ml of ethanol was refluxed for 2 hours. To the hot solution was added 1 ml of iM-sodium carbonate and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water, followed by ether and dried under vacuum at 80 ° C. The solid was dissolved in 50/50 methanol / chloroform and dried over silica gel and purified by chromatography using a gradient from 20% to 50% acetone in hexane to yield 496 mg of the title compound as a brown solid: masses (electroretrocity, m / e): M + H 375.1, mp = 121-124 ° C.

Example 97 or • HCl salt of 4- (benzothiazol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 500 mg (1.8 mM) of 4-chloro-6,7-diethoxy-quinoline -3-carbonitrile and 353 mg (2.35 mM) of 6-aminobenzothiozole in 15 ml of ethanol was refluxed for 3 hours. To the hot solution 2 drops of concentrated HCl were added and the sample was heated for 5 minutes at 100 ° C, then a solid was isolated by filtration. The solid was removed in 20 ml of ethanol and digested for 1 hour. The hot solution was filtered and the isolated solid was washed with ethanol and dried under vacuum at 80 ° C to yield 666 mg of HCl salt of 4- (benzothiazol-6-ylamino) -6,7-diethoxy-quinolin-3- carbonitrile as a brown solid: mass spectrum (electrohority, m / e): M + H 391.0, mp = 285-287 ° C.

Example 98 4- (Benzo [l, 3] dioxo-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline -3-carbonitrile and 258 mg (1.88 mM) of 3,4- (methylenedioxy) aniline in 10 ml of ethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 526 mg of 4- (Benzo [1,3] dioxo-5-ylamino) -6,7-diethoxy-quinolin-3-. carbonitrile as a brown solid: mass spectrum (electroretrocity, m / e): M + H 378.0, mp 200-203 ° C.

Example 99 6,7-Dietoxy-4- (lH-indazol-6-ylamino) -quinolin-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 250 mg (1.88 mM) of 6-aminoindazole in 10 ml of ethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate and the sample was heated for 5 minutes to 100 ° C, then poured into 300 ml of ice water.

The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 448 mg of 6,7-Dietoxy-4- (1H-indazol-6-ylamino) -quinolin-3-carbonitrile as a solid. brown: mass spectrum (electroretrocity, m / e): M + H 374.1, mp 143-145 ° C.

Example 100 6,7-Dietoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylamino) -quinolin-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6, 7-diethoxy-quinoline-3-carbonitrile and 330 mg (1.88 mM) of 1-Amino-4-methyl-coumarin in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to produce 431 mg of 6,7-Dietoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylamino) - quinoline-3-carbonitrile as a brown solid: mass spectrum (electrohority, m / e): M + H 416.0, mp 282-284 ° C.

Example 101 6,7-Dietoxy-4- (lH-indol-6-ylamino) -quinolin-3-carbonitrile A solution of 964 mg (3.50 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 830 mg (6.29 mM) of 6-Aminoindole in 5 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 712 mg of 6,7-Dietoxy-4- (lH-indol-6-ylamino) -quinolin-3-carbonitrile as a solid. yellow: mass spectrum (electrorrocio, m / e): M + H 373.0, mp = 128 -130 ° C.

EXAMPLE 102 6,7-Dietoxy-4- (lH-indazol-6-ylamino) -quinolin-3-carbonitrile A solution of 500 mg (2.00 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 975 mg (2.61 mM) of 6-Aminoindazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 738 mg of the title compound as a brown solid: mass spectrum (electrorootium, m / e): M + H 345.9, pf = 180-183 ° C.

Example 103 4- (lH-Benzotriazol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 1.07 mg (3.87 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 675 mg (5.00 mM) of 5-Aminobenzotriazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solution was made acidic by the addition of concentrated HCl and the solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C. The solid was removed in 200 ml of methanol and 500 μl of 5 N sodium hydroxide and eluted for 20 minutes. To this heterogeneous mixture 100 ml of glacial acetic acid were added and the volume was reduced to a total of 100 ml by boiling. To the mixture at room temperature, 500 ml of cold ice water was added and the solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 738 mg of 4- (lH-Benzotriazole-5- ilamino) -6,7-diethoxy-quinoline-3-carbonitrile as a brown solid: mass spectrum (electropartum, m / e): M + H 375.0, pf = decomposes at 115 ° C.

EXAMPLE 104 4- (1, 3-DÍQXQ-2, 3-dihydro-lH-isoindol-5-ylamino) -6,7-diethoxyquinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro 6,7-diethoxy-quinoline-3-carbonitrile and 305 mg (1.88 mM) of 4-Aminophthalimide in 10 ml of ethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 348 mg of 4- (1,3-Dioxo-2,3-dihydro-lH-isoindol-5-ylamino) -6, 7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrohority, m / e): M + H 402.9, mp = 248-251 ° C.

Example 105 4- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6 , 7-diethoxy-quinoline-3-carbonitrile and 232 mg (1.54 mM) of 1,4-Benzodioxan-6-amine in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 526 mg of 4- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -6, 7- dietoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrohority, m / e): M + H 402.9, mp 225-227 ° C.

Example 106 4- (lH-Indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy) -quinolin-3-carbonitrile A solution of 400 mg (1.19 mM) of 4-chloro-6,7 - (2-methoxyethoxy) -quinolin-3-carbonitrile and 174 mg (1.31 mM) of 6-Aminoindazole in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 362 mg of 4- (lH-Indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy) - quinoline-3-carbonitrile as an orange solid: mass spectrum (electropartum, m / e): M + H 432.0, mp 105-110 ° C.

Example 107 4- (1, 4-Dioxo-l, 2,3,4-tetrahydro-phthalacin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4 -chloro-6,7-diethoxy-quinoline-3-carbonitrile and 273 mg (1.54 mM) of 4-Aminophthalhydrazide in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of Sodium carbonate and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solution was made acidic by the addition of concentrated HCl and the solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C. The solid was removed in 200 ml of methanol and 500 μl of 5 N sodium hydroxide and boiled for 20 minutes. To this heterogeneous mixture 100 ml of glacial acetic acid were added and the volume was reduced to a total of 100 ml by boiling. To the mixture at room temperature, 500 ml of cold ice water was added and the solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C. The solid was digested in 400 ml of ethanol until the volume was reduced to 150 ml. The hot solution was filtered and the solid was washed with ethanol and dried under vacuum at 80 ° C to yield 121 mg of the title compound as a white solid: mass spectrum (electroretrocity, m / e): M + H 418.0, mp > 270 ° C.

Example 108 6,7-Dietoxy-4- (indan-5-ylamino) -quinolin-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 205 mg (1.54 mM) of 5-Aminoindane in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C. The brown solid was dissolved digested in 200 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the hot solution and washed with ethanol followed by ether and dried under vacuum at 80 ° C to yield 435 mg of 6,7-Dietoxy-4- (indan-5-ylamino) -quinolin-3-carbonitrile as a brown solid: mass spectrum (electrorrocio, m / e): M + H 374.0, mp 85-88 ° C.

Example 109 4- (2,4-Dioxo-1,4-dihydro-2H-benzo [dj [1,3] oxacin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 274 mg (1.54 mM) of 5-Aminoisatonic Anhydride and 161 mg (1.44 mM) of pyridine hydrochloride in 15 ml of 2-methoxyethanol it was refluxed for 3 hours. The hot solution was filtered and the solid was washed with ethanol to dryness under vacuum at 60 ° C yielding 482 mg of the HCl salt of 4- (2,4-Dioxo-l, 4-dihydro-2H-benzo [d] [1,3] oxacin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile as a gray solid: mass spectrum (electroretrocity, m / e): M + H 418.9, pf > 270 ° C.

EXAMPLE 110 6,7-Dietoxy-4- (l-oxo-indan-5-ylamino) -quinolin-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinolin-3 -carbonitrile, 227 mg (1.54 mM) of 6-Amino-1-Indanone and 161 mg (1.44 mM) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 483 mg of 6,7-Dietoxy-4- (1-oxo-indan-5-ylamino) -quinolin-3-carbonitrile as a white solid: mass spectrum (electrorrocio, m / e): M + H 388.0, pf = Decomposed at 263 ° C.

Example 111 6,7-Dietoxy-4- (3-oxo-l, 3-dihydro-isobenzofuran-5-ylamino) -quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6,7 -dietoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of 6- Aminophthalide and 161 mg (1.44 mM) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours.

To the hot solution was added 1 ml of sodium carbonate IM and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C to yield 535 mg of 6,7-Dietoxy-4- (3-oxo-l, 3-dihydro-isobenzofuran-5-ylamino) - quinoline-3-carbonitrile as a white solid: mass spectrum (electrohority, m / e): M + H 390.1, mp = 280-284 ° C.

Example 112 4- (1, 1-Dioxo-lH-benzo [bj thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile A solution of 400 mg (1.44 mM) of 4-chloro-6, 7- diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of 6-Amino-1,1-dioxobenzo [b] thiophene and 161 mg (1.44 mM) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was subjected at reflux for 6 hours. To the hot solution was added 1 ml of sodium carbonate, and the sample was heated for 5 minutes at 100 ° C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 ° C. The solid was dissolved in acetone and dried on silica gel under high vacuum. Purification of the compound was obtained by chromatography using a gradient of 30% to 50% acetone in hexane. The first of the three components of the isolated mixture of the column was the desired product. Removal of the solvent by evaporation afforded 69 mg of 4- (1,1-Dioxo-lH-benzo [b] thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: masses (electrorrocio, m / e): M + H 421.9, pf ~ = I55-160 ° C.

Example 113 4- (2,3-Dihydro-lH-indol-6-ylamino) -6,7-methoxy-quinoline-3-carbonitrile A solution of 400 mg (1.61 mM) of 4-chloro-6,7-methoxy -quinolin-3-carbonitrile and 366 mg (1.77 mM) of 6-aminoindoline hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours. The hot solution was filtered to isolate the resulting solid, which was then washed with water followed by ether and dried under vacuum at 80 ° C. The solid was dissolved in methanol and chloroform one by one and dried on silica gel under high vacuum. Purification of the compound was obtained by chromatography using a gradient of 30% to 60% acetone in hexane. The first of the three components of the isolated mixture of the column was the desired product. The fractions from the column were reduced to a volume of 10 ml and then diluted with 250 ml of hexane. The resulting solid was isolated, washed with hexane and dried under vacuum at 80 ° C to give 16 mg of 4- (2,3-dihydro-lH-indol-6-ylamino) -6,7-diethoxy-quinolin-3-. carbonitrile as a brown solid: mass spectrum (electro-iron, m / e): M + H 347.0, mp 175 ° C.

Example 114 4- (lH-Indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml of ethanol, and 3.40 g (25.8 mmol) of 5-aminoindole was heated to reflux under N2 for 3.5 hours. The heat was removed, it was made basic with saturated sodium bicarbonate and the solvents were separated, making them azeotropic with ethanol. The solids were collected and washed with hexane, then water. The solids were dissolved in 200 ml of ethyl acetate, Darco added and filtered. The solvent was removed and dried in vacuo overnight (50 ° C). It was washed twice more with ether to remove the initial aminoindole material. 4,372 g of red-brown solid: mass spectrum (electro-tolerance, m / e): M + H 330.2.

Example 115 7-Ethoxy-4- (indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile A mixture of 500 mg (1.90 mmol) of 4-chloro-7-ethoxy-6-methoxy-quinoline-3 -carbonitrile, 30 ml of ethanol, and 304 mg (2.28 mmol) of 6-aminoindazole was heated to reflux , under N2 The heat was removed at 4 hours and made basic with saturated sodium bicarte. The solvents were removed, the residue was suspended with hexane, the solids were collected and dried. It was washed with water and dried in vacuo, yielding 546 mg of brown solid: mass spectrum (electroorphite, m / e): M + H 359.9.

Example 116 7-Benzyloxy-4-chloro-6-methoxy-quinolin-3-cartrile A total of 500 mg (1.63 mM) of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-cartrile was taken in ml of oxalyl chloride (2M in CHC13) and allowed to stand for 15 minutes followed by reflux for 1 h. The solution was allowed to cool and then diluted with 300 ml of hexane to give a green solid. The solid was isolated and washed with excess hexane and dried under vacuum at 40 ° C to yield 586 mg of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-cartrile as the hydrogen chloride salt. This compound was taken immediately for the next step.

Example 117 7-Benzyloxy-4- (2,3-dihydro-lH-indol-6-ylamino) -6-methoxy-quinoline-3-cartrile A solution of 586- mg (1.60 mM) of 7-benzyloxy-4- chloro-6-methoxy-quinoline-3-cartrile, 560 mg (1.70 mM) of 6-Aminoindoline dihydrochloride salt and 208 mg (1.80 mM) of pyridine hydrochloride in 13 ml of 2-methoxyethanol was refluxed for 3 hours. hours. The reaction was allowed to cool to room temperature and the resulting solid was isolated and washed with excess ethanol and dried under vacuum at 80 ° C. The resulting solid was digested in 300 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the hot solution and the digestion process was repeated a second time. The solid was again isolated from the hot solution to yield 206 mg of 7-benzyloxy-4- (2,3-dihydro-l-indol-6-ylamino) -6-methoxy-quinoline-3-cartrile as a brown solid.

EXAMPLE 118 4- (2,3-Dihydro-lH-indol-6-ylamino) -7-hydroxy-6-methoxy-quinoline-3-cartrile To 5 ml of trifluoroacetic acid were added 206 mg of 5-benzyloxy-4- (2,3-dihydro-lH-indol-6-ylamino) -6-methoxy-quinoline-3-cartrile and the reaction was refluxed for 1.5 h. The TFA was removed under vacuum and the resulting film was dissolved in 7 ml of methanol followed by the addition of 50 ml of ice-cold saturated sodium bicarte. The solution was allowed to stand at 10 ° C for 1 h. The resulting solid was isolated, washed with an excess of water and dried under vacuum at 80 ° C to yield 107 mg of 4- (2,3-dihydro-lH-indol-6-ylamino) -7-hydroxy-6-methoxy -quinolin-3-cartrile. This compound was taken directly in the next step without purification.

Example 119 4- (2,3-Dihydro-lH-indol-6-ylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-cartrile To a solution at 0 ° C which consisted of 2 ml of chloroform, 1 ml of tetrahydrofuran, 167 mg (0.64 mM) of triphenyl phosphine, 52 μl (0.40 mM) of 4-hydroxypropylpyridine and 107 mg (0.32 mM) of 4- (2,3-dihydro-) lH-indol-6-ylamino) -7-hydroxy-6-methoxy-quinoline-3-cartrile, 101 μL (0.64 mM) of DEAD was added slowly. The reaction was allowed to proceed at 0 ° C for 15 minutes and then allowed to warm to room temperature. The heterogeneous solution was allowed to stir at room temperature for 7 hours. The CCF and the ES MS showed no signs of product formation. An additional 1 ml of chloroform and 500 ml of tetrahydrofuran was added and the reaction was refluxed for 14 hours. Once again no signs of product formation were observed. The volume of the reaction was reduced to 1 ml by heating and then filling to 4 ml by the addition of tetrahydrofuran. Once the reaction had cooled to room temperature, and additional 80 mg (0.32 mM) of triphenyl phosphine was added, 25 μL (0.20 mM) of 4-hydroxypropylpyridine was added followed by the slow addition of 50 μL (0.32 mM) of DEAD. The reaction quickly turned into a light brown solution. After six hours at room temperature, the CCF and the mass spectrum showed that the reaction had been complete. 10 ml of IN HCl followed by 20 ml of water were added to the reaction mixture. The solution was extracted five times with 25 ml portions of chloroform. The aqueous layer was allowed to stand for 3 hours at room temperature and the resulting brown solid was isolated by filtration. The filtrate was treated with solid sodium bicarbonate until a yellow solid precipitated from the solution. The precipitate was isolated and washed with excess water followed by 1 ml of diethyl ether and dried under vacuum at 80 ° C to give 57 mg of 4- (2,3-dihydro-lH-indol-6-ylamino) -6 -methoxy-7- (3-pyridin-4-yl-propoxy) -quinolin-3-carbonitrile as a yellow solid: mass spectrum (electropartic, m / e): M + H 452.3, 226.7 M + 2H / 2 , mp = 100-105 ° C.

Example 120 2,3-Dihydro-benzo [1,4] dioxin-β-carboxylic acid methyl ester A solution of 19.6 g (109 mmol) of 2,3-dihydro-benzo [1,] dioxin-6-carboxylic acid (J. Chem. Soc., 3445, 1957) in 400 mL of MeOH containing 4 mL of H2SO4 was refluxed overnight. Sodium bicarbonate added (18 g), the solvent was removed and the residue was triturated seven times with Et20. The washings were combined, filtered through anhydrous MgSO4 and evaporated to yield 20.7 g of the title compound as a pale yellow oil: mass spectrum (electronic impact, m / e): 194.

Example 121 7-Nitro-2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid methyl ester Nitric acid (18 mL) was added dropwise to a solution of 15.0 g (77.3 mmol) of methyl ester of the acid ~ 2, 3-dih'i? ro > -benzo [1,4] dioxin-6-carboxylic acid in 45 mL of HOPAc. The solution was heated at 60 ° C for 1.5 h. Then an additional 9 ml of HN03 was added and heating was continued for 1.5 h at 70 ° C. The reaction was poured into ice-H20 and the solid product was collected, washed well with H20 and dried. Recrystallization of heptane-toluene produced 16.8 of the title compound as yellow crystals: mass spectrum (electronic impact, m / e): 239.

Example 122 Methyl ester of 7-amino-2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid A mixture of 12.0 g (50.2 mmoles) of 7-nitro-2,3-dihydro methyl ester -benzo [1,4] dioxin-6-carboxylic acid, 11.2 g (201 mmol) of pulverized Fe and 13.3 g (257 mmol) of NH4C1 in 175 mL of MeOH and 70 mL of H20 were refluxed for 5.5 h. An additional 11.2 g of Fe and 13.3 g of NH4C1 were added and the mixture was heated for an additional 5.5 h. Finally, 5.5 g of Fe and 6.5 g of NH 4 Cl were added and the mixture was heated for 4 h. The cold reaction was filtered through Celite, the pad washed well with MeOH and the filtrate and washings were combined. The solvent was removed and the residue was suspended in H20 and collected. The crude product was filtered through silica (CHC13) to give 9.5 g of the title compound as brown crystals: mass spectrum (electroretrocity, m / e): M + H 209.9.

Example 123 9-0x0-2, 3,6, 9-tetrahydro- [1,4] -dioxino [2, 3-g] quinoline-8-carbonitrile A solution of 9.71 g (46.5 mmol) of methyl ester of acid 7 amino-2, 3-dihydro-benzo [1,4] dioxin-6-carboxylic acid and 11.1 g (92.9 mmol) of dimethylformamide dimethyl acetal in 45 ml of DMF was refluxed under N2 for 6 h. The volatile material was removed and the residue was azeotroped with toluene and dried in vacuo to give formamidine as a purple syrup. The n-butyllithium (102 mmol) in hexane was diluted with 70 mL of THF at -78 ° C under N2. A solution of 4.31 g (105 mmol) of acetonitrile in 85 mL of THF was added over 15 minutes and the solution was stirred for 25 minutes. The crude formamidine was dissolved in 90 mL of THF and added dropwise to the cold solution for 0.5 h. After stirring for 1.25 h, the reaction was cooled to -78 ° C with 13.4 mL of acetic acid. This was allowed to warm to room temperature and the volatile material was removed in vacuo. The residue was suspended with H20 and the crude product was collected by filtration, washed with H20 and dried. The solid material was boiled with MeOH, harvested and dried in va cuo (50 ° C) to yield 7.62 g of the title compound as a brown powder: mass spectrum (electroretrocity, m / e): M + H 228.8.

Example 124 9-chloro-2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile A mixture of 7.06 g (31.0 mmol) of WAY 170839 and 35 mL of P0C13 was refluxed for 3.5 h. P0C13 was removed and ice-H20 was added followed by solid NaHCO3, pH 8. The product was harvested, washed well with H20 and dried in vacuo to yield 7.42 g of 9-chloro-2,3-dihydro [1, 4] dioxino [2, 3-g] quinoline-8-carbonitrile: mass spectrum (electroretrocity, m / e): M + H 246.8.

Example 125 9- (lH-Indazol-6-ylamino) -2,3-dihydro [1,4] dioxino [2, 3-g] quinoline-8-carbonitrile A mixture of 1.00 g (4.07 mmol) of 9-chloro -2,3-dihydro [1,4] dioxino [2, 3-g] quinoline-8-carbonitrile and 0.649 g (4.88 mmol) of 6-aminoindazole in 25 mL of EtOH was refluxed under N2 for 5.7 h. Saturated NaHCO3 was added and the solvent was removed. The residue was suspended with H20, filtered, washed with H20 and cold EtOH and dried. The crude product was boiled with EtOH, filtered and dried in vacuo (50 ° C) to yield 1.06 g of 9- (lH-indazol-6-ylamino) -2, 3-dihydro [1,4] dioxin [2]. , 3-g] quinoline-8-carbonitrile as brown crystals: mass spectrum (electroretrocity, m / e): M + H 344.3.

Example 126 6-Ethoxy-4- (lH-indazol-6-ylamino) -7-methoxyquinoline-3-carbonitrile A mixture of 1.00 g (3.82 mmoles) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.609 -g (4.58 mmoles) of 6-aminoindazole in 2o mL of EtOH was refluxed under N2 for 8 h. Saturated NaHCO3 was added, the solvent was removed and the residue was azeotroped twice with EtOH. The solid was suspended with cold EtOH, harvested, washed twice with H20 and dried. Recrystallization from EtOH yielded 0.646 g of 6-ethoxy-4- (lH-indazol-6-ylamino) -7-methoxyquinoline-3-carbonitrile as brown crystals: mass spectrum (electroretrocity, m / e): M + H 359.9 .

Example 127 6,7-Dietoxy-4- (1-methyl-2, 5-dioxo-2, 3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepin-7-ylamino) -quinolin -3-carbonitrile A mixture of .5 g (1.8 mmoles) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 0.35 g (1.8 mmoles) of 7-amino-1-methyl-2, 5- dioxo-2, 3,4, 5-tetrahydro-lH-benzo [e] [1,4] diazepine, and 0.21 g of pyridine hydrochloride was refluxed in ethoxyethanol for 5 hours. The solvent was removed under reduced pressure. The residue was stirred with ammonium hydroxide and the insoluble material was collected to give 0.8 g of the title compound as a brown solid, crystals: mass spectrum (electroretrocity, m / e): M + H 446.0.

Example 128 4- (lH-Indazol-6-ylamino) -6,7, 8-trimethoxy-quinoline-3-carbonitrile A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile , 0.147 g of 6-aminoindazole, 0.020 g of pyridine hydrochloride, and 15 ml of ethoxyethanol were stirred under nitrogen, at reflux temperature for 1 hour. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate at pH 9. The product was collected, washed with water and dried to give 0.332 g of 4- (lH-indazol-6-ylamino) -6,7,8-trimethoxy-quinolin-3. -carbonitrile as a solid, mp 243-245 ° C; mass spectrum (El, m / e): M 375.1331.

EXAMPLE 129 6,7-Dimethoxy-4- (4-methyl-2-oxo-l, 2-dihydro-quinolin-7-ylamino) -quinolin-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7 dimethoxy-quinoline-3-carbonitrile, 0.174 g of carboesteryl 124, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol were stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. Sodium carbonate was added to this mixture at pH 9. The product was collected, washed with water and dried to give 0.356 g of 6,7-dimethoxy-4- (4-methyl-2-oxo-1,2-dihydroxy). quinolin-7-ylamino) -quinolin-3-carbonitrile as a solid, mp; 300 ° C; mass spectrum (El, m / e): M 387.1446.

EXAMPLE 130 6, 7-Dimethoxy-4- (2-methyl-benzothiazol-5-ylamino) -quinolin-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole hydrochloride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. Sodium carbonate was added to this mixture at pH 9. The product was collected, washed with water and dried to give 0.356 g of 6,7-dimethoxy-4- (2-methyl-benzothiazol-5-ylamino) -quinolin-3. - carbonitrile as a solid, mp 118-120 ° C; mass spectrum (El, m / e): M 376.0973.

Example 131 6, 7-Dimethoxy-4- (2-oxo-2,3-dihydro-benzothiazol-6-ylamino) -quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3- carbonitrile, 0.166 g of 6-amino-2-benzothiazolinone, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust the pH to 7. The product was collected, washed with water and dried to give 0.326 g of 6,7-dimethoxy-4- (2-oxo-2, 3 -dihydro-benzothiazol-6-ylamino) -quinolin-3-carbonyl trity as a solid, mp 285-287 ° C; mass spectrum (electrorrocio, m / e): M + H 379.0858.

Example 132 6,7-Dimethoxy-4- (quinolin-5-ylamino) -quinolin-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 5- aminoquinoline 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200 ° C for 2 'hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate at pH 9. The product was collected, washed with water and dried to give 0.132 g of 6,7-dimethoxy-4- (quinolin-5-ylamino) -quinolin-3-carbonitrile -like a solid, mp 115 ° C (decomposed); mass spectrum (El, m / e): M 356.1276.

Example 133 4- (Isoquinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 5- aminoisoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol were heated under nitrogen in a sealed tube at 200 ° C for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate at pH 9. The product was collected, washed with water and dried to give 0.100 g of 4- (isoquinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 140 ° C (decomposed); mass spectrum (El, m / e): M 356.1279.

Example 134 6, 7-Dimethoxy-4- (quinolin-8-ylamino) -quinolin-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 5- aminoisoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol were heated under nitrogen in a sealed tube at 200 ° C for 2 hours. The mixture was cooled and added to 100 ml of water. Sodium carbonate was added to this mixture at pH 9. The product was collected, washed with water and dried to give 0.167 g of 6,7-dimethoxy-4- (quinolin-8-ylamino) -quinolin-3-carbonitrile as a solid, mp 150 ° C (decomposed); mass spectrum (El, m / e): M 356.1271.

Example 135 4- (8-Hydroxy-quinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.233 g of 5-amino-8-hydroxyquinoline hydrochloride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust the pH to 7. The product was collected, washed with water and dried to give 0.210 g of 4- (8-hydroxy-quinolin-5-ylamino) -6, 7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 150 ° C (decomposed); mass spectrum (El, m / e): M 372. 1228 Example 136 4- (lH-Indol-4-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol were stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust the pH to 7. The product was collected, washed with water and dried to give 0.249 g of 4- (lH-indol-4-ylamino) -6, 7- dimethoxy-quinoline-3-carbonitrile as a solid, mp 260 ° C (decomposed); mass spectrum (El, m / e): M 344.1282.

Example 137 4- (lH-Indazol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.132 g of 5-aminoindazole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol were stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust the pH to 7. The product was collected, washed with water and dried to give 0.252 g of 4- (lH-indazol-5-ylamino) -6, 7- dimethoxy-quinoline-3-carbonitrile as a solid, mp 290-295 ° C; mass spectrum (El, m / e): M 345.1217.

Example 138 4- (lH-Indazol-6-ylamino) -5, 8-dimethoxy-quinoline-3-carbonitrile A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile, 0.093 g of 6-aminoindazole and 5 ml of ethoxyethanol was stirred under nitrogen at room temperature. reflux for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate at pH 9. The product was collected, washed with water, dried and washed with 10 ml of hexane-ethyl acetate (4: 1) to give 0.189 g of 4- (1H-indazole). 6-ylamino) -5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 302-305 ° C; mass spectrum (El, m / e): M 345.1223.

Example 139 4- (lH-Indazol-6-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile hydrochloride A mixture of 0.362 g of 4-chloro-7 -methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile, 0.267 g of 6- aminoindazole and 10 ml of ethoxyethanol were stirred under nitrogen at reflux temperature for 30 minutes. The mixture was cooled and a mixture of ethyl acetate / acetone / methyl alcohol (5: 5: 2) was added to 50 ml. The product was collected, washed with water, dried and washed with 10 ml of hexane-ethyl acetate (4: 1) to give 0.189 g of 4- (lH-indazol-6-ylamino) -7-methoxy-6- ( 3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile as a solid, mp 100 ° C (decomposed); mass spectrum (electrorrocio, m / e): M + H 459.2146.

Example 140 4- (3H-Benzotriazol-5-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile hydrochloride A mixture of 0.362 g of 4-chloro-7 -methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile, 0.268 g of 5-aminobenzotriazole and 10 ml of ethoxyethanol were stirred under nitrogen at reflux temperature for 30 minutes. The mixture was cooled and a mixture of ethyl acetate / acetone / methyl alcohol (5: 5: 2) was added to 50 ml. The product was collected, washed with water, dried and washed with 10 ml of hexane-ethyl acetate (4: 1) to give 0.142 g of 4- (3H-benzotriazol-6-ylamino) -7-methoxy-6 hydrochloride. - (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile as a solid, mp 260 ° C (decomposed); mass spectrum (electrorrocio, m / e): M + H 460.2096.

Example 141 4- (lH-Indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 159.8 mg (1.2 mmoles) of 6-aminoindazole in 10 mL of 2-ethoxyethanol were added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr. After cooling, most of the solvent was evaporated and the residue was diluted with ether. The precipitate was collected by filtration and withdrawn in water. The aqueous suspension was neutralized to pH 7-8 by the addition of saturated aqueous sodium carbonate solution and stirred for 15 minutes. The separated solid was filtered and washed with water and ether. After drying in vacuo, 297.5 mg (94.3%) of the product was obtained as a dark yellow solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 315.8. HRCIMS m / z: calculated 315,112 for C18H? 3N50 (M +), observed 315.1124.

Example 142 4- (3H-Benzotriazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-6- were reacted methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole to give 302.9 mg (95.8%) of the product as a solid yellow, pf > 250 ° C, mass (electrorrocio, m / e): M + H 316.9. Calculated HRCIMS: 316.107 for C? 7H? 2N60 (M +), observed 316.1081.

Example 143 4- (lH-Indazol-6-ylamino) -7-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 200.0 mg (0.914 mmol) of 4-chloro-7- were reacted methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 105.6 mg (0.914 mmol) of pyridine hydrochloride with 147.8 mg (1.1 mmol) of 6-aminobenzotriazole to give 280.0 mg (97.3%) of the product as a solid dark yellow, mp > 250 ° C, mass (electrorrocio, m / e): M + H 315.9. HRCIMS: calculated 315,112 for C18H? 3N50 (M +), observed 315.1124.

Example 144 4- (3H-Benzotriazol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 218.6 mg (1.0 mmol) of 4-chloro-7- were reacted methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1.0 mmol) of pyridine hydrochloride with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole to give 231.0 mg (73.1%) of the product as a solid light brown, mp > 250 ° C, mass (electrorrocio, m / e): M + H 316.9. HRCIMS: calculated 316.107 for d7H? 2N60 (M +), observed 316.1063.

Example 145 7-Hydroxy-4- (lH-Indazol-6-ylamino) -quinolin-3-carbonitrile A reaction mixture of 1.74 g (5.52 mmoles) of 4- (lH-Indazol-6-ylamino) -7-methoxy -quinolincarbonitrile and 15.3 g of pyridine hydrochloride was heated at 200-210 ° C for 1.5 hr. After cooling, the mixture was taken in aqueous 3% NH 4 OH solution. The precipitate was collected by filtering and washing with water. Drying in va cuo gave 1.66 g (63.8%) of the product as a dark brown solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 301.9. HRCIMS: calculated 302.1042 for C17HnN60 (M +), observed 302.1079.

Example 146 4- (lH-Indazol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 1.0 g (4.57 mmoles) of 4-chloro-7-methoxy were heated. -3-quinolinecarbonitrile, 724.8 mg (5.48 mmoles) of 5-aminoindole and 528.3 mg (4.57 mmoles) of 5-aminoindole in 35 mL of 2-ethoxyethanol at 120 ° C for 2 hours. The work gave 1.38 g of the product as a greenish-gray solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 314.9. HRCIMS: calculated 314,117 for C? 9H14N40 (M +), observed 314.1135.

Example 147 7-Hydroxy-4- (3H-benzotriazol-5-ylamino) -quinolin-3-carbonitrile Using an analogous procedure to that described in Example 145, 1.45 g (4.58 mmol) of 4- (3H-benzotriazole) were heated. 5-ylamino) -7-methoxy-3-quinoline-3-carbonitrile and 10 g of pyridine hydrochloride for 1 hour. The work gave 1.04 g (75.4%) of the product as a dark brown solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 303.3. HRCIMS: calculated 301.0838 for C? 8H10N5O (M +), observed 301.0833.

Example 148 4- (lH-Indazol-6-ylamino) -8-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 328.0 mg (1.5 mmol) of 4- chloro-8-methoxy were heated 3-quinolinecarbonitrile, 219.7 mg (1.65 mmoles) of 6-aminoindazole and 105.6 mg (173.3 mmoles) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol at 100 ° C for 2 hours. The work gave 373.8 mg (79%) of the product as a yellow solid, m.p. 242 ° C (decomposition), mass (electrorrocio, m / e): M + H 315.9. HRCIMS: calculated 315,112 for C? 8H? 3N50 (M +), observed 315.1126.

Example 149 4- (3H-Benzotriazol-5-ylamino) -8-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy were heated -3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 155.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol at 100 ° C for 1 hour. The work gave 213.5 mg (67.6%) of the product as a yellow solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 316.9. HRCIMS: calculated 316.107 for C? 7H12N60 (M +), observed 316.1079.

Example 150 4- (lH-Indol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 141, 248.7 mg (1 mmol) of reflux was carried out for 0.5 hours. 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 158.6 mg (1.2 mmol) of 5-aminoindole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. The work gave 338.7 mg (98.5%) of the product as a yellow solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 344.9. HRCIMS: calculated 344.127 for C2oHi6N402 (M +), observed 344.1277.

Example 151 4- (lH-Benzoimidazol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of the mixture was refluxed for 1 hour. 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 159.8 mg (1.2 mmol) of 5-aminobenzoimidazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. The work gave 233.6 mg (67.7%) of the product as a brown solid, m.p. 230 ° C (decomposed), mass (electrorrocio, m / e): M + H 345.9. HRCIMS: calculated 346.1304 for C? 9H? 5N502 (M +), observed 346.1325.

Example 152 6, 7-Dimethoxy-4- (2-methyl-lH-Benzoimidazol-5-ylamino) -quinolin-3-carbonitrile Using an analogous procedure to that described in Example 150, 248.7 mg were refluxed for 4 hours ( 1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 294. 4 mg (2.0 mmol) of 2-methyl-5-aminobenzimidazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. The work gave 220.2 mg (61.3%) of the product as a sand-colored solid, m.p. 207 ° C (decomposed), mass (electrorrocio, m / e): M + H 359.9. HRCIMS: calculated 359,138 for C20H? 7N5O2 (M +), observed 359.1403.

EXAMPLE 153 6,7-Dimethoxy-4- (quinolin-6-ylamino) -quinolin-3-carbonitrile Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-4 were refluxed for 6 hours. chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 173.8 mg (1.2 mmol) of 6-aminoquinoline and 115.6 mg (1 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol. The work gave 212.5 mg (59.5%) of the product as an orange solid, m.p. 241-243 ° C, mass (electrorrocio, m / e): M + H 356.8. HRCIMS: calculated 356.127 for C20H? 7N5O2 (M +), observed 356.1275.

Example 154 4- (4-Chloro-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) were refluxed overnight. ) of 4-chloro-6,7-dimethoxy-3-quinoline-carbonitrile, 213.2 mg (1.2 mmol) of l-amino-4-chloronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride in 12 mL of 2-ethoxyethanol . The work gave 290.1 mg (74.4%) of the product as a yellowish-green solid, m.p. > 250 ° C, mass (electrorrocio, m / e): M + H 390.2. HRCIMS: calculated 389.093 for C22H16N3O2 (M +), observed 389.0938.

EXAMPLE 155 6,7-Dimethoxy-4- (5,6,7,8-tetrahydro-naphthalen-1-ylamino) -quinoline-3-carbonitrile Using an analogous procedure to that described in Example 150, they were refluxed for 2 hours. hours 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 176.7 mg (1.2 mmol) of l-amino-5, 6, 7, 8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride in 12 mL of 2-ethoxyethanol. The work gave 195.1 mg (54.3%) of the product as a yellow solid, m.p. 248 ° C (decomposed), mass (electrorrocio, m / e): M + H 360.1. HRCIMS: calculated 359,163 for C22H16N302 (M +), observed 359.1632.

Example 156 4- (3H-Benzotriazol-5-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 150, 278.7 mg (1 mmol) were refluxed for 10 minutes. ) of 4-chloro-6,7-dimethoxy-3-quinoline-carbonitrile, 161.3 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. The work gave 246.3 mg (65.4%) of the product as a yellow solid, m.p. 205 ° C (decomposed), mass (electrorrocio, m / e): M + H 376.9. HRCIMS: calculated 376.128 for C? 9H16N603 (M +), observed 376.1264.

Example 157 4- (lH-Indazol-6-ylamino) -6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy] -quinolin-3-carbonitrile A reaction mixture of 196.5 mg (0.5 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile, 500.9 mg (5 mmol), 1-methylpiperazine and 74.5 mg (0.5 mmol) of sodium iodide in 10 mL of DME was heated at 135 ° C for 15 hours under N in a sealed tube.

After cooling, the solvent was removed and the residue was taken in 15 mL of brine. The aqueous solution was extracted with 15% methanol / methylene chloride. The organic solvent was dried over NaSO4 and filtered. Removal of the solvent gave the crude solid product. Purification of the crude product over preparative TLC (developing solvent: 15% methanol / methylene chloride) to give a foamy yellow solid. Trituration of the foamy solid with ether yielded 117.9 mg (51.6%) of the product as a yellow solid, m.p. 179 ° C (decomposed), mass (electrorrocio, m / e); M + H 458.0.

Example 158 7-. { 2- [(2-hydroxy-ethyl) -amino] -ethoxy} -4 (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 min.) Of 7-8 were heated at 135 ° C for 15 hours. (2-Chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile, 375.6 mg (5.0 mmol) of 2- (methylamino) -ethanol and 75.0 mg (0.5 mmol) ) of sodium iodide in 5 mL of DME. The work gave 116.4 mg (54.0%) of the product as a yellow solid, m.p. 179 ° C (decomposed), mass (electrorrocio, m / e): M + H 433.0.

Example 159 7-. { 2- [Bis- (2-hydroxy-ethyl) -amino] -ethoxy} -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of sodium sulfate were heated at 135 ° C for 15 hours. - (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile, 525.7 mg (5.0 mmol) of diethanolamine and 75.0 mg (0.5 mmol) of sodium iodide in 6 mL of DME. The work gave 109.1-mg (47.2%) of the product as a yellow solid, m.p. 150 ° C (decomposed), mass (electrorrocio, m / e): M + H 463.0.

Example 160 7- fe- (4-Hydroxy-piperidin-1-yl) -ethoxy] -4- (-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using an analogous procedure to that described in the Example 157, 196.5 mg (0.5 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile were heated at 135 ° C for 16 hours, 505.8 mg (5.0 mmol) of 4-hydroxypiperidine and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME. The work gave 97.9 mg (42.8%) of the product as a white matte solid, m.p. 174 ° C (decomposed), mass (electroretrocity, m / e): M + H 459.0.

Example 161 7-. { 2- [(4- (2-Hydroxy-ethyl) -piperazin-1-yl) -ethoxy] -4- (1 H -indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using a procedure analogous to described in Example 157, 196.5 mg (0.5 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinolin- were heated at 135 ° C for 16 hours. 3-carbonitrile, 651.0 mg (5.0 mmol) of 1- (2-hydroxyethyl) piperidine and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME. The work gave 90.5 mg (37.1%) of the product as a yellow solid, m.p. 174 ° C (decomposed), mass (electroretrocity, m / e): M + H 488.0.

EXAMPLE 162 7- [2- (1,4-Dioxa-8-aza-spiro [4, 5] dec-8-yl) -ethoxy] -4- (1 H -indazol-6-ylamino) -6-methoxy- quinolin-3-carbonitrile Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6) were heated at 135 ° C for 16 hours. -ylamino) -6-methoxy-quinoline-3-carbonitrile, 716.0 mg (5.0 mmol) of 1,4-dioxa-8-azaspiro [4, 5] decane and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME. The work gave 173.1 mg (69.2%) of the product as a white matte solid, m.p. 245 ° C (decomposed), mass (electrorrocio, m / e): M + H 501.0.

Example 163 4- (lH-Indazol-6-ylamino) -6-methoxy-7- (2-thiomorpholin-4-yl-ethoxy) -quinolin-3-carbonitrile Using an analogous procedure to that described in Example 157, they were heated at 135 ° C for 16 hours 173.0 mg (0.44 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile, 454.0 mg (4.4 mmoles) of thiomorpholine and 66.0 mg (0.44 mmoles) of sodium iodide in 4 mL of DME. The work gave 108.4 mg (53.5%) of the product as a light yellow solid, m.p. 213-215 ° C, mass (electrorrocio, m / e): M + H 461.0.

Example 164 7- [2- ([1, 3] Dioxoloan-2-ylmethyl-methyl-amino) -ethoxy] -4- (1 H -indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using a procedure analogous to that described in Example 157, 173.0 mg (0.44 mmoles) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy were heated at 135 ° C for 16 hours. -quinolin-3-carbonitrile, 515.5 mg (4.4 mmol) of 2- ([1, 3] -dioxolan-2-ylmethyl-methylamine and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME. 136.1 mg (65.2%) of the product as a yellow solid, mp 185-187 ° C, mass (electropartite, m / e): M + H 475.1.

Example 165 7- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl) -ethoxy] -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile Using a procedure Analogous to that described in Example 157, 173.0 mg (0.44 mmol) of 7- (2-chloro-ethoxy) -4- (lH-indazol-6-ylamino) -6-methoxy- were heated at 135 ° C for 16 hours. quinoline-3-carbonitrile, 586.0 mg (4.4 mmol) of 1, 2, 3, 4-tetrahydroisoquinoline and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME. The work gave 109.3 mg (50.6%) of the product as a yellow solid, m.p. 170-173 ° C, mass (electrorrocio, m / e): M + H 491.0.

Example 166 7- (2-Chloroethoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile A mixture of 0.50 g (1 equivalent) of 7- (2-chloro-ethoxy) -4 -chloro-6-methoxy-quinoline-3-carbonitrile, 0.25 g (1.1 equivalents) of 6-aminoindazole, 0.22 g (1.1 equivalents) of pyridine hydrochloride and 15 ml of 2-methoxyethanol were heated in an oil bath to 120 ° C for 2 hours. The progress of the reaction was verified by thin layer chromatography (acetone / hexane 1: 1). 2 hours later, the reaction mixture was cooled to room temperature; A total of 25 ml of 1M sodium bicarbonate was added and the reaction was stirred for 1 hour. The resulting precipitate was collected, washed with water and dried in vacuo at 60 ° C overnight to yield 0.645 g (97%) of the desired product; mass spectrum (electrohority, m / e): M + H 393.9 (M + H) +; Analysis calculated for C2oH? 6ClN5? 2: 2 H20: Calculated C: 55.88; H: 4.69; N: 16.29; Found C: 55.63; H: 4.78; N.15.24.

Example 167 7- (2-Dimethylaminoethoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile A mixture of 0.67 g (1 equivalent) of 7- (2-chloroethoxy) -4- ( lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equivalents) of sodium iodide and 15 ml of 2M dimethylamine in tetrahydrofuran was heated at 135 ° C for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated to give 0.50 g. The crude product was purified by chromatography (Silica Gel: ethyl acetate, ethyl acetate / methyl alcohol / triethylamine 6: 4: 0.1) to give 0.312 g (46%) of the pure product. PF 218-219 ° C: mass spectrum (electrorrocio, m / e): M + H = 402.9.

Example 168 4- (lH-Indazol-6-ylamino) -6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinoline-3-carbonitrile The title compound was prepared by the procedure of Example 167 using 0.616 g of 7- (2-chloroethoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile, 0.094 g of sodium iodide and 2.03 ml of morpholino to give, after purification by chromatography (Silica gel: ethyl acetate, ethyl acetate / methyl alcohol / triethylamine 6: 4: 0.1) 0.196 g (28%) of the desired product. MP 133-135 ° C: mass spectrum (electrorrocio, m / e): M + H = 445.0.

Example 169 4- (3H-Benzotriazol-5-ylamino) -7- (2-chloroethoxy) -6-methoxyquinoline-3-carbonitrile The title compound was prepared by the procedure of Example 166 using 0.442 g of 7- (2- chloro-ethoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.22 g of 5-amino-benzotriazole, 0.190 pyridine hydrochloride and 15 ml of 2-methoxyethanol to give 0.48 g (82%) of the product desired: mass spectrum (electrorrocio, m / e) M + H = 394.8.

EXAMPLE 170 7- (3- (Chloropropoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile The title compound was prepared by the procedure of Example 166 using 0.311 g of 7- (3 -chloro-propoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoimidazole, 0.128 of pyridine hydrochloride and 12 ml of ethoxyethanol to give 0.367 g (90%) of the desired product. 280-285 ° C: mass spectrum (electrorrocio, m / e) M + H = 407.9.

Example 171 4- (lH-Indazol-6-ylamino) -6-methoxy-7- (3-morpholin-4-ylpropoxy) quinoline-3-carbonitrile The title compound was prepared by the procedure of Example 167 using 0.408 g of (3-chloropropoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile, 1.4 g of morpholine, 0.060 of sodium iodide and 12 ml of ethylene glycol dimethyl ether to give 0.255 g (56%) ) of the desired product. MP 143-145 ° C; HRMS: C25H26N603; m / z 458.2084 d (mu) -1.7.

Example 172 4- [3-Chloro-4- (l-methyl-2-imidazolylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile In the manner of Example 141 the reaction of 4-chloro-6,7-diethoxy -3-quinoline-carbonitrile with 3-chloro-4- (1-methyl-2-imidazolylthio) aniline (WO-9615118) gave the title compound as a persimmon solid, mp 285-290 ° C.

Example 173 4- [3-Chloro-4- (l-methyl-2-imidazolylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile In the manner of Example 141 the reaction of 4-chloro-6,7-dimethoxy -3-quinoline-carbonitrile with 3-chloro-4- (1-methyl-2-imidazolylthio) aniline (WO-9615118) gave the title compound as a white solid, mp 302-307 ° C.

Example 174 4- [3-Chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -6-nitro-quinoline-3-carbonitrile A mixture of 5.00 g (21.5 mmol) of 4-chloro -6-nitro-3-quinolinecarbonitrile, 250 ml of ethanol and 6.18 g (25.8 mmol) of 3-chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -aniline (WO-9615118) was heated to low reflux N2 The heat was removed at 3 1/2 hours and made basic with saturated sodium bicarbonate solution. The solvents were separated and made azeotropes with ethanol. The residue was suspended with hexane and the solids were collected. It was washed with water, dried in vacuo. The solids were boiled in hexane to remove excess aniline, and dried. It was boiled in 2 L of ethyl acetate, and due to the extreme insolubility, the solids were collected and dried in vacuo, yielding 5.90 g of yellow solid: mass spectrum (electroretrocity, m / e): M + H-437.2, 439.1 Example 175 6-Amino-4- [3-chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -quinolin-3-carbonitrile A mixture of 5,734 g (13.1 mmol) of 4- [ 3-chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -6-nitro-quinoline-3-carbonitrile, 250 ml of ethanol and 14.83 g (65.6 mmol) of tin chloride hydrate it was heated to reflux under N2. The heat was removed at 2 1/2 hours and a large volume of ice water was added. It was made basic with sodium bicarbonate and stirred for 2 hours. With the now basic mixture, it was extracted with chloroform, the organic layer was shaken with Darco, dried with sodium sulfate and filtered. The solvent was separated and dried in vacuo, yielding 2.86 g of yellow-brown solid: mass spectrum (electroretrocity, m / e): M + H = 407.3, 409.3.

Example 176 N-. { 4- [3-Chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -3-cyano-quinolin-6-yl} -acrylamide Dissolved most 1.00 g (2.46 mmoles) of 6-amino-4- [3-chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -quinolin-3-carbonitrile in 3.5 ml of hot DMF, 12 ml of THF were added and cooled to 0 ° C. 377 μl of triethylamine and 225 μl (2.70 mmoles) of acryloyl chloride were added. The ice bath was removed after 15 minutes and the solvent was separated after 2 hours. The residue was suspended in water, the solids were collected and dried in the air overnight. The mixture was boiled in ethyl acetate, the solids were collected and dried in vacuo, yielding 670 mg of yellow-brown solid: mass spectrum (electroretrocity, m / e): M + H = 461.1, 462.2.

Example 177 6-Amino-4- [lH-indol-5-ylamino) -quinolin-3-carbonitrile 200 mg of 10% Palladium on carbon was covered with 75 ml of ethanol. 2.00 g (6.07 mmol) of 4- [lH-indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile and 477 μl (15.2 mmol) of hydrazine were added. It was heated to reflux under N2 for 2 hours. It was filtered hot through celite and washed thoroughly with hot methanol. The solvent was removed and dried in vacuo (50 ° C), giving 1.89 g of brown solid: mass spectrum (electroretrocity, m / e): M + H = 300.2 Example 178 3-Chloro-4- (1,3-thiazol-2-ylsulfanyl) aniline To a suspension of 3.8 g of sodium hydride (60% in mineral oil) in 100 ml of dimethylformamide was added slowly a solution of 10.0 g of 2-mercaptothiazole in 100 ml of dimethylformamide. 15 minutes later a solution of 15.0 g of 3-chloro-4-fluoronitrobenzene in 50 ml of dimethylformamide was added. 4 hours later, the mixture was poured into water. The resulting solid was collected, washed with water and dried in vacuum. This material was mechanically stirred at reflux in a mixture of 830 ml of methanol, 230 ml of water, 37.0 g of ammonium chloride and 30.1 g of iron powder for 4 hours. The boiling mixture was filtered. The solvent was removed from the filtrate and the residue was extracted with hot ethyl acetate. The ethyl acetate solution was filtered through a short silica gel column. The solvent was removed and the residue was recrystallized from ether-hexane to give 17.7 g of a white matte solid: mass spectrum (electroretro, m / e): M + H 243.1. Using a procedure similar to that described above, the following intermediates need to be prepared to prepare some of the compounds of this invention. 3-Chloro-4- (IH-imidazol-1-yl) aniline 2- [(4-amino-2-chlorophenyl) sulfanyl] -4 (3H) -quinazolinone N- (4-amino-2-chlorophenyl) -N - (3-pyridinylmethyl) acetamide 2-chloro-Nl- [5- (trifluoromethyl) -1,4,4-thiadiazol-2-yl] -1,4-benzenediamine 3-chloro-4- [(4,6- dimethyl-2-pyrimidinyl) sulfanyl] aniline 3-chloro-4- [(-methyl-2-pyrimidinyl) sulfanyl] aniline 4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) aniline 4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (chloro) aniline Example 179 1- (2-chloro-4-aminobenzyl) -lH-imidazole A solution of 10 g of 4-bromomethyl-3-chloro-nitrobenzene and 5.44 g of imidazole in 125 ml of tetrahydrofuran was refluxed for 4 hours. The solvent was removed and the residue was dissolved in ethyl acetate, the solution was washed with water and dried over magnesium sulfate. The solvent was removed and the residue was extracted several times with ether. The ether extracts were diluted with two volumes of hexane. L- (2-Chloro-4-nitrobenzyl) -lH-imidazole (4.3 g) crystallized as a white solid. A 4 g portion of this material was mechanically stirred at reflux with 153 ml of methanol, 52 ml of water, 8.1 g of ammonium chloride, and 6.6 g of iron powder for 2 hours. The hot mixture was filtered and the solids were washed with methanol-tetrahydrofuran mixtures. The solvents were removed from the combined filtrates. The residue was extracted several times with hot ethyl acetate. The ethyl acetate solution was treated with magnesium sulfate and activated charcoal. Filtration and removal of the solvent gave 3.9 g of the title compound. Using the methods described in Examples 1-179 above and the methods described in patent applications WO-98/43960 and WO-99/09016, the compounds of this invention listed in Table 5 were prepared.

Table 5 180. 4- (2-Hydroxy-naphthalene-1-yl-240- 371.9 (M + H) ylamino) -6,7-dimethoxy-i-dec. ? quinoline-3-carbonitrile I-r ~ 1 T "" p 181 ¡4- (2, 3-Dihydro- 200-201 ¡364.0 (M + H) i benzo [1,4] dioxin-6-ylamino) - 16, 7-dimethoxy-quinolin-3-! carbonitrile - -i -i 182 4- (2-Mercaptc) -benzothiazole-6- > 255. 394 8 (M + H) iylamino) -6,7-dimethoxy-i dec. ? quinolin-3-ca rbonitrile 183 4- (6-Hydroxy-naphthalene-1-yl2202-372-0 (M + H) ylamino) -6,7-dimethoxy-i dec. 1 quinolin-3-carbonitrile t "T" 1 184 4- (lH-Indazol-6-ylamino) -5- > 260 ¡315. 8 (M + H) i met i-quinolin-3- 1 carbonitrile Table 5 (continued) 185 4- (2-chloro-5-methoxyanilino) - 185-187 339.9 (M + H) 5-methoxyquinoline-3-carbonitrile 186 4- [(2-Amino-4- 215 354.9 (M + H) chlorophenyl) amino] -6, 7- dec. dimethoxy-3-quinolinecarbonitrile - - - -i 187 4- [(3-Hydroxy-2- 277-282 372.2 (M + H) naphthyl) amino] -6,7-dimethoxy-3-dec. quinolinecarbonitrile 4-. { 3-Chloro-4- [(1-methyl-1H-467.2 (M + H) imidazole) sulfanyl] anilino} -7- methoxy-6-nitro-3-quinolinecarbonitrile-t-189 6-Amino-4-. { 3-chloro-4- [(1- 437.0 (M + H) methyl-lH-imidazol-2-yl) sulfanyl] anilino} -7- methox? -3-quinolinecarbonitrile Table 5 (continued) 190 (E) -N- (4- { 3-chloro-4- [(1- 548.1 (M + H), methyl-lH-imidazol-2- 274.7 (M + 2H) + 2-yl) sulfanil] anilino.) .3-cyano-7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide h- _! _. T-- H 191 4- [3-chloro-4- (1,3-thiazole-2- 470.0 (M + H) ylsulfanyl) anilino) -7-methoxy-6-nitro-3-quinolinecarbonitrile -? 192 6-amino-4- [3-chloro-4- (1, 3- 440.1 (M + H; thiazol-2-ylsulfanyl) anilino] -7-methoxy-3-quinolinecarbonitrile I- '- -t- f " 193 (E) -N- (4- [3-chloro-4- (1, 3- 551.1 (M + H), thiazol-2-ylsulfanyl) anilino] -276.2 (M + 2H) +2 3-cyano- 7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide Table 5 (continued) 194 4- [3-chloro-4- (lH-imidazole-1- ¡421.3 (M + H), ¡Il) anilino] -7-methoxy-6-nitro- ¡¡211.1 (M + 2H) +2 • - 3-quinolinecarbonitrile i i i 1 1 1 195 6-amino-4- [3-chloro-4- (lH- ¡391.2 (M + H), ! imidazol-l-il) anilino] -7- ¡196.2 (M + 2H) +2 1"methoxy-3-quinolinecarbonitrile '• i 1 1 T 196 (E) -N-. {4- [3-chloro-4- (lH- ¡502.4 (M + H), ! Imidazol-1-yl) anilino] -3- 251.7 (M + 2H) + 2 i cyano-7-methoxy-6-quinolinyl} - i i 4- (dimethylamino) -2-butenamide ¡I 1, 1 -I 197 4-. { 3-chloro-4- [(4-oxo-3,4- 531.2 (M + H), i) dihydro-2- 266.2 (M + 2H) +2 1-quinazolinyl) sulfanyl] anilino} '' -7-methoxy-6-nitro-3-quinoline- ¡¡i carbonitrile i iL_L. J Table 5 (continued) 198 6-amino-4-. { 3-chloro-4- [(4-oxo-501.3 (M + H), 3, 4-dihydro-2-251.1 (M + 2H) +2 quinazolinyl) sulfanyl] anilino} -7-methoxy-3-quinoline-carbonitrile -., __ - H 199 (E) -N- (4- { 3-chloro-4- [(4-oxo-612.4 (M + H), 3,4-dihydro-2-306.7 (M + 2H) +2 quinazolinyl) sulfanyl] anilino.} - 3-cyano-7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide 200 6-methoxy-7- [3- (4- 139-141 510.2 (M + H), morpholinyl) propoxy] -4- [4- (4- 255.7 (M + 2H) +2 pyridinylmethyl) anilino] -3 - quinolinecarbonitrile --I 201 6-methoxy-7- [3- (4-1-11-11) 510.3 (M + H), morpholinyl) propoxy] -4- [4- (3- 255.7 (M + 2H) +2 pyridinylmethyl) anilino] -3 - quinolinecarbonitrile Table 5 (continued) 202 6-methoxy-7- [3- (4- 168-170 510.2 (M + H), morpholinyl) propoxy] -4- [4- (2-25.7 (M + 2H) +2 pyridinylmethyl) anilino] -3 - Table 5 (continued) 206 N- (4- { [6- (acetylamino) -3- 515.1 (M + H) cyano-7-methoxy-4-quinolinyl] amino) -2- chlorophenyl) -N- ( 3- pyridinylmethyl) acetamide h- "H 207 4- [3-chloro-4- (1, 3-dimethyl-270-272 509.2 (M + H; 2,4,6-trioxohexahydro-5- Table 5 (continued) 210 6-methoxy-7- [3- (4- 152-154 515.3 (M + H), morpholinyl) propoxy) -4- (4- (2-258.3 (M + 2H) +2 thienylmethyl) anilino] -3 - quinolinecarbonitrile 211 6-methoxy-4- (4-phenoxyanilino) 154-155 479.3 (M + H) 7- [2- (2H-l, 2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile I- t - -i 212 6-methoxy-4- (4-phenoxyanilino; 188-189 479.3 (M + H) 7- [2- (1 H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile I-213 4- (4-benzylanilino) -6-methoxy- 167-170 477.4 (M + H) 7- [2- (2 H-1,2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile Table 5 ( continuation) 214 4- (4-benzylanilino) -6-methoxy- 477.5 (M + H) 7- [2- (lH-l, 2,3-triazole-l- Table 5 (continued) 218 6-methoxy-7- [3- (4- 132-134 503.4 (M + H), Table 5 (continued) 222 (E) -N- [4- (3-chloro-4- ([5-617.3 (M + H), (trifluoromethyl) -1, 3, 4-309.3 (M + 2H) +2 thiadiazol-2-yl) aminojanilino) -3-cyano-7-ethoxy-6-quinolinyl] -4- (dimethylamino) -2-butenamide 223 4- [3-chloro-4- (4- 462.2 (M + H), pyridinyloxy) anilino] -7- 231.6 (M + 2H) +2 ethoxy-6-nitro-3-quinolinecarbonitrile • I- -I 224 6-amino- - [3-chloro-4- (4-543.4 (M + H) pyridinyloxy) anilino] -7- 272.2 (M + 2H +2 ethoxy-3-quinolinecarbonitrile 225 (E) -N-. { 4- [3-chloro-4- (4-543.4 (M + H), pyridinyloxy) anilino] -3-272.2 (M + 2H) +2 cyano-7-ethoxy-6-quinolinyl} - 4- (dimethylamino) -2-butenamide Table 5 (continued) 226 4-. { 3-chloro-4- [(3-461.3 M + H) pyridinylmethyl) amino] anilino} 231.4 (M + 2H) +2 -7-methoxy-6-nitro-3-quinolinecarbonitrile • I 1- 227 6-amino-4-. { 3-chloro-4- [(4- 166-172 516.2 (M + H) phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7- methoxy-3-quinolinecarbonitrile i- 1- 228 6-amino-4 (3-chloro-4- { [5-506.3 (M + H) (trifluoromethyl) -1,3,4-thiadiazole- 2-yl] amino.} Anilino) -7-ethoxy-3-quinolinecarbonitrile (-j -h- T "229 6-methoxy-7- [3- (4-10-10-10 523.5 (M + H), morpholinyl) propoxy] -4- [4- (2- 262.4 (M + 2H) +2 phenylethyl) anilmo] -3-quinolinecarbonitrile Table 5 (continued) 230 (E) -N- (4- (3-chloro-4- [(4- 154-157 627.3 (M + H), phenyl-1,3-thiazole-2-31.4.3 (M + 2H) +2 il sulfanyl] anilino.} - 3-cyano-7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide - | X- \ H 231 4- [3-chloro-4- (lH-imidazol-1- 130-133 519.3 (M + H), il) anilino] -6-methoxy-7- [3- (4- 260.3 (M + 2H) +2 orfolinyl) propoxy] -3- quinolinecarbonitrile I- t- 232 6-methoxy-7- (3- (4-13-13-137 512.2 (M + H), morpholinyl) propoxy] -4- [4- (3- 256.7 (M + 2H) +2 pyridinyloxy) anilino] -3-quinolinecarbonitrile-t- -i 233 4- [3-chloro-4- (4- 174 546.1 (M + H), pyridinyloxy) anilino] -6- dec, 273.8 (M + 2H) +2 methoxy-7- [3- (4-morpholinyl) propoxy] -3- quinolinecarbonitrile Table 5 (continued) 234 6-methoxy-7- [3- (4- 129-131 512.1 (M + H), morpholinyl) propoxy] 4- [4- (4- 256.8 (M + 2H) +2 pyridinyloxy) anilino) -3- quinolincarbonitrile i- 1 1 235 4- [2-chloro-4- (1,3-thiazole-2- 122 568.0 (M + H), Table 5 (continued) 238 6-methoxy-7- [3- (4-1186-187-500.3 (M + H), morpholinyl) propoxy] 4- [4- (2H-250.8 (M + 2H) +2 1,2,3-triazol-2-ylmethyl) anilino] -3-quinolinecarbonitrile-239 6-methoxy-7- [3- (4-120-201-500.2 (M + H), morpholinyl) propoxy] -4- [ 4- (1H-250.7 (M + 2H) +2 1,2,3-triazol-l-ylmethyl) anilino] -3-quinoline-carbonitrile h- j _ | _ | 240 4- (2,4-dichloro-5- J223-226 485.1 (M + H; methoxyanilino) -6-methoxy-7- [2- (2H-1, 2,3-triazol-2-yl) ethoxy] -3- quinolinecarbonitrile Table 5 (continued) 241 4- (2,4-dichloro-5-196-197 485.1 (M + H) methoxyanilino) -6-methoxy-7- [2- (lH-l, 2,3-triazol-l-yl) ethoxy ] -3- quinolinecarbonitrile - - H 242 7-ethoxy-6-nitro-4- [4- [(4-594.0 (M + H) phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinoline -carbonitrile h- H 243 6-amino-7-ethoxy-4- [4- [(4- 564.0 (M + H, phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinolinecarbonitrile L_.

Table 5 (continued) 244 (E) -N- (3-cyano-7-ethoxy-4- [4-675.0 (M + H), [(4-phenyl-1,3-thiazole-2- 228.2 (M + 2H) + 2? Yl) sulfanyl] -3- (trifluoromethyl) anilino] -6-? quinolinyl} -4- (dimethylamino) -12-butenamide rt ~ ~ r T 245 4- [3-chloro-4- (lH-imidazol-1- 449 1 (M + H),? Ylmethyl) anilino] -7- etox? -6- 225 2 (M + 2H) +2? Nitro-3-quinolinecarbonitrile 246 6-amino-4- [3-chloro-4- (1H-! 19.2 (M + H),? imidazol-1-ylmethyl) anilino] - 210. 3 (M + 2H) +2 17-ethoxy-3-quinolinecarbonitrile 247 (E) -N-. { 4- [3-chloro-4- (1H-530. 2 (M + H), imidazol-1-ylmethyl) anilino] - 265. 8 (M + 2H) +2 3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2-butenamide Table 5 (continued) 248 4-. { 3-Chloro-4- [(4-methyl-2-493.0 (M + H) pyrimidinyl) sulfanyl] anilino} -7-Ethoxy-6-nitro-3-quinolinecarbonitrile i- 1- 249 6-amino-4- (3-chloro-4- [(4,463.1 (M + H) methyl-2-pyrimidinyl) sulfanyl] anilino .}. -7-ethoxy-3-quinolinecarbonitrile h- | _μ f- -H 250 (E) -N- (4- (3-chloro-4- [(4- 574.1 (M + H), methyl-2- 287.8 (M + 2H) + 2-pyrimidinyl) sulfanyl) anilino. -cyano-7-ethoxy-6-quinolinyl) -4- (dimethylamino) -2-buteneamide 251 4-. { 3-chloro-4- [(4,6-dimethyl-2-507.1 (M + H) pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile Table 5 (continued) 252 6-amino-4-. { 3-chloro-4- [(4,6-477.1 (M + H; dimethyl-2-pyrimidinyl) sulfanyl) anilino} -7-ethoxy-3-quinolinecarbonitrile - - - - H 253 (E) -N- (4- { 3-chloro-4- [(4,6-588.1 (M + H] dimethyl-2- 294.8 (M + 2H) +2 pyrimidinyl) sulfanyl] anilino} 3-cyano-7-ethoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide r ~ -254 4- [4- (lH-imidazole-2- 156-158 499.3 (M + H), ilmethyl) anilino) -6-methoxy-7- 250.3 (M + 2H) +2 [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile I- 1- 1- -i 255 6-methoxy-7- [3- (4-180 501.3 (M + H), morpholinyl) propoxy] -4- [4- (1H-dec. 251.3 (M + 2H) + 2-tetraazol-1-ylmethyl) anilino] - 3-quinolinecarbonitrile Table 5 (continued) 256 6-methoxy-7- [3- (4- 123 501.2 (M + H) morpholinyl) propoxy) -4- [4- (2H-desc, 251.3 (M + 2H +2 tetraazol-2-ylmethyl) anilino] -3-quinolinecarbonitrile 1-257 4-. { 3-chloro-4- [(4,6-dimethyl-2-1-113 591.1 (M + H), pyrimidinyl) 296.2 (M + 2H) +2 sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile h- _μ. \ - - H 258 4-. { 3-chloro-4- [(4-methyl-2-10-113 ¡577 1 (M + H), pyrimidinyl) ¡289 2 (M + 2H) + 2 sulfanyl) anilino} -6-methoxy-7- 577 1 (M + H), [3- (4-morpholinyl) propoxy) -3- 289 2 (M + 2H) +2 quinolinecarbonitrile h- | _j__ - 1 259 (E) -N- [4- (3-chloro-4- { [2- 194-198 601.3 (M + H), (phenylsulfanyl) acetyl] amino} a 301.1 (M + 2H) +2 nilino) -3-cyano-7-methoxy-6-quinolinyl] -4- (dimethylamino) -2-butenamide? __ .j Table 5 (continued) 260 4- [4- (2,6- 160-162 571.4 (M + H) dimethoxyphenoxy) anilino) -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile h- -f- f- H 261 6-methoxy-4- [4- (3- 132-134 541.5 (M + H; methoxyphenoxy) anilino] -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile-1-- 1 262 6-methoxy-4-. { 4- [(1-methyl-1H-208-210 531.3 (M + H) imidazol-2-yl) sulfanyl] anilino) -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile Table 5 (continued) 263 ¡(E) -N-. { 4- [3-chloro-4- (1, 3- 595 .1 (M + H), thiazol-2-ylsulfanyl) anilino] -i 298.1 (M + 2H) +2 i 3- cyano-7-methoxy-6- i -quinolinyl) -4- [(2-methoxyethyl) (methyl) amino] -2- i ibutenamide ir 1 I "" "T" 1 264 (E) -N- (4- { 3-chloro-4- [(5-627 1 (M + H),! Phenyl-1,3-thiazole-2-¡¡314 1 (M + 2H) +2 y1) Sulfanyl] anilino.]. 3-Cyano-i 7-methoxy-6-quinolinyl) -4- i (dimethylamino) -2-butenamide i J ~ 265 ( E) -N- (4- { 3-chloro-4- [(4 - ¡641. 3 (M + H),! I phenyl-1,3-thiazole-2-¡¡¡321. 2 ( M + 2 H) + 2 yl) sulfanyl] anilino.] - 3-cyano-i 7-ethoxy-6-quinoline) -4- i (dimethylamino) -2-butenamide i Table 5 (continued) 266 4-. { 3-Chloro-4- [(4,6-dimethyl-2-U73-176 478.4 (M + H) pyrimidinyl) sulfanyl] anilino} -6,7-dimethoxy-3-quinolinecarbonitrile h- _, r-- H 267 6,7-dimethoxy-4- (. {6- [(4-phenyl-250,498.3 (M + H) 1,3-thiazol-2-yl) sulfanyl] -3- (dec. Pyridinyl). amino) -3- quinolinecarbonitrile - I + - 268 4- (3-chloro-4- [(1-methyl-1 H-232-234 547.3 (M + H; imidazol-2-yl) sulfanyl] anilino. -6- methoxy-7- [3- (1H-1,2,3-triazol-2-yl) propoxy] -3-quinolinecarbonitrile Table 5 (continued) 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 (16)

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: where: X is a ring system of aryl or bicyclic heteroaryl of 8 to 12 atoms where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, 0 and S with the proviso that the bicyclic heteroaryl ring does not contain OO bonds , SS or SO and where the aryl or bicyclic heteroaryl ring may optionally be mono-, di-, tri, or tetra substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 carbon, 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 a 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 atoms of carbon, 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 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino; or X is a radical having the formula: wherein A is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, or di-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 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 3-10 carbon atoms, mercapto, and benzoylamino; T is bonded to a carbon of A and is: -NH (CH2) m-, -0 (CH2) m-, -S (CH2) m-, -NR (CH2) m-, - (CH2) m- - (CH2) mNH-, - (CH2) mO-, - (CH2) mS- or - (CH2) mNR-; L is an unsubstituted phenyl ring or a phenyl ring 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 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 carbon atoms, N, N-dialkylaminoalkoxy of 3 -10 carbon atoms, mercapto, and benzoylamino; provided that L can be an unsubstituted phenyl ring only when m > 0 and T is not -CH2NH- or -CH20-; or L is a 5- or 6-membered heteroaryl ring, wherein the heteroaryl ring contains from 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain 0-0, SS or SO, and wherein the heteroaryl ring is mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 carbon, 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, alkynyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 atoms of carbon carbon, alkenoxyloxymethyl 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, 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 / R ( C (R6) 2) p-N ^ / N- (C (R6) 2) kY-, RβR9-CH- - (C (R6) 2) kY-. (C (R6) 2) P R7- (C (R6) 2) g-Y-. Rr (C (R6) 2) p-M- (C (R6) 2) k-Y-. »Het. (C (R6) 2) q-W- (C (R6) 2) k-Y-: o Ri and R are as defined above and Gi or G2 or both are R2-NH-; or if any of the substituents Ri, G2, G3 or R4 are located contiguous to carbon atoms then they can be taken together as the divalent radical -O-C (R) 2-0-; And it's a divalent radical selected from the group consisting of R7 is -NR6R6, -OR6, -J, -N (R6) 3+, or -NR6 (OR6); 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, thia-z-ol, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, N tetrahydropyran, and n; where the Het 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. -0R6, optionally mono or disubstituted on carbon with monovalent radicals - (C (Rβ) 2) sORβ or - (C (R) 2) sN (R) 2, and optionally mono or disubstituted on a carbon saturated with divalent radicals - 0- u -0 (C (R6) 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; with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2 is selected from the group consisting of or 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 (6) 2) P-N N- (CÍRß) 2) (C (R6) 2) P R7- (C (R6) 2) s-. R7- (C (R6) 2) P-M- (C (R6) 2) v. R8R9-CH- - (C (R6) 2) r. , 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, (C (R6) 2) P / \ Rr (C (R6) 2) p- ^ 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- .0 Het- (C (R6) 2) q-W- (C (R6) 2) r- " Rß, and R9 are each, independently, (C (R6) 2) rNR6R6. or (C (R6) 2) r0R6; J is independently hydrogen, rine, fluorine or bromine; 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; m is 0-3; 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 also provided that when Y is -NR6- and R? be -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 -NR6-, then k = 2-4; when Y is -0- and M or W is -0-, then k = 1-4; when it 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. 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 a substituted or unsubstituted bicyclic aryl or heteroaryl ring system, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, characterized in that X is the radical: and A is a phenyl ring, or a pharmaceutically acceptable salt thereof.

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

6. The compound according to claim 4, characterized in that Ri and R4 are hydrogen or a pharmaceutically acceptable salt thereof. The compound according to claim 3, characterized in that the ring system of aryl or bicyclic heteroaryl is selected from the group consisting of naphthalene, 1, 2, 3, 4-tetrahydronaphthalene, indane, 1-oxo-indane, 1, 2, 3, 4-tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-l, 3-dihydro-isobenzofuran, benzothiaphene, 1,1-dioxo-benzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo-2, 3-dihydro-lH-isoindole, benzotriazole, lH-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzooxazole, purine, phthalimide, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido [2, 3- b] pyridine, pyrido- [3, 4-b] pyrazine, pyrido [3,2-c] pyridazine, pyrido [3,4-b] pyridine, lH-pyrazolo [3,4-d] pyrimidine, 1.4 -Benzodioxane, pteridine, 2 (1H) -quinolone, 1 (2H) -isoquinolone, 2-oxo-2, 3-dihydro-benzthiazole, 1,2-methylenedioxybenzene, 2-oxindole, 1,4-benzisoxacin, benzothiazole, quinoxaline , quinolin-N-oxide, isoquinoline-N-oxide, quinoxalin-N-or xido, quinazolin-N-oxide, benzoacin, phthalazine, 1,4-dioxo-l, 2, 3, 4-tetrahydro-phthalazine, 2-oxo-l, 2-dihydro-quinoline, 2,3-dioxo-1, 4-dihydro-2H-benzo [d] [1, 3] oxacin, 2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH-benzo [e] [1, 4] diacepine, or cinnoline or a pharmaceutically acceptable salt thereof. The compound according to claim 4, characterized in that L is a 5- or 6-membered heteroaryl ring or a pharmaceutically acceptable salt thereof. The compound according to claim 8, characterized in that the heteroaryl ring is selected from the group consisting of pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole, and 1, 2,4-triazole or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 4, characterized in that L is a substituted phenyl ring or a pharmaceutically acceptable salt thereof. The compound according to claim 1, characterized in that it is: a) 4- (2,3-dihydro-lH-indol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically salt acceptable thereof; b) 4- (benzoth? azol-6-lamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; c) 4- (benzo [1,3] dioxol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; d) 6,7-diethoxy-4- (lH-indazol-6-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; e) 6,7-d-ethoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylammo) -quinom-3-carbonitrile or a pharmaceutically acceptable salt thereof; f) 6,7-diethoxy-4- (lH-indol-6-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; g) 6, 7-dimethoxy-4- (1H-indazol-6-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; h) 4- (1,3-dioxo-2,3-dihydro-lH-isoindol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; i) 4- (2,3-dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-d-ethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; j) 4- (lH-indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; k) 4- (1, 4-dioxo-1, 2,3,4-tetrahydro-phthalacin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; 1) 6,7-diethoxy-4- (indan-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; m) 4- (2, -dioxo-l, 4-dihydro-2H-benzo [d] [1, 3] oxacin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt of the same; n) 6,7-diethoxy-4- (3-oxo-l, 3-dihydro-isobenzo-furan-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; o) 4- (1,1-dioxo-lH-benzo [b] thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; p) 4- (2,3-dihydro-lH-indol-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; q) 7-ethoxy-4- (indazol-6-ylamino) -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; r) 4- (2,3-dihydro-lH-indol-6-ylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; s) 9- (lH-indazol-6-ylamino) -2, 3-dihydro [1, 4] dioxino [2, 3-g] quinoline-8-carbonitrile or a pharmaceutically acceptable salt thereof, t) 6.7 -dietoxy-4- (l-methyl-2, 5-dioxo-2, 3,4,5-tetrahydro-lH-benzo [e] [1,4] diazepin-7-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; u) 4- (lH-indazol-6-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; v) 6, 7-dimethoxy-4- (4-methi1-2-oxo-1,2-dihydro-quinolin-7-ylamino) -quinolin-3-carbonitrile w) 6,7-dimethoxy-4- (2- methyl-benzothiazol-5-ylamino) -quinolin-3-carbonitrile x) 6,7-dimethoxy-4- (2-oxo-2,3-dihydro-benzothiazol-6-ylamino) -quinolin-3-carbonitrile or a salt pharmaceutically acceptable thereof; y) 6, 7-dimethoxy-4- (quinolin-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; z) 4- (isoquinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; aa) 6,7-dimethoxy-4- (quinolin-8-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; bb) 4- (8-hydroxy-quinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; cc) 4- (lH-indol-4-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; dd) 4- (lH-indazol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ee) 4- (lH-Indazol-6-ylamino) -5,8-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ff) 4- (lH-indazol-6-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; gg) 4- (3H-benzotriazol-5-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; hh) 4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ii) 4- (3H-benzotriazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; j j) 4- (lH-indazol-6-ylamino) -7-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; kk) 4- (3H-benzotriazol-5-ylamino) -7-methoxy-quinoline-3-carbonityl or a pharmaceutically acceptable salt thereof; 11) 7-hydroxy-4- (lH-indazol-6-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; mm) 4- (1H-indol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; nn) 7-hydroxy-4- (3H-benzotrizol-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; oo) 4- (lH-indazol-6-ylamino) -8-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; pp) 4- (3H-benzotriazol-5-ylamino) -8-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; qq) 4- (lH-indol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; rr) 4- (lH-benzoimidazol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof, ss) 6,7-dimethoxy-4- (2-methyl-lH- benzoimidazol-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; tt) 6,7-dimethoxy-4- (quinolin-6-ylamino) -quinolin-3-carbornitrile or a pharmaceutically acceptable salt thereof; uu) 4- (4-chloro-naphthalene-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; vv) 6,7-dimethoxy-4- (5,6,7,8-tetrahydronaphthalen-1-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ww) 4- (3H-benzotriazol-5-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; xx) 4- (lH-indazol-6-ylamino) -6-methoxy-7- [2- (4-methyl-piperazin-1-yl) ethoxy] -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; yy) 7-. { 2- [(2-hydroxy-ethyl) -amino] -ethoxy} - (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; zz) 7-. { 2- [bis- (2-hydroxy-ethyl) -amino] -ethoxy} -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; aaa) 7- [2- (4-hydroxy-piperidin-1-yl) -ethoxy] -4- (-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; bbb) 7- (2- [(4- (2-hydroxy-ethyl) -piperazin-1-yl) -ethoxy] -4- (lH-indazol-6-ylamino) -6-methoxy-quinolin-3- carbonitrile or a pharmaceutically acceptable salt thereof; ccc) 7- [2- (1, 4-dioxa-8-aza-spiro [4, 5] dec-8-yl) -ethoxy] -4- (lH-indazole- 6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ddd) 7- [2- ([1, 3] dioxolan-2-ylmethyl-methylamino) -ethoxy] -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile eee) 7- (2- (3,4-dihydro-lH-isoquinolin-2-yl) -ethoxy] -4- (lH-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; fff) 4- (lH-indazol-6-ylamino) -6-methoxy-7- (2-thiomorpholin-4-yl-ethoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ggg) 7- (2-chloroethoxy) -4- (lH-indazo] -6-yl-amino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; hhh) 7- (2-dimethylaminoethoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; iii) 4- (lH-indazol-6-ylamino) -6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; JJJ) 4- (3H-benzotriazol-5-ylamino) -7- (2-chloroethoxy) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; kkk) 7- (3-chloropropoxy) -4- (lH-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; 111) 4- (lH-indazol-6-ylamino) -6-methoxy-7- (3-morpholin-4-ylpropoxy) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; mmm) 4- [3-chloro-4- (1-methyl-2-imidazolylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnn) 4- [3-chloro-4- (l-methyl-2-imidazolylthio) phenylamino) -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ooo) 6-amino-4- [3-chloro-4- (1-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ppp) N-. { 4- [3-chloro-4- (l-methyl-lH-imidazol-2-ylsulfanyl) -phenylamino] -3-cyano-quinolin-6-yl} acrylamide or a pharmaceutically acceptable salt thereof; qqq) 6-amino-4- (lH-indol-5-ylamino) -quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; rrr) 4- (lH-indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; sss) 4- (2-Hydroxy-naphthalene-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ttt) 4- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; uuu) - (2-Mercapto-benzothiazol-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; vvv) 4- (6-Hydroxy-naphthalene-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; www) 4- (lH-Indazol-6-ylamino) -5-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; xxx) 4- (2-chloro-5-methoxyanilino) -5-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; yyy) 4- [(2-Amino-4-chlorophenyl) amino) -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; zzz) 4- [(3-hydroxy-2-naphthyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; aaaa) 4- (3-chloro-4- [(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} - 7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; bbbb) 6-amino-4-. { 3-Chloro-4- [(1-methyl-lH-imidazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; cccc) (E) -N- (4- { 3-chloro-4- [(1-methyl-lH-imidazol-2-yl) sulfanyl] anilino) -3-cyano-7-methoxy-6-quinolinyl ) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; dddd) 4- [3-chloro-4- (1, 3-thiazol-2-ylsulfanyl) anilino) -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; eeee) 6-amino-4- [3-chloro-4- (1, 3-thiazol-2-ylsulfanyl) anilino] -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ffff) (E) -N- (4- [3-chloro-4- (1, 3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; gggg) 4- [3-chloro-4- (lH-imidazol-1-yl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; hhhh) 6-amino-4- [3-chloro-4- (lH-imidazol-1-yl) anilino] -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; iiii) (E) -N-. { 4- [3-chloro-4- (lH-imidazol-1-yl) anilino] -3-cyano-7-methoxy-6-quinolinyl} -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; j j j j) 4-. { 3-Chloro-4- [(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; kkkk) 6-amino-4-. { 3-Chloro-4- [(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; 1111) (E) -N- (4- (3-chloro-4- [(-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino.} - 3-cyano-7-methoxy-6- quinolinyl) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; mmmm) 6-methoxy-7- [3- (-morpholinyl) propoxy] -4- [4- (4-pyridinylmethyl) anilino ] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnnn) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; oooo) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-pyridinylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; pppp) (E) -N- (4-. {- - (acetyl (3-pyridinylmethyl) amino] -3-chloroanilino.} - 3-cyano-7-methoxy-6-quinolinyl) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; qqq) N- (2-chloro-4- [(3-cyano-7-methoxy-6-nitro-4-quinolinyl) amino] phenyl}. - (3-pyridinylmethyl) acetamide or a pharmaceutically acceptable salt thereof; rrrr) N-. { 4- [(6-amino-3-cyano-7-methoxy-4-quinolinyl) amino] -2-chlorophenyl} -N- (3-pyridinylmethyl) acetamide or a pharmaceutically acceptable salt thereof; ssss) N- (4- { [6- (acetylamino) -3-cyano-7-methoxy-4-quinolinyl] amino) -2-chlorophenyl) -N- (3-pyridinylmethyl) acetamide or a pharmaceutically acceptable salt Of the same; tttt) 4- [3-chloro-4- (1, 3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; uuuu) 4-. { 3-Chloro-4- [(-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; vvvv) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- (4- (3-thienylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; wwww) 6-methoxy-7 - [3- (4-morpholinyl) propoxy) -4- (4- (2-thienylmethyl) -anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; xxxx) 6-methoxy-4- (4-phenoxyanilino) -7- [2- (2H-1, 2, 3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; yyyy) 6-methoxy-4- (4-phenoxyanilino) -7- [2- (1 H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; zzzz) 4- (4-benzylanilino) -6-methoxy-7- [2- (2H-1, 2, 3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; aaaaa) 4- (4-benzylanilino) -6-methoxy-7- [2- (1H-1, 2, 3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; bbbbb) 6-methoxy-7- [3- (4-morpholinyl) propoxy) -4- [4- (2-pyridinyloxy) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; cecee) 4-. { 3-Chloro-4- [(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ddddd) 4- [4- (2-furylmethyl) anilino) -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; eeeee) 6-methoxy-7- [3- (4-morpholinyl) propoxy) -4- [4- (tetrahydro-2-furanylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; fffff) 4- [4- (3-furylmethyl) anilino) -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ggggg) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- (4- (tetrahydro-3-furanylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof, hhhhh) 4- ( 3-chloro-4- { [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino.} Anilino) -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt acceptable thereof; iiiii) (E) -N- [4- (3-chloro-4. {[[5- (trifluoromethyl) -1,4,4-thiadiazol-2-yl] amino.} anilino) -3-cyano -7-ethoxy-6-quinolinyl] -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; j j j j) 4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; kkkkk) 6-amino-4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; lllll) (E) -N- (4- [3-chloro-4- (4-pyridinyloxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl.} -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; mmmmm) 4-. { 3-Chloro-4- [(3-pyridinylmethyl) amino] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnnnn) 6-amino-4-. { 3-Chloro-4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ooooo) 6-amino-4 (3-chloro-4. {[[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino.} anilino) -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ppppp) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-phenylethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; q) (E) -N- (4- (3-chloro-4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino.} - 3-cyano-7-methoxy-6 -quinolinyl) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; rrrrr) 4- [3-chloro-4- (lH-imidazol-1-yl) anilino] -6-methoxy-7 - [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; sssss) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinyloxy) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ttttt) 4- [3-chloro-4- (4-pyridinyloxy) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; uuuu) 6-methoxy-7- [3- (4-morpholinyl) propoxy] 4- [4- (4-pyridinyloxy) anilino) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; vvvvv) 4- [2-chloro-4- (1, 3-thiazol-2-ylsulfanyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; wwwww) N- [2-chloro-4- (. {3-cyano-6-methoxy-7- [3- (4-morpholinyl) propoxy] -4-quinolinyl}. amino) phenyl] -N- ( 3-pyridinyl-methyl) acetamide or a pharmaceutically acceptable salt thereof; xxxxx) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (lH-tetraazol-5-ylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; yyyyy) 6-methoxy-7- [3- (4-morpholinyl) propoxy] 4- [4- (2H-1, 2, 3-triazo1-2-ylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; zzzzz) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1 H-1, 2, 3-triazol-1-ylmethyl) anilino] -3-quinoline-carbonitrile or a salt pharmaceutically acceptable thereof; aaaaaa) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [2- (2H-1, 2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically salt acceptable thereof; bbbbbb) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [2- (lH-1, 2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutically salt acceptable thereof; cccccc) 7-ethoxy-6-nitro-4- [4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinoline-carbonitrile or a salt pharmaceutically acceptable thereof; dddddd) 6-amino-7-ethoxy-4- [4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt of the same; eeeeee) (E) -N- (3-cyano-7-ethoxy-4- [4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -6 -quinolinyl.} -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; ffffff) 4- [3-chloro-4- (lH-imidazol-l-ylmethyl) anilino] -7-ethoxy -6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; gggggg) 6-amino-4- [3-chloro-4- (lH-imidazol-1-ylmethyl) anilino] -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; hhhhhh) (E) -N-. { 4- [3-chloro-4- (lH-imidazol-1-ylmethyl) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; iiiiii) 4-. { 3-Chloro-4- [(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; jjjjjj) 6-amino-4-. { 3-Chloro-4- [(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; kkkkkk) (E) -N- (4- { 3-chloro-4- [(4-methyl-2-pyrimidinyl) sulfanyl) anilino} -3-cyano-7-ethoxy-6-quinolinyl) -4- (dimethylamino) -2 -butenamide or a pharmaceutically acceptable salt thereof; Lililí) 4-. { 3-Chloro-4- [(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; mmmmmm) 6-amino-4-. { 3-Chloro-4- [(4,6-dimethyl-2-pyrimidinyl) sulfanyl) anilino} -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnnnnn) (E) -N- (4- (3-chloro-4- [(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino.}. 3-cyano-7-ethoxy-6-quinolinyl) -4 - (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; oooooo) 4- [4- (lH-imidazol-2-ylmethyl) anilino) -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; pppppp) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (IH-tetraazol-1-ylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; q) 6-methoxy-7- [3- (4-morpholinyl) propoxy) -4- [4- (2H-tetraazol-2-ylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; rrrrrr) 4-. { 3-Chloro-4- [(4,6-dimethy1-2-pyrimidinyl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ssssss) 4-. { 3-Chloro-4 - [(4-methi1-2-pyrimidinyl) sulfanyl) anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy) -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ttttt) (E) -N- [4- (3-chloro-4. {[[2- (phenylsulfanyl) acetyl] amino} anilino) -3-cyano-7-methoxy-6-quinolinyl] -4 - (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; uuuuuu) 4- [4- (2,6-dimethoxyphenoxy) anilino) -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; vvvvvv) 6-methoxy-4- [4- (3-methoxyphenoxy) anilino] -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; wwwwww) 6-methoxy-4- (4- [(1-methyl-lH-imidazol-2-yl) sulfanyl] anilino) -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically salt acceptable thereof; xxxxxx) (E) -N- (4- [3-chloro-4- (1, 3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinolinyl) -4- [(2 -methoxyethyl) (methyl) amino] -2-butenamide or a pharmaceutically acceptable salt thereof; yyyyyy) (E) -N- (4-. {3-chloro-4- [(5-phenyl-1, 3-thiazol-2-yl) sulfanyl] anilino.} - 3-cyano-7-methoxy -6-quinolinyl) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; zzzzzz) (E) -N- (4- (3-chloro-4- [(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino.} - 3-cyano-7- 'ethoxy- 6-quinolin) -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; aaaaaaa) 4-. { 3-Chloro-4- [(4,6-dimethy1-2-pyrimidinyl) sulfanyl] anilino} 6,6-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; bbbbbbb) 6, 7-dimethoxy-4- (. {6- [3- (4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3-pyridinyl] amino] -3-quinolinecarbonitrile or a salt pharmaceutically acceptable thereof; ccccccc) 4-. { 3-Chloro-4- [(1-methyl-1H-imidazol-2-yl) sulfanii] anilino} -6-methoxy-7- [3- (1H-1,2,3-triazol-1-yl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof. 12. The use of a compound of formula 1 for the manufacture of a medicament for treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof. where: X is a ring system of aryl or bicyclic heteroaryl of 8 to 12 atoms where the bicyclic heteroaryl ring contains from 1 to 4 heteroatoms selected from N, O and S with the proviso that the bicyclic heteroaryl ring does not contain any linkages. -0, SS or SO and where the aryl or bicyclic heteroaryl ring may optionally be mono-, di-, tri, or tetra substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 atoms of 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 carbon, 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 a atoms of carbon, 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 atoms of carbon, 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; or X is a radical that has the formula: where A is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, or di-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 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 3-10 carbon atoms, mercapto, and benzoylamino; T is bonded to a carbon of A and is: -NH (CH2) m-, -0 (CH2) m-, -S (CH2) m-, -NR (CH2) m-, - (CH2) m- - (CH2) mNH-, - (CH2) m0-, - (CH2) mS- or - (CH2) mNR-; L is an unsubstituted phenyl ring or a mono-, di- or tri phenyl ring 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 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 carbon atoms, N, N-dialkylaminoalkoxy of 3 -10 carbon atoms, mercapto, and benzoylamino; provided that L can be an unsubstituted phenyl ring only when m > 0 and T is not -CH2NH- or -CH20-; or L is a 5- or 6-membered heteroaryl ring, wherein the heteroaryl ring contains from 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain OO, SS or SO bonds, and wherein the heteroaryl ring is mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 atoms of carbon, 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 carbon, 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-, -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, 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 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, R8R9-CH-M- (C (R6) 2 ) kY- R7- (C (R6) 2) g-Y-. R7- (C (R6) 2) p-M- (C (R6) 2) k-Y-. or Het- (C (R6) 2) q-W- (C (R6) 2) k-Y-; or Ri and R4 are as defined above and Gi or G2 or both are R2-NH-; or if any of the substituents Ri, G2, G3 or R4 are located contiguous to carbon atoms then they can be taken together as the divalent radical -O-C (Rβ) 2 ~ 0-; And it's a divalent radical selected from the group consisting of - (CH2) to -O- - -NN-- R 6 R7 is -NR6R6, -0R6, -J, -N (R6) 3+, or -NR6 (0R6); M is > NR6, -O-, > N- (C (R6) 2) PNR6R6, or > N- (C (R6) 2) P0R6; W is > NRe, -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; where the Het is mono- or di-substituted on a carbon or nitrogen with R6, optionally mono- or di-substituted on a carbon with hydroxy, -N (Re) 2, or -0R6, optionally mono or disubstituted on carbon with monovalent radicals - (C (R6) 2) sORe or - (C (R6) 2) SN (Re) 2, and optionally mono or disubstituted on a carbon saturated with divalent radicals -0- or -0 (C (R) 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 atoms of carbon, 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, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms carbon, 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; with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2 is selected from the group consisting of R R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, (CÍRe ^ p / \ Rr (C (R6) 2) PN ^ ^ - (CÍRehJr (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) 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, R7- (C (R6) 2) S- • R7- (C (R6) 2) p-M- (C (R6) 2) r- R8R9-CH- - (C (R6) 2), -. Or Het- (C (R6) 2) q-W- (C (R6) 2) r-: Ra, and Rg are each, independently, (C (R6) 2) rNR6R6, or (C (R6) 2) r0R6; J is independently hydrogen, chloro, fluoro or bromo-bromo; Q is alkyl of 1-6 carbon atoms or hydrogen; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; m is 0-3; 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, fugu ^ 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 -0- and RT is -0R6, then p = 1-4, when Y is -NR6-, 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 bound through a nitrogen atom and Y is -0- or -NR6-, then k = 2-4 13. The use according to claim 12, 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. 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 in need thereof where: X is a ring system of aryl or bicyclic heteroaryl from 8 to 12 atoms where the heteroaryl ring or bicyclic contains from 1 to 4 heteroatoms selected from N, O and S with the proviso that the bicyclic heteroaryl ring does not contain OO, SS or SO bonds and where the aryl or bicyclic heteroaryl ring can optionally be mono-, di- or , tri, or tetra substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 atom 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 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino; or X is a radical that has the formula: ytyL where A is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, or di-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 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 3-10 carbon atoms, mercapto, and benzoylamino; T is bonded to a carbon of A and is: -NH (CH2) m-, -0 (CH2) m-, -S (CH2) m-, -NR (CH2) m-, - (CH2) m- - (CH2) mNH-, - (CH2) mO-, - (CH2) mS- or - (CH2) mNR-; L is an unsubstituted phenyl ring or a mono-, di- or tri phenyl ring 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 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 carbon atoms, N, N-dialkylaminoalkoxy of 3 -10 carbon atoms, mercapto, and benzoylamino; provided that L can be an unsubstituted phenyl ring only when m > 0 and T is not -CH2NH- or -CH20-; or L is a 5- or 6-membered heteroaryl ring, wherein the heteroaryl ring contains from 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain OO, SS or SO bonds, and wherein the heteroaryl ring is mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 atoms of carbon, 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 carbon, 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-, -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, alkynyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 atoms of carbon 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, 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-: o Ri and R4 are as defined above and G_ or G2 or both are R2-NH-; or if any of the substituents Ri, G2, G3 or R4 are located contiguous to carbon atoms then they can be taken together as the divalent radical -O-C (R6) 2-0-; And it's a divalent radical selected from the group consisting of - (CH2) a-, -O-, and -N-. R7 is -NR6R6, -0R6, -J, -N (R6) 3+, or -NR6 (OR6); M is > NR6, -O-, > N- (C (R6) 2) pNR6R6, or > N- (C (R6) 2) POR6; W is > NRd, -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, -triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and; where the Het is mono- or di-substituted on a carbon or nitrogen with R6, optionally mono- or disubstituted on a carbon with hydroxy, -N (R6) 2, or -OR6, optionally mono or disubstituted on carbon with monovalent radicals - (C (Rβ) 2) S0R6 or - (C (R6) 2) SN (Re) 2, and optionally mono or disubstituted on a carbon saturated with divalent radicals -0- or -0 (C (R6) 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; with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; 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, R7- (C (R6) 2) ^. R7- (C (R6) 2) p- - (C (R6) 2) r- R8R9-CH- - (C (R6) 2) r. .o Heí: (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, (C (R6) 2) P / \ Rr (C (R6) 2) P ~ N? OR-. { C (ñ &) z) r (C (R6.2) p R7- (C (R6) 2) S-. R7- (C (R6) 2) P- - (C (R6) 2) r R8Rg-CH-M- (C (R6) 2), Q, 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; 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; m is 0-3; 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 -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 bound through a nitrogen atom and Y is -O- or -NRe ~, then k = 2-4. 15. A pharmaceutical composition, characterized in that it comprises a compound of formula 1 having the structure where: X is an aryl or bicyclic heteroaryl ring system of 8 to 12 atoms where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S with the proviso that the bicyclic heteroaryl ring does not contain OO bonds , SS or SO and where the aryl or bicyclic heteroaryl ring may optionally be mono-, di-, tri, or tetra substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 a. 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 atoms of carbon, 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; or X is a radical that has the formula: where A is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, or di-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 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 3-10 carbon atoms, mercapto, and benzoylamino; T is bonded to a carbon of A and is: -NH (CH2) m-, -0 (CH2) m-, -S (CH2) m-, -NR (CH2) m-, ~ (CH2) m- - (CH2) mNH-, - (CH2) m0-, - (CH2) mS- or - (CH2) mNR ~; L is an unsubstituted phenyl ring or a phenyl ring 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 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 carbon atoms, N, N-dialkylaminoalkoxy of 3 -10 carbon atoms, mercapto, and benzoylamino; provided that L can be an unsubstituted phenyl ring only when m > 0 and T is not -CH2NH- or -CH20-; or L is a 5- or 6-membered heteroaryl ring, wherein the heteroaryl ring contains from 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain OO, SS or SO bonds, and wherein the heteroaryl ring is mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, 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 atoms of carbon, 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 carbon, 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-, -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, 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, 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, § RßR9-CH- - (C (R6) 2) k-Y-. R7- (C (R6) 2) Q-Y-. Rr (C (R6) 2) P-M- (C (R6) 2) k-Y-. or Het- (C (R6) 2) q-W- (C (R6) 2) k-Y-: or Ri and R4 are as defined above and Gi or G2 or both are R2-NH-; or if any of the substituents Ri, G2, G3 or R4 are located contiguous to carbon atoms then they can be taken together as the divalent radical -O-C (R6) 2-0-; And it is a divalent radical selected from the group consisting of - (CH2) to -N- RR R7 is -NR6R6, -OR6, -J, -N (R6) 3+, or -NR6 (OR6); 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; where the Het is mono- or di-substituted on a carbon or nitrogen with Rβ, optionally mono- or di-substituted on a carbon with hydroxy, -N (R6) 2, or -OR6, optionally mono or disubstituted on carbon with monovalent radicals - (C (R6) 2) sOR6 or - (C (R6) 2) SN (R6) 2, 'and 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; with the proviso that the alkenyl or alkynyl portion is attached to a nitrogen or oxygen atom through a saturated carbon atom; 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 / \ Rt- (C (R6) 2) p-N N- (C (ñ6) 2) r (C (R6) 2) P R7- (C (R6) 2) s-. R7- (C (R6) 2) p- - (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, (C (R6) 2) P / \ Rr (C (R6) 2) p- N- (C (R6) 2) r-. (C (R6) 2) p R7- (C (R6) 2) s-. R

7. (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 Rg are each, independently, (C (R6) 2) rNR6R6. or (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; 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; m is 0-3; 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 R 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 also provided that when Y is -NR6- and R7 is -NRdRe. -N (R6) 3+ or -NR6 (OR6); then g = 2-6; when M is -0- and R is -0R6, then p = 1-4; when Y is -NR6-, then k = 2-4; when Y is -0- 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 -0- or -NR6-, then k = 2-4; and a pharmaceutical carrier. 16. 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 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-O-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 V This invention provides compounds of formula (1), where RX- t Gl f 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.