MXPA06008154A - Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof - Google Patents

Abstract

This invention is directed to methods of preparing 4-substituted quinoline compounds as intermediates in the manufacture of receptor tyrosine kinase inhibitors and intermediate compounds used in the methods thereof, wherein the4-substituted quinoline compound has the general formula (I);and wherein substitutions at LG”, PG, A, G, R1 and R4 are set forth in the specification.

Description

QUINASINE RECEPTOR INHIBITORS QUINOLINE INTERMEDIARIES AND THE SYNTHESIS OF THEM FIELD OF THE INVENTION This invention is directed to methods of preparing 4-substituted quinoline compounds as intermediates in the preparation of inhibitors of tyrosine kinase receptors and the intermediates used in such methods.

BACKGROUND OF THE INVENTION Protein tyrosine kinases (PTK) are critical for the regulation of cell growth and differentiation. A general class of PTK comprises the tyrosine kinase receptors (RTK). Once activated, usually through binding of a ligand, an RTK initiates signals for various activities, such as cell growth and replication. The RTKs comprise one of the largest families of PTK and present diverse biological activities. Up to the present, at least nineteen (19) distinct subfamilies of RTK have been identified. One such subfamily is the "HER" family of RTK, which includes the epidermal growth factor receptor (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). Under certain conditions, different studies have shown that, as a result of either a mutation or overexpression, these RTKs can be subsensitized; which results in an uncontrolled cell proliferation that can lead to the growth of tumors and different types of cancer (Wilks, AF, Adv. Cancer Res., 60, 43 (1993) and Parsons, JT; Parsons, SJ, Important Advances in Oncology, DeVita, VT Ed., JB Lippincott Co., Phila., 3 (1993)). For example, overexpression of the receptor kinase product of the ErbB2 oncogenes has been associated with breast and ovarian cancer in humans (Slamon, DJ et al., Science, 244, 707 (1989) and Science, 235, 177 ( 1987)). In addition, deregulation of EGFR kinase has been associated with epidermoid tumors (Reiss, M., et al., Cancer Res., 51, 6254 (1991)), breast tumors (Mac as, A. et al., Antlcancer Res., 7, 459 (1987)) and tumors that involve other important organs (Gullick, WJ, Brit. Med. Bull., 47, 87 (1991)). It is also known that these RTKs are involved in the crucial processes for the progress of tumors, such as apoptosis, angiogenesis and metastasis. Therefore, inhibitors of these RTKs are potentially of therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. Accordingly, many of the more recent studies deal with the development of specific RTK inhibitors as potential anti-cancer therapeutic agents (eg, Traxler, P., Exp. Opin. Ther.Patents, 8, 1599 (1998) and Bridges, AJ, Emerging Drugs, 3, 279 (1998)). Quinoline derivatives are known to be important intermediates in the synthesis of RTK inhibitors. For example, in the following US Patents, quinoline derivatives are disclosed and it is stated that the compounds are committed to the inhibition of PTK activity: 6,288,082 (September 11, 2001) and 6,297,258 (October 2, 2001). ). In addition, various methods for the preparation of quinoline derivatives are known in the art, but these methods present serious limitations. One such method is the thermal cycling reaction. (Sabnis, RW, et al., J. Hetero, Chem., 29, 65 (1992); Mehta, NC, et al., J. Ind. Chem. Soc, 55 (2), 193 (1978); Bredereck. , H., et al., Chem. Ber., 98 (4), 1081 (1965); Hall, J., et al., Fur Chem., 131, 293 (2000)). Although it is commonly used, this method requires high temperature conditions, which limits its use in the large-scale production of quinoline and quinoline derivatives. This method also requires high dilution conditions, which result in a generalized decrease in yield. Furthermore, the yields of the thermal cycling reactions are typically 50% or less. Another limitation is that many of the reactions used in the preparation of the quinoline derivatives often generate undesired side products. For example, the chlorination reaction used in the preparation of quinoline derivatives has the opposite of generating a viscous tar and decomposition products that are difficult to clean and eliminate, which results in highly variable yields, typically in a range between 24-64. %. Recently, other methods for the preparation of quinoline derivatives have begun to be investigated. One such method comprises the use of microwave-assisted methodology for the preparation of quinolones from aromatic amines. (Dave, C.G., et al., Ind. J. Chem., 41 B, 650 (2002)). However, these newer methods also suffer from the same limitations as previously mentioned, such as the requirement of high temperature conditions. Accordingly, there remains a need for new quinoline compounds in the preparation of RTK inhibitors and methods of preparation said quinoline compounds without the limitations mentioned. In particular, there remains a need for methods of preparing said quinoline compounds without the requirement of high temperature conditions.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to methods of preparing 4-substituted quinoline compounds as intermediates in the preparation of RTK inhibitors and to the intermediates used in said methods.

Therefore, in one aspect, the present invention is a method of preparing a 4-substituted quinoline compound comprising step of reacting a compound of formula (II): with a reagent of formula POLG'3, where LG 'is halo, to provide a compound of formula (I): where LG is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate, LG "is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate or halogen; a protective group selected from the group consisting of acyl, CH3OC (O) -, EtOC (O) -, Fmoc, trifluoroacetamide, Troc, Fenoc, benzamide, Teoc and cyclic imides, such as phthalimide, maleimide and 2,5-dimethylpyrrole; is O, NR or S, R is H, alkyl, alkenyl or alkynyl, and G, R1 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 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkyloxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkyloxy imethyl 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, alkylsulfonamide of 1-6 carbon atoms, alkenylsulfonamide of 2-6 carbon atoms, alkynylsulfonamide of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms carbon, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms carbon, 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 / (GÍRefeJp Rr (C (Rβ) 2) gY-, Rr (C (R6) 2) PM- (C (R6) 2) kY-, or Het- (C (R6) 2) qW- (C (R6) 2- Y- or Ri and R4 are as defined above and G is R2-NH-, or if any of the substituents Ri, R4 0 G are located on contiguous carbon atoms then they can be taken together as the divalent radical -O-C (R6) 2-O; And it is a divalent radical selected from the group formed by «A (CHzJa, O, and H - 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) P-OR6; W is > NR6, - O - or is a link; Het is selected from the group consisting of morpholino, thiomorpholino, S-oxide of thiomorpholino, S, S-thiomorpholino dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2-triazole, 1,4-triazole, thiazole, thiazolidine, tetrazol, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and H where Het is optionally mono- or di-substituted on carbon or nitrogen with R6, optionally mono- or di-substituted on carbon with hydroxy, - N (R6) 2, or - ORß, optionally mono or di-substituted on e! carbon with the monovalent radicals - (C (R6) 2) s OR6 or - (C (R6) 2) SN (Rβ) 2, and optionally mono or di-substituted on a carbon saturated with divalent radicals - O - or - O (C (R6) 2) s O-; 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 between halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azide, 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 atoms of carbon or alkyl of 1-6 carbon atoms; with the proviso that the alkenyl or alkynyl group is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2, is selected from the group formed by 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) pM- (C (R6) 2) r-, RsRg-CH- 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, phenylcarboalkyl of 2-7 carbon atoms, R7- (C (R6) 2) s-, R7- (C (R6) 2) pM- (C (R6) 2) r-, R8R9-CH- M- (C (R6) 2) r- or Het - (C (R6) 2) qW- (C (R6) 2) r-; R8 and R9 are each, independently, - (C (R6) 2) rNR6R6, or - (C (R6) 2) rOR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is an 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; x = 0-3; y = 0-1; z = 0-3; or a salt of it. The present invention is also directed to a method for synthesizing a compound of formula (Vlll): (Vlll), which comprises the steps of: a. reacting a compound of formula (I): (I) with a nucleophilic reagent of formula HZ- (CH2) n-X; or b (i), reacting a compound of formula (II): (ll), with a nucleophilic reagent of formula HZ- (CH2) n-X to form a compound of formula (IX): (ix); and b (ii). cyclizing the compound of formula (IX) with a reagent of formula POLG 'to produce the compound of formula (Vlll). where LG, LG \ LG ", PG, A, G, Ri and R are as defined above, and Z can be NR ', O or S, n is 0 or 1, and X can be cycloalkyl of 3 to 7 atoms of carbon, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms or is a pyridinyl, pyrimidinyl or phenyl ring, wherein said pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, di- or trisubstituted 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, azide, 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 can be a bicyclic aryl ring system or bicyclic heteroaryl of 8 to 12 atoms, where the ring Bicyclic heteroaryl contains 1 to 4 heteroatoms selected from N, O and S, provided that the bicyclic heteroaryl ring contains no O-O, S-S, or S-O bonds and where the bicyclic aryl ring or bicyclic heteroaryl may optionally be mono- di-, tri- or tetrasus 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, azide, hydroxyalkyl of 1-6 atoms of carbon, 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 atoms carbon, 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 atoms of carbon, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino, or X can be a radical of the following formula: where A is a pyridinyl, pyrimidinyl or phenyl ring; wherein said pyridinyl, pyrimidinyl or phenyl ring may be optionally mono- or disubstituted 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 carbon, azide, 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 -, - O (CH2) m - - S (CH2) m -, - NR (CH2) m -, - (CH2) m (CH2) m NH-, - (CH2) m O-, - (CH2) m S- or - (CH2) mNR-, and L is an unsubstituted phenyl ring or a phenyl ring mono-, di- or trisubstituted 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, azide, 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 no, 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 L can be a 5- or 6-membered heteroaryl ring, wherein said heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, with the proviso that the heteroaryl ring does not contain O-O, S-S or S bonds - O, and where the heteroaryl ring is optionally 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, azide, hydroxyalkyl of 1-6 carbon atoms. carbon, 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. In another aspect, the present invention is an intermediate aryl-2-propenamide compound used in the foregoing method of preparing a 4-substituted quinoline compound of formula (I), wherein said aryl-2-propenamide compound is of the following formula ( II): where LG, PG, A, G, R-i and R4 are as defined above.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formulas (I), (II) and (Vlll) can be easily prepared according to the following reaction schemes or modifications thereof. In the following reaction schemes LG, LG ', LG ", X, PG, A, G, Ri and R4 are selected from the groups defined above.Figure 1 illustrates preferred embodiments of the method of preparing a quinoline compound 4- replaced.

SCHEME 1 £ V) In Scheme 1, LG, LG ', LG ", PG, A, G, Ri and R4 are as defined above The quinoline compounds of the present invention possess a protecting group (PG) selected from the group consisting of acyl, CH3OC (O) -, EtOC (O) -, Fmoc, trifluoroacetamide, Trac, Fenoc, benzamide, Teoc and cyclic imides such as phthalimide, maleimide and 2,5-dimethylpyrrole in the substituted A attached at position 6 of the quinoline rings The method of preparing the quinoline compounds of the present invention has many different advantages over the above methods of preparing compounds with a quinoline core.Most significantly, a cyclization step at high temperature is not necessary example, 250 ° C) in the method of the invention In addition, the present method generates little or no insoluble and viscous tar, and the formation of decomposition products is minimized.Furthermore, this method reduces the number of steps necessary. to prepare the desired quinoline compounds. The method shown in Scheme 1 shows that the compound of formula (II) can be converted into a compound of formula (I) by forming the intermediate (VII). However, the intermediate of the formula (VII) can also be isolated. Therefore, this method allows the formation of a quinoline compound with various leaving groups in the 4-position. These quinoline compounds can then be substituted by reacting them with a nucleophilic reagent. With these advantages, the present method overcomes many of the limitations of the above methods, resulting in greater production and a more cost-effective way to prepare the compounds with quinoline nucleus for use in the preparation of RTK inhibitors. . In a preferred embodiment, the compounds of formula (I), (II) and (Vlll) are subjected to the following conditions: When Rβ is an alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, said Alkenyl or alkynyl group is attached to a nitrogen or oxygen atom through a saturated carbon atom. In addition, when Y is - N R6 - and R7 is - N R6 Rβ, - N (R6) 3+, or - N R6 (O Re), then g = 2-6; when M is - O - and R7 is - O R6 then p = 1-4; when Y is - N R6 - then k = 2-4; when Y is - O - and M or W is - O - then k = 1-4; when W is not a bond with Het bound through a nitrogen atom then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is - O - or - N R6 - then k = 2-4. For the purposes of this invention, the term "alkyl" includes linear and branched alkyl groups, which may contain as much as 12 carbon atoms. Preferably, the alkyl group contains between 1 to 6 carbon atoms, although it is even more preferred to be 1 to 4 carbon atoms. The term "alkenyl" refers to an aliphatic hydrocarbon radical containing a double bond and includes straight and branched chain alkenyl groups of 2 to 6 carbon atoms. Said alkenyl groups may exist in their E or Z configurations; The compounds of this invention include both configurations. The term "alkynyl" includes straight and branched chain groups containing from 2 to 6 carbon atoms with at least one triple bond. The term "cycloalkyl" refers to alicyclic hydrocarbon groups possessing from 3 to 12 carbon atoms and includes, by way of example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl or adamantyl. For the purposes of this invention, the term "aryl" is defined as an aromatic hydrocarbon group and may be substituted or unsubstituted. The aryl group preferably contains between 6 and 12 carbon atoms and may be selected from, by way of example, the following groups: phenyl, -naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphtenyl, acenaphthylenyl or phenanthrenyl. The aryl group may be optionally mono-, di-, tri- or tetrasubstituted with substituents selected from, for example, the group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, -SO3H, -SO2NH2, -SO2NH-alkyl, -SO2N (alkyl) 2, -CO2H, CO2NH2) CO2NH-alkyl and -CO2N ( alkyl) o2. Preferred substituents for aryls and heteroaryls include: alkyl, halogen, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, arylalkyl and alkylaryl. For the purposes of this invention, the term "heteroaryl" is defined as a system of heterocyclic aromatic rings (monocyclic or bicyclic), wherein the heteroaryl groups are five or six membered rings containing 1 to 4 heteroatoms selected from the group consisting of S , N and O, and include, by way of example: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,4-oxadiazole, 1,4-triazole, 1-methyl-1, 2,4-triazole, 1 H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole , benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, pyrrolidinyl; (2) a bicyclic aromatic heterocycle, wherein the phenyl, pyridine, pyrimidine or pyridine ring is: (i) fused to a 6-membered aromatic heterocyclic ring (unsaturated) containing a nitrogen atom; (ii) fused to a 5- or 6-membered aromatic heterocyclic ring (unsaturated) containing two nitrogen atoms; (iii) fused to a 5-membered aromatic heterocyclic ring (unsaturated) containing a nitrogen atom together with either an oxygen atom or a sulfur atom; or (v) fused to a 5-membered aromatic heterocyclic ring (unsaturated) containing a heteroatom selected from O, N or S. Preferably, the bicyclic heteroaryl group contains 8 to 12 carbon atoms. For the purposes of this invention, the term "alkoxy" is defined as C-i-Ce-alkyl-O-; where the term alkyl is as previously defined. For the purposes of this invention, the term "alkanoyloxymethyl" is defined as -CH2OC (O) R, where R is an alkyl of 1 to 6 carbon atoms. The terms "alkylaminoalkoxy" and "dialkylaminoalkoxy" refer to alkylamino and dialkylamino groups with one or two alkyl groups (the same or different) attached to the nitrogen atom that is bonded to an alkoxy group of 1 to 6 carbon atoms. Preferably, the dialkylaminoalkoxy group consists of 3 to 10 carbon atoms and an alkylaminoalkoxy group consists of 2 to 9 carbon atoms. For the purposes of this invention, the term "alkylthio" is defined as CrC6-alkyl-S. For the purposes of this invention, "alkoxyalkyl" and "alkylthioalkyl" indicate an alkyl group as previously defined which is further substituted with an alkoxy or alkylthio as previously defined. A preferred alkoxyalkyl group is alkoxymethyl (for example, alkoxy-CH2-). For the purposes of this invention, the term "hydroxy" is defined as an HO- group. Still further, for the purposes of this invention, the term "hydroxyalkyl" is defined as an HO-alkyl- group, wherein the alkyl group consists of 1 to 6 carbons. For the purposes of this invention, the term "benzoylamino" is defined as a group Ph-OC (O) NH-. The terms "monoalkylamino" and "dialkylamino" refer to portions containing one or two alkyl groups, wherein the alkyl chain is from 1 to 6 carbons and the groups may be the same or different. The terms "monoalkylaminoalkyl" and "dialkylaminoalkyl" refer to monoalkylamino and dialkylamino portions with one or two alkyl groups (the same or different) attached to the nitrogen atom that is bonded to an alkyl group of 1 to 6 carbon atoms. Preferably, the dialkylaminoalkyl group consists of 3 to 10 carbon atoms and the alkylaminoalkyl group consists of 2 to 9 carbon atoms. For the purposes of this invention, the term "mercapto" is defined as a -SH group. For the purposes of this invention, the term "carboxy" is defined as a -COOH group. For the purposes of this invention, the terms "alkenoyl amino" and "alkynylamino" are defined as an -NH-COOR group, where R is alkenyl or alkynyl of 3 to 8 carbon atoms. For the purposes of this invention, the term "carboalkoxy" is defined as -CO2R, where R is alkyl of 1 to 6 carbon atoms. For the purposes of this invention, the term "carboalkyl" is defined as -COR, where R is alkyl of 1 to 6 carbon atoms. For the purposes of this invention, the term "carboxyalkyl" is defined as a group HOOCR-, where R is alkyl of 1 to 6 carbon atoms. For the purposes of this invention, the term "carboalkoxyalkyl" is defined as a group -R-CO2-R ', where R and R' are alkyl and together they comprise between 2 and 7 carbon atoms. For the purposes of this invention, the term "aminoalkyl" is defined as H2N-alkyl, wherein the alkyl group consists of 1 to 5 carbon atoms.

"Azide" is a radical of the formula -N3. For the purposes of this invention, the term "alkanoylamino" is defined as a group -NH-COOR, where R is alkyl of 1 to 6 carbon atoms. An "acyl" is a radical of the formula - (C = O) -alkyl or - (C = O) -perfluoroalkyl, wherein the alkyl radical or the perfluoroalkyl radical is from 1 to 6 carbon atoms; preferred examples include without limitation, acetyl, propionyl, butyryl, trifluoroacetyl. For the purposes of this invention, the term "alkylsulfinyl" is defined as a radical R'SO-, where R 'is an alkyl radical of 1 to 6 carbon atoms. An alkylsulfonyl is a radical R'SO2-, where R 'is an alkyl radical of 1 to 6 carbon atoms. Alkylsulfonamide, alkenylsulfonamide, alkynylsulfonamide are radicals R'SO2NH-, where R 'is an alkyl radical of 1 to 6 carbon atoms, an alkenyl radical of 2 to 6 carbon atoms or an alkynyl radical of 2 to 6 carbon atoms, respectively . The term "substituent" is used herein to refer to a radical which may be an atom, a functional group or a group that replaces a hydrogen radical in a molecule. Unless expressly defined otherwise, it is considered that any of the substituents may be optionally substituted with one or more groups selected from: alkyl, halogen, haloalkyl, hydroxyalkyl, nitro, amino, hydroxy, cyano, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, oxo, alkylthio, mercapto, haloalkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, acyl, -CO2-alkyl, -SO3H, -SO2NH2, -SO2NH-alkyl, -SO2NH- (alkyl) 2, -CO2H, -CO2NH2, -CO2NH-alkyl and -C02N- (alkyl) 2. For the purposes of this invention, a "halogen" is one of the elements of non-metals belonging to the group Vil A of the periodic table.

Accordingly, a halogen of the present invention is a monovalent group derived from fluorine, chlorine, bromine, iodine or astatin. Preferred halogens are selected from the group consisting of chlorine, fluorine and bromine. For the purposes of this invention, the term "substituted" refers to the case where a hydrogen radical of a molecule has been replaced by another radical which may be an atom, a functional group or a group; these radicals are referred to collectively as "substituents." For the purposes of this invention, the term "protecting group" refers to a group introduced into a molecule to protect a sensitive functional group or a specific position in the molecule against any reaction when the molecule is exposed to reagents or conditions to transform or react another part of the molecule. The protective group can then be removed. Suitable protecting groups are well known in the art and include acid-labile, base-labile, light-removable or eliminable groups under neutral conditions. See, for example, Green, Protecting Groups in Organic Synthesis, Wiley, p. 218-288 (1985), whose content is incorporated in this document as a reference. In the present invention, suitable protecting groups are acyl groups, CH3OC (O) -, EtOC (O) -, Fmoc, trifluoroacetamide, Troc, Fenoc, benzamide, Teoc and cyclic imides, such as phthalimide, maleimide and 2.5- dimethylpyrrole. In a preferred embodiment, the protecting group is acyl. The compounds of this invention may contain an asymmetric carbon atom and therefore may originate stereoisomers, such as enantiomers and diastereomers. The stereoisomers of the present invention are named according to the Cahn-lngold-Prelog system. Although shown without taking into account the stereochemistry in the formulas (I), (II) and (Vlll), the present invention includes all possible individual stereoisomers; as well as racemic mixtures and other mixtures of R and S stereoisomers (scae mixtures which are mixtures of unequal amounts of enantiomers) or salts thereof. It should be taken into account that the stereoisomers of the invention having the same relative configuration in a chiral center may nevertheless have different designations R and S depending on the substitution in the indicated chiral center. The method described above also includes the preparation and formation of salts of the compounds of the formulas (I), (II) and (Vlll). As a base that is, the quinoline can form various acid salts. The salts of the compounds of the formulas (I), (II) and (Vlll) can be obtained easily by methods known to those skilled in the art. For the purposes of this invention, salts are those that derive from organic and inorganic acids. Said organic and inorganic acids may be any of the known acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similar acceptable acids. The common mineral acids are HCl, HSO and HNO3. These lists are only offered to provide examples and are not intended to be exhaustive. Therefore, it should not be considered that the present invention is limited to these examples.

GENERAL SYNTHESIS SCHEME 1 Scheme 1 illustrates, in part, the synthesis of a 4-substituted quinoline compound of formula (I) from the initial protected aryl-2-propenamide compound of formula (II). As shown in Scheme 1, the aryl-2-propenamide compound of formula (II) is treated with a phosphoryl halide by a Bischler-Napieralski reaction, which results in a compound of formula (I) which is halogenated in position 4. See Bischler, A., Napieralski, B, Ber., 26, 1903 (1893), incorporated herein by reference, by a general description of the Bischler-Napieralski reaction. However, the intermediate compound of formula (VII) can also be isolated, whereby the synthesis of quinoline with either a morpholino, mesylate, tosylate or triflate group at position 4 is obtained. This protected anilinquinoline can be further reacting to form a 4-substituted quinoline in the presence of a catalytic amount of an acid, such as methylsulfonic acid, pyridinium hydrochloride, hydrochloric acid, sulfuric acid or trifluoroacetic acid, and a nucleophilic reagent of formula HZ- (CH2) nX, where Z may be NR ', O or S, n is 0 or, and X may be a cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms , or is a pyridinyl, pyrimidinyl or phenyl ring, wherein said pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, di- or trisubstituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 a. carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azide, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 atoms of 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 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 no, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino, or X can be a bicyclic aryl ring system 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 O-O, S-S or S-O bonds and where the bicyclic aryl ring or bicyclic heteroaryl may be optionally mono-, di- or tri-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, azide, 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 2-7 carbon atoms, carboalqui 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 atoms carbon, 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 can be a radical of the following formula: / YTY where A is a pyridinyl, pyrimidinyl or phenyl ring; wherein said 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, azide, 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 atoms carbon, 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 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 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 attached to a carbon of A and is: -NH (CH2) m -, -0 (CH2) m - -S (CH2) m -, -NR (CH2) ) m -, - (CH2) m (CH2) m NH-, - (CH2) m O-, - (CH2) m S-, or - (CH2) mNR-, and L is an unsubstituted phenyl ring or a mono-, di- or trisubstituted phenyl ring 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, azide, 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, c arboalkyl 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 carbon, 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-alkylaminoalicylic acid from 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 L may be a 5- or 6-membered heteroaryl ring wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S, provided that the heteroaryl ring contains no O-O, S-S or S-bonds. Or, and where the heteroaryl ring is optionally mono- or di-substituted with a s Applicant 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, azide, 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 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-dialqui laminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino. In another preferred embodiment, the phosphoryl halide used in the above Bischler-Napieralski reaction is phosphoryl chloride. For the purposes of this invention, a leaving group is a labile atom or a group of labile atoms which may or may not be charged, which are separated during a substitution or displacement reaction. For the above method, suitable leaving groups may be halo, morpholino, o-mesyl, o-tosyl or triflate. In a preferred embodiment, the leaving group is morpholino. As shown in Scheme 1, the aryl-2-propenamide compound of the formula (ll) can be prepared by various reaction routes, as described in the following schemes 2 and 3.

SCHEME 2 Scheme 2 illustrates a way to form an aryl-2-propenamide compound of formula (II) followed by the synthesis of a halogenated 4-quinoline compound of formula (I). As shown in Scheme 2, the arylamines are reacted with orthoformate to prepare arylformimidates. The arylformimidates are then condensed with active methylene compounds (for example, cyanoacetylmorinoin to provide the aryl-2-propenamides of formula (II)) The Bischler-Napieralski reaction, together with the treatment of the aryl-2-propenamides with a halide of phosphoryl (for example, phosphoryl chloride) results in 4-halogenated quinolines (e.g., 4-chloroquinolines).

SCHEME 3 Scheme 3 illustrates a second route to form an aryl-2-propenamide compound of formula (II) followed by the synthesis of a 4-halogenated quinoline compound of formula (I).

As shown in Scheme 3, active methylene compounds (e.g., cyanoacetylmorpholino) are condensed with orthoformate to produce alkoxymethylene derivative compounds. These alkoxymethylene derivative compounds are then reacted with arylamines to obtain the aryl-2-propenamides of formula (II). The Bischler-Napieralski reaction, together with the treatment of the aryl-2-propenamides with a phosphoryl halide (e.g., phosphoryl chloride) results in 4-halogenated quinolines (e.g., 4-chloroquinolines). The following examples are offered in order to help achieve a better understanding of the invention and are not intended, and should not be construed, as limitations in any way on the invention defined in the claims defined below.

EXAMPLE 1 Synthesis of 6-acetamide-4-chloro-3-cyano-7-ethoxy-quinoline.

Preparation of 4-cyanoacetylmorpholino. A 4-mouth 500 ml balloon was loaded with morpholino (77 g, 0.088 mol). Ethyl cyanoacetate (100.0 g, 0.088 mol) was added. After the addition, the reaction mixture was stirred. The mixture became progressively yellow to light. The mixture was heated at 100-110 ° C for 3.0 hours. A solid formed after cooling to room temperature. Ethyl acetate (150 ml) and heptanes (300 ml) were added and the mixture was stirred for 30 minutes at room temperature. The solid was filtered after which 95.2 g (71% yield) of 4-cyanoacetylmorpholino were obtained. 1 H NMR: d (DMSO-d 6) 4.02 (s, 2H); 3.37 (m, 2H); 3.55 (m, 4H); 3. 45 (m, 2H).

Preparation of propenamide. A 4-mouth 250 ml balloon was charged with 4-cyanoacetylmorpholino (7.21 g, 0.047 mol), aniline (10.0 g, 0.051 mol) and IPA (72 ml). The balloon was equipped with an agitator, a thermocouple and protection with N2. The mixture was heated to 50-60 ° C. The first of three portions of triethyl orthoformate (7.8 ml) was added. After one hour, the second portion of triethyl orthoformate (7.8 ml) was added. Finally, after another hour, the third portion of triethyl orthoformate (7.8 ml) was added. The resulting solution was maintained at 80 ° C for 21 hours. Brown solids were formed after cooling to room temperature. The solids were filtered, washed with IPA (2 x 15 ml) and dried to obtain 8.43 g (51% yield) of the desired compound. 1 H NMR: d (DMSO-d 6) 10.69 (d, 1 H); 8.93 (s, 1 H,), 8.30 (d, 1 H), 7. 82 (d, 1H); 6.86 (dd, 1 H); 4.13 (q, 2H); 3.61 (m, 8H); 2.07 (s, 3H); 1.37 (t, 3H).

Preparation of 6-acetamide-4-chloro-3-cyano-7-ethoxy-quinoline. In a 3-neck, 50 ml balloon equipped with a stirrer, a probe for measuring temperature, a condenser and protection with nitrogen was charged propenamide (2.0 g, 5.58 mmol) and suspended in acetonitrile (16 ml). The mixture was heated to 60-65 ° C and phosphorus oxychloride (2.57 g, 1.56 ml, 3.0 eq, d = 1645 g / ml) was added dropwise over 2 min. The mixture became clear and deep red within 30 min. The mixture was kept for 14 hours and then cooled to 0-15 ° C. Water (5 ml) was added to maintain the temperature of the contents <; 20 ° C. The pH was adjusted to 8-10 using either 8% aqueous potassium carbonate or 50% aqueous sodium hydroxide. The mixture can be treated under the different conditions of isolation and purification that are listed below: 1. The organic solvent is removed with a rotary evaporator. Toluene (20 ml) is added to the mixture which is stirred for 1 hour at room temperature, then it is filtered and washed with water (25 ml) and heptane (2 x 25 ml). The solids are dried overnight at 55-60 ° C under complete vacuum to obtain the crude product. 2. Alternatively, isopropyl acetate (30 ml) is added and the mixture is stirred for a minimum of 30 min. The pH was checked again to ensure that it was maintained at a value of 8-10. You can add aqueous potassium carbonate if necessary. The layers were separated and the organic phase was washed with water (2 x 30 ml) and saline (30 ml). Silica gel 60 (30 g) was added to the organic phase and the mixture was stirred for a minimum of 30 min. The mixture was filtered and washed with isopropyl acetate (30 ml). The organic phase was concentrated to dryness to obtain the crude compound. This work of isolation and purification still leaves small amounts of polar impurities in the product.

Claims (25)

NOVELTY OF THE INVENTION CLAIMS

1. - A method of preparing a 4-substituted quinoline compound comprising the step of reacting a compound of the following formula (II): di) with a reagent of formula POLG'3, where LG 'is halo, to provide a compound of the following formula (I): where; LG is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate; LG "is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate and halogen; PG is a protective group selected from the group consisting of acyl, CH3OC (O) -, EtOC (O) -, Fmoc , trifluoroacetamide, Troc, Fenoc, benzamide, Teoc, phthalimide, maleimide and 2,5-dimethylpyrrole, A is O, NR or S, R is H, alkyl, alkenyl or alkynyl, and G, 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 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoxyloxy of 3-8 carbon atoms, alkynoxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenyloxymethyl 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 atoms of carbon, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamide of 1-6 carbon atoms, alkenylsulfonamide of 2-6 carbon atoms, alkynylsulfonamide of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, 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,

R? - (0 (RHMP-N N-tCf? Airifc-Y ^ Fa-c-y-tcoyzifc-? -

R7- (C (R6) 2) gY-, R7- (C (R6) 2) pM- (C (R6) 2) kY- or Het- (C (R6) 2) qW- (C (R6) 2 -Y-, or R, and R4 are as defined above and G is R2-NH-, or if any of the substituents R-i, R4 or G are located on carbon atoms contiguous then they can be taken together as the divalent radical -O-C (R6) 2-O; And it is a divalent radical selected from the group consisting of 6 < CH; áa. O, and N 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) P-OR6; W is > NR6, -O- or is a link; Het is selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino dioxide, piperidine, pyrrolidine, aziridine, pyridine, midazole, 1,2,3-triazole, 1, 2,4- triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and

H where Het is optionally mono- or di-substituted on carbon or nitrogen with Re, optionally mono- or di-substituted on the carbon with hydroxy, -

N (R6) 2, or - ORT, optionally mono or di-substituted on carbon with the monovalent radicals: - (C (R6) 2) S OR6 or - (C (R6) 2) SN (R6) 2, and optionally mono or di-substituted on a carbon saturated with the divalent radicals - O - or - O (C (Rβ) 2) s O -; 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 , nitro, cyano, azide, 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 group is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2, is selected from the group formed by

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) PM- (C (R6) 2) r-, R8R9-CH-, M- (C (R6) 2) -, or Het - (C (R6) 2) q - W - (C (R6) 2) r -; 5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenylcarboalkyl of 2-7 carbon atoms,

R7- (C (R6) 2) s-, R7- (C (R6) 2) PM- (C (R6) 2) r-, R8R9_CH-, M- (C (R6) 2) r-, or Het - (C (R6) 2) q- W- (C (R6) 2) r-; R8, and R9 are each, independently - (C (R6) 2) rNR6R6, or - (C (Rβ) 2) r OR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is an 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; x = 0-3; y = 0-1; z = 0-3; or a salt of it. 2. The method according to claim 1, further characterized in that LG 'is chlorine. 3. The method according to claim 1, further characterized in that it comprises the step of substituting the LG group "in a compound of formula (I) with a nucleophile." 4. The method according to claim 1, further characterized because it comprises the step of forming the compound of formula (II) by condensation of an active methylene compound of formula (IV): with an arylformimidate compound of formula (III) Y) ("where LG, PG, A and G are as previously defined.) 5. The method according to claim 4, further characterized in that LG is morpholino, PG is acyl, A is amino and G is ethoxy. The method according to claim 4, further characterized in that it comprises the step of forming the arylformimidate by reaction of an arylamine of formula (V):

(V) with orthoformate, where PG, A and G are as previously defined. 7. The method according to claim 6, further characterized in that the arylamine compound is N- (4-amino-2-ethoxyphenyl) acetamide. 8. The method according to claim 6, further characterized in that the orthoformate is triethyl orthoformate. 9. The method according to claim 1, further characterized in that it comprises the step of forming the compound of formula (II) by reacting an alkoxymethylene compound of formula (VI):

(VI) with an arylamine of formula (V):

(V) where LG, PG, A and G are as previously defined. 10. The method according to claim 9, further characterized in that LG is morpholino, PG is acyl, A is amino and G is ethoxy. 11. The method according to claim 9, further characterized in that it comprises the step of forming the alkoxymethylene compound by condensation of an active methylene compound of formula

(IV) with orthoformate, where LG is as previously defined. 12. The method according to claim 11, further characterized in that the active methylene compound is morpholincyanoacetate.

13. The method according to claim 11, further characterized in that the orthoformate is triethyl orthoformate.

14. The method according to claim 1, further characterized in that the treatment of the compound of formula (II) with phosphoryl chloride takes place at a temperature in the range of 60 to 100 ° C.

15. The method according to claim 1, further characterized in that a compound of the following formula (VII): is an intermediate that formed after the reaction of a compound of formula (II) with POLG'3, but before the formation of a compound of formula (I), where LG, LG ', PG, A, G, Ri and R4 are as previously defined.

16. The method according to claim 15, further characterized in that LG is morpholino.

17. The method according to claim 16, further characterized in that the compound of formula (VII) is N- [3-cyano-7-ethoxy-4- (4-morpholinyl) -6-quinolinyl] acetamide.

18. The method according to claim 1, further characterized in that the compound of formula (I) is N- [4-chloro-3-cyano-7-hydroxy-6-quinolinyl] acetamide.

19. The method according to claim 1, further characterized in that the compound of formula (II) is morpholin cyanoenamine.

20. A method of preparing a 4-substituted quinoline compound of the following formula (Vlll): (Vlll) where said method comprises the steps of: a. reacting a compound of formula (I): (i) with a nucleophilic reagent of formula HZ- (CH2) n-X; or b (i). reacting a compound of formula (II): (ll) with a nucleophilic reagent of formula HZ- (CH2) n-X to form a compound of formula (IX): (IX); and b (ii). cyclizing the compound of formula (IX) with a reagent of formula POLG 'to produce the compound of formula (Vll1); where: LG is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate; LG 'is halo; LG "is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, triflate and halogen; PG is a protective group selected from the group consisting of acyl, CH3OC (O) -, EtOC (O) -, Fmoc , trifluoroacetamide, Troc, Fenoc, benzamide, Teoc and cyclic imides such as phthalimide, maleimide and 2,5-dimethylpyrrole, A is O, NR or S, R is H, alkyl, alkenyl or alkynyl, and G, 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 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoxyloxy of 3-8 carbon atoms, alkynoxyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenyloxymethyl of 4-9 atoms of carbon, 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, alkylsulfonamide of 1-6 carbon atoms, alkenylsulfonamide of 2-6 carbon atoms, alkynylsulfonamide of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamide 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-alkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R7- (C (R6) 2) gY-, R7- (C (R6) 2) pM- (C (R6) 2) kY- or Het- (C (R6) 2) qW- (C (R6) 2 -Y-, or R, and R are as defined above and G is R2-NH-, or if any of the substituents Ri, R4 or G are located on contiguous carbon atoms then they can be taken together as a divalent radical - OC (R6) 2-O; Y is a divalent radical selected from the group consisting of Re | CHaa, O, and N; 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) P-OR6; W is > NR6, -O- or is a link; Het is selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,4-triazole , thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and H where Het is optionally mono- or di-substituted on carbon or nitrogen with R6, optionally mono- or di-substituted on the carbon with hydroxy, - N (R6) 2 or - ORß, optionally mono or di-substituted on the carbon with the monovalent radicals - (C (R6) 2) s OR6 or - (C (R6) 2 ) SN (R6) 2, and optionally mono or di-substituted on a carbon saturated with divalent radicals - O - or - O (C (R6) 2) s O -; 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 of halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azide, 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 group is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2, is selected from the group formed by R3 S S B R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Rt- (C (R6) 2) S-, Rt- (C (R6) 2) P- M- (C (R6) 2) r-, R8R9-CH-, M- (C (R6) 2) ^ -, or Het - (C (Re) 2) q - W - (C (R6) 2) r -; R5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenylcarboalkyl of 2-7 carbon atoms, R7- (C (R6) 2) s-, R7- (C (R6) 2) P- M- (C (R6) 2) r-, R8R9-CH-, M- (C (R6) 2) r - or Het - (C (R6) 2) q - W - (C (R6) 2) r -; R8 and Rg are each, independently - (C (R6) 2) rNR6R6 or - (C (R6) 2) r OR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is an 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; x = 0-3; y = 0-1; z = 0-3; Z can be NR ', O or S; n is 0 or 1; and X may be cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms, or is a pyridinyl, pyrimidinyl or phenyl ring, wherein said pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or trisubstituted 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, azide, 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, alcan 1-6 carbon atoms, 3-8 carbon atoms alkenoyl amino, 3-8 carbon atoms alkynylamino, 2-7 carbon atoms carboxyalkyl, 3-8 carbon atoms carboalkoxyalkyl, 1-5 aminoalkyl 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 carbon, mercapto and benzoylamino, or X can be a system of bicyclic aryl rings 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 heteroaryl ring bicyclic ring does not contain O-O, S-S, or S-O bonds and where the bicyclic aryl ring or bicyclic heteroaryl may be optionally mono-, di-, tri- or tetrasubstituted with a substituent selected from the group consisting of halogen, oxo, thio , alkyl of 1-6 atoms of ac rbono, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azide, 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-dia lkylaminoalcoxy of 3-10 carbon atoms, mercapto, and benzoylamino, or X can be a radical of the following formula: YYTY where A is a pyridinyl, pyrimidinyl or phenyl ring; wherein said 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, azide, 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 atoms carbon, 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 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 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 -, - O (CH2) m -, -S (CH2) m -, -NR ( CH2) m -, - (CH2) m (CH2) m NH-, - (CH2) m O-, - (CH2) m S-, or - (CH2) mNR-, and L is an unsubstituted phenyl ring or a phenyl ring mono-, di-, or trisubstituted 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, azide, hydroxyalkyl of 1-6 atoms of carbon, 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 arbono, 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 L can be a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S, with the proviso that the heteroaryl ring does not contain O-O, S-S, or S-O bonds, and wherein the heteroaryl ring is optionally 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, azide, 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, alkyl thio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 atoms of carbon, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-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 a salt of it.

21. The method according to claim 20, further characterized because LG 'is chlorine.

22. - A compound of the following formula (II): from where; LG is an outgoing group selected from the group consisting of morpholino, o-mesyl, o-tosyl or triflate; or PG is a protective group selected from the group consisting of acyl, CH3OC (O) -, EtOC (O) -, Fmoc, trifluoroacetamide, Troc, Fenoc, benzamide, Teoc and cyclic imides such as phthalimide, maleimide and 2,5-dimethylpyrroi; A is O, NR or S; R is H, alkyl, alkenyl or alkynyl; and G, 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 carbon atoms. carbon, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms , 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, alkylsulfonamide of 1-6 carbon atoms, alkenylsulfonamide of 2-6 carbon atoms, alkynylsulfonamide of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, 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, R -ÍQR? Ti -N N- (G (RHHIC-Y Rr (C (R6) 2) gY-, R7- (C (R6) 2) pM- (C (R6) 2) kY- or Het- ( C (R6) 2) qW- (C (R6) 2-Y-; or R ^ and R are as defined above and G is R2-NH-; or if any of the substituents Ri, R or G are located on contiguous carbon atoms can then be taken together as the divalent radical -OC (R6) 2-O; Y is a divalent radical selected from the group consisting of (CH ^ a.O. and N- Z R7 is - NR6R6, - OR6 , -, - N (R6) 3+ or - R6 (OR6); M is> NR6, -O-, > N- (C (R6) 2) PNR6R6, or> N- (C (R6) 2) P- OR6; W is> NR6, -O- or is a bond; Het is selected from the group consisting of morpholino, thiomorpholino, thiomorpholino S-oxide, S, S-thiomorpholino dioxide, piperidine, pyrrolidine, aziridine , pyridine, imidazole, 1,2,3-triazole, 1,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxo-ane, tetrahydropyran and H where Het is optionally mono- or di-substituted on a carbon or nitrogen with Rβ, optionally mono- or di-substituted on a carbon with hydroxy, -N (Rβ) 2, or -OR6, optionally mono- or di-substituted on a carbon with the monovalent radicals - (C (R6) 2) s OR6 or - (C (R6) 2) s N (R6) 2, and optionally mono or di-substituted on a carbon saturated with divalent radicals - O - or - O (C (R6) 2) s O -; 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 of halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms carbon, nitro, cyano, azide, 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 group is attached to a nitrogen or oxygen atom through a saturated carbon atom; R2, is selected from the group formed by 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-, M- (C (R6) 2) - , or Het - (C (Rβ) 2) q - - (C (R 6) 2) r -; s is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenylcarboalkyl of 2-7 carbon atoms, Rt- (C (R6) 2) S-, Rt- (C (R6) 2) P- M- (C (R6) 2) ^ -, R8Rg-CH-, M- (C (R6) 2), -, or Het - (C (Rβ) 2) q - - (C (R6) 2) r -; R8 and Rg are each, independently - (C (R6) 2) rNR6R6 or - (C (R6) 2) r OR6; J is independently hydrogen, chlorine, fluorine or bromine; Q is an 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; x = 0-3, y = 0-1, z = 0-3; or a salt of it.

23. The compound according to claim 22, further characterized in that it comprises the following conditions: when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, said alkenyl or alkynyl group is attached to a Nitrogen atom or oxygen through a saturated carbon atom; and further with the proviso that when Y is - N R6 - and R7 is - N R6 R6, - (R6) 3+ or - N R6 (O R), then g = 2-6; when M is - O - and R7 is - O R6, then p = 1-4; when Y is - N R6 -, then k = 2-4; when Y is - O - and M or W is - O -, then k = 1-4; when W is not a bond with Het bound through a nitrogen atom, then q = 2-4; and when W is a bond with Het bonded through a nitrogen atom and Y is - O - or - N R6 -, then k = 2-4.

24. The compound according to claim 22, further characterized in that LG is morpholino.

25. The compound according to claim 24, further characterized in that PG is acyl, A is amino, G is ethoxy, R-i is H and R is H.