WO 2005/070890 PCT/US2005/001384 - 1-TITLE QUINOLINE INTERMEDIATES OF RECEPTOR TYROSINE KINASE INHIBITORS AND THE SYNTHESIS THEREOF BACKGROUND OF THE INVENTION Field of the Invention [0001] 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. Related Background Art [0002] Protein tyrosine kinases (PTKs) are critical in regulating cell growth and differentiation. One general class of PTK is the receptor tyrosine kinase (RTK). Once activated, usually through the binding of a ligand, an RTK initiates signaling for various activities, such as cell growth and replication. [0003] The RTKs comprise one of the larger families of PTKs and have diverse biological activity. At present, at least nineteen (19) distinct subfamilies of RTKs have been identified. One such subfamily is the "HER" family of RTKs, which includes epidermal growth factor receptor (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). [0004] Under certain conditions, as a result of either mutation or over expression, studies have shown that these RTKs can become deregulated; the result of which 2 WO 2005/070890 PCT/US2005/001384 is uncontrolled cell proliferation which can lead to tumor growth and cancer (Wilks, A. F., Adv. Cancer Res., 60,43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)). For example, over expression of the receptor kinase product of the ErbB2 oncogene has been associated with human breast and ovarian cancers (Slamon, D. J. et al., Science, 244, 707 (1989) and Science, 235, 177 (1987)). [0005] In addition, deregulation of EGFR kinase has been associated with epidermoid tumors (Reiss, M., et al., Cancer Res., 51, 6254 (1991)), breast tumors (Macias, A. et al., Anticancer Res., 7, 459 (1987)), and tumors involving other major organs (Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)). [0006] These RTKs are known to also be involved in processes crucial to tumor progression, such as apoptosis, angiogenesis and metastasis. [0007] Therefore, inhibitors of these RTKs have potential therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. Accordingly, many recent studies have dealt with the development of specific RTK inhibitors as potential anti cancer therapeutic agents (e.g., Traxler, P., Exp. Opin. Ther. Patents, 8, 1599 (1998) and Bridges, A. J., Emerging Drugs, 3, 279 (1998)). [0008] Quinoline derivatives are known to be important intermediate compounds in the synthesis of RTK inhibitors. For example, in the following US patents, quinoline derivatives are disclosed and the compounds are stated to be involved in inhibiting PTK activity: 6,288,082 (September 11, 2001) and 6,297,258 (October 2, 2001). [0009] In addition, various methods for the preparation of quinoline derivatives are known in the art, but these methods contain serious limitations. One such method is the thermal cyclization reaction. (Sabnis, R.W., et al., J. Hetero. Chem., 29, 65 (1992); Mehta, N.C., et al., J. Ind. Chem. Soc, 55(2), 193 (1978); Bredereck, H., et al., Chem. Ber., 98(4), 1081 (1965); Salon, J., et al., fur Chem., 131, 293 (2000)). Although commonly used, this method requires high temperature conditions, which limits its use for large-scale production of quinoline and quinoline derivatives. This method also requires high dilution conditions, which results in an overall decrease in throughput. Furthermore, the yields from thermal cyclization reactions are typically 50% or less. 3 WO 2005/070890 PCT/US2005/001384 [0010] Another limitation is that many reactions used in preparing quinoline derivatives often generate unwanted by-products. For example, the chlorination reaction used in preparing quinoline derivatives suffers from the generation of viscous tars and decomposition products that are difficu It to clean and remove, which results in yields that vary widely, typically in the range from 24-64%. [0011] Recently, there has been research into other methods for the preparation of quinoline derivatives. One such method involves the use of microwave-assisted methodology for the preparation of quinolones from aromatic amines. (Dave, C. G., et al., Ind. J. Chem., 4IB, 650 (2002)). However, these newer methods also suffer from the same foregoing limitations, such as the high temperature conditions requirement. [0012] Accordingly, there continues to be a need for novel quinoline compounds used in the preparation of RTK inhibitors and methods of preparing such quinoline compounds without the foregoing limitations. In particular, there is a need for methods of preparing such quinoline compounds without the requirement of high temperature conditions. SUMMARY OF THE INVENTION [0013] This invention relates to methods of preparing 4-substifuted quinoline compounds as intermediates in the manufacture of RTK inhibitors and intermediates used in the methods thereof. [0014] Thus, in one aspect, the present invention is a method of preparing a 4-subsrituted quinoline compound comprising the step of reacting a compound of formula (II): 4 WO 2005/070890 PCT/US2O05/001384 with a reagent of formula POLG'3) wherein LG' is halo, to provide a compound of formula (I): wherein LG is a leaving group selected from the group consisting of morpholine, o-mesyl, o-tosyl, trifilate, LG" is a leaving group selected from the group consisting of morpholine, o-mesyl, o-tosyl, trifilate, or halogen; PG is a protecting group selected from the group consisting of acyl, CH3OC(O)-, EtOC(O)--, Fmoc, trifluoroacetamide, Troc, Phenoc, benzamide, Teoc and cyclic imides such as pthalimide, maleimide and 2,5-dimethylpyrrole; A is O, NR, or S, R is H, alkyl, alkenyl or alkynyl; and G, 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 carbon atoms, alkynylosy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,' alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl 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, 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, WO 2005/070890 PCT/US2005/001384 RaRs-C-M-{C(R6)2)k-Y- R7-(C(R^)2)g-Y-, R7-(C(R^)2)p-M-(C(R6)2)k-Y-, or Het-(C(R6)2)qW-(C(RNR6, -O-, >N-(C(R6)2)PNR6R6) or >N-(Cfll^p-OR"; W is >NR6, -O- or is a bond; Het is is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophcne, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and wherein Het is optionally mono- or di-substituted on carbon or nitrogen with R<5, optionally mono- or di-substituted on carbon with hydroxy, -N(R6)2, or -OR6, optionally mono or di-substituted on carbon with the mono-valent radicals -(C(R6)2)s ORj or -(C(R<5)2)S N(Rg)2, and optionally mono or di-substituted on a saturated carbon with divalent radicals -O- or -O(C(R6)2)S O-; R" is hydrogen, alkyl of 1-6 carbon atoms, alkenj'l of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-1 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, orphenyl optionally substituted with one or more halogen, 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 6 WO 2005/070890 PCT/US2005/001384 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 moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; R.2, is selected from the group consisting of 1. WO 2005/070890 PCT/US2005/001384 8 WO 2005/070890 PCT/US2005/001384 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-(CCR^)-, R7-(C(Rs)2)p-M-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 morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene; tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and 3o WO 2005/070890 PCT/US2005/001384 wherein Het is optionally mono- or di-substituted on caibon or nitrogen with R6, optionally mono- or di-substituted on carbon with hydroxy, -N(R")2, or -OR", optionally mono or di-substituted on carbon with the mono-valent radicals -(C(R<;)2)S ORtf or -(C(R$)2)S N(Rs)2, and optionally mono or di-substituted on a saturated carbon with divalent radicals -O- or -O(C(R$)2)S O-; R$ 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 afoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, 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, 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 moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; R.2, is selected from the group consisting of 31 WO 2005/070890 PCT/US2005/001384 3^ WO 2005/070890 PCT/US2005/001384 R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Rr-(C(R")2)S-, RT-(C(R*)2)P-M-NR6, -O-, >N-(C(R")2)pNR6R", or >N-{CCR^p-OR6; \V is >NR6, -O- or is a bond; Het is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-txiazole, thiazole, thiazolidine, tetrazole, piperazine, furan, fhiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and wherein Het is optionally mono- or di-substitutecf on carbon or nitrogen with Rg, optionally mono- or di-substituted on carbon with hydroxy, -N(Rfi)2, or -OR6, optionally mono or di-substituted on carbon with the mono-valent radicals -(C(R6)2)s ORfi or -(C(R6)2)S N(R6)2, and optionally mono or di-substituted on a saturated carbon with divalent radicals -O- or-O(C(R6)2)S O-; {0 WO 2005/070890 PCT/US2005/001384 Rs 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 halogen, 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, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, bejizoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; R.2, is selected from the group consisting of hi WO 2005/070890 PCT/US2005/001384 HI WO 2005/070890 PCT/US2005/001384 ^3 WO 2005/070890 PCT/US2005/001384 g=l-6; k=0-4; n is 0-1; m is 0-3; p=2-4; q=0-4; i=i-4; s=l-6; u=0-4 and v=0-4, wherein the sum of u+v is 2-4; x= 0-3; y=0-l; z=0-3; ZcanbeNR'.OorS; n isO or 1; and X can be cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups, or is a pyridinyl, pyrimidinyl, or phenyl ring, wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with a substiiuent 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, berizoyl, 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, alkynoylamino 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 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 WO 2005/070890 PCT/US2005/001384 heteroaryl ring does not contain O-O, S-S, or S-O bonds and where the bicyclic aryl or bicyclic heteroaryl ring may be optionally 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 carbon atoms, dialkyl amino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino 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 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, alkylamnino 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, alkynoylamino 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, WO 2005/070890 PCT/US2005/001384 N,N-dialkylaminoalkoxy of 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 - -