MXPA05003519A - 4,6-diaminosubstituted-2-[oxy or aminoxy]-[1,3,5]triazines as protein tyrosine kinase inhibitors - Google Patents

Abstract

The invention is directed to compounds of Formulae (I, II, III) or (IV):wherein R, R1, R2, R3, A1 and A2 are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially VEGFR-2 (KDR), c-fms, c-met and tie-2 kinases. The invention is also directed toward methods of preparation of the compounds of Formulae (I, II, III) and (IV).

Description

2-rOXl O AMINOXp-p .3,51TRIAZLNAS 4,6-DIAMINOSUSTITUlDES AS PROTEIN INHIBITORS TYROSIN KINASE INTERREFERENCE TO RELATED REQUESTS In accordance with article 35 of the U.S.C. section 119 (e), this application claims the benefit of provisional application No. 60 / 414,636, filed on October 1, 2002, the content of which is hereby incorporated in its entirety.

FIELD OF THE INVENTION The invention relates to novel substituted triazines which function as inhibitors of the protein tyrosine kinase. More particularly, the invention relates to 4-diamino-substituted 2- [oxy or aminoxy] - [1, 3,5] triazines which function as inhibitors of VEGFR-2 (KDR), c-fms, c-met and tie-2 kinases.

BACKGROUND OF THE INVENTION Protein kinases are enzymes that serve as key components of signal transduction pathways by catalyzing the transfer of terminal phosphate from ATP to the hydroxy group of protein residues tyrosine, serine and threonine. As a consequence, inhibitors and substrates of protein kinase are valuable tools to assess the physiological consequences of protein kinase activation. It has been shown that overexpression or inappropriate expression of normal or mutant protein kinases in mammals plays an important role in the development of many diseases, including cancer and diabetes. Protein kinases can be divided into two classes: those that preferentially phosphorylate tyrosine residues (protein tyrosine kinases) and those that preferentially phosphorylate serine and / or threonine residues (serine protein / threonine kinases). Proteins tyrosine kinases carry out various functions, ranging from the stimulation of cell growth and differentiation to the interruption of cell proliferation. They can be classified as either tyrosine kinase receptor proteins or as an intracellular tyrosine kinase protein. The receptor proteins of tyrosine kinases, which possess an extracellular ligand binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are distributed among 20 subfamilies. Tyrosine receptor kinases, of the epidermal growth factor (EGF) family that includes the HER-1, HER-2 / neu and HER-3 receptors, contain an extracellular binding domain, a domain of transmembrane and an intracellular cytoplasmic catalytic domain. The receptor binding leads to the initiation of phosphorylation processes dependent on multiple intracellular tyrosine kinases, which ultimately results in oncogenic transcription. It has been linked to breast, colorectal and prostate cancers with this family of receptors. The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are structurally and functionally related, but exert different biological effects. The expression of IGF-1 R has been associated with breast cancer. Met serves as the high affinity receptor for hepatocyte growth factor (HGF), signaling through which it produces proliferation, dissemination and derivation morphogenesis. Over-expression of c-Met has been linked to several cancers, including hereditary renal papillary carcinomas, ovarian cancer, squamous cell carcinomas of the head and neck, and others. The platelet-derived growth factor receptors (PDGF) mediate cellular responses that include proliferation, migration and survival and include PDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptors have been linked to diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy. Fibroblast growth factor receptors (FGRs) consist of four receptors that are responsible for the production of blood vessels., the excrescence of extremities, and the growth and differentiation of numerous cell types. Vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells, is produced in high amounts by many tumors, including ovarian carcinomas. The known receptors for VEGF, flt and KDR, are called VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A related group of receptors, tie-1 and tie-2 kinases has been identified in hematopoietic and vascular endothelial cells. VEGF receptors have been associated with vasculogenesis and angiogenesis. Intraceluid tyrosine kinase proteins are also known as non-receptor tyrosine kinase proteins. More than 24 of these kinases have been identified and have been classified into 11 subfamilies. Serine / threonine protein kinases, like cell tyrosine kinase proteins, are predominantly intracellular. Diseases such as diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease and cancer are examples of pathogenic conditions that have been related to abnormal activity of protein tyrosine kinase. That is why there is a need for selective and potent inhibitors of the small molecule protein tyrosine kinase. The patents of E.U.A. Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and the international PCT applications WO 01/47897 and WO 01/47921 are indicative of recent attempts to synthesize said inhibitors.

BRIEF DESCRIPTION OF THE INVENTION The invention responds to the current need for selective and potent inhibitors of protein tyrosine kinase. One embodiment of the invention is directed to the novel compounds of the formula I: T or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: R is -OH or -NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino , halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra, -S03Ra or -S02NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ri is hydrogen, alkyl, hydroxy or alkoxy; hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R 3 is a direct bond or C 1-6 alkyl, C? -6 alkoxy, C? -6 thioalkyl, C? -6 hydroxyalkyl or C? -6 carboxyalkyl; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C, amino, aminoalkyl, haloalkyl, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORc, alkyl, -COORc, -CONRcRd, -N (R-,) CORc, -S02Rc, -S03Rc or -S02NRcRd; a 5 to 7 membered monocyclic or 8 to 10 membered monocyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C -? - 6alkyl, amino, halogen, hydroxy , alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONRcRd, -NHCORcRd, NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd; or -CORc, -COORc or -CONRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. In another embodiment, the invention is directed to the novel compounds of formula II: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRaRb, -S02Ra or -P03RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino , halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONRcRd, -NHCORcRd, -NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; hydrogen, alkyl, hydroxy or alkoxy; R is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R3 is a direct bond or alkyl of C -? - 6, C? --6 alkoxy, thioalkyl of d-6, hydroxyalkyl C-? -6 or carboxyalkyl of C-? -6; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more C? amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORe, -COORe, -CONReRf, -N (R?) CORe, -S02Re, -S03Re or -S02NReRf; a 5 to 7 membered monocyclic or bicyclic 8 to 10 membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-α-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Ra, -S02Ra, -S03Ra or -S02NRaRb; or -CORe, -COORe or -CONReRf, where Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. In yet another embodiment, the invention is directed to the novel compounds of Formula III: III or a pharmaceutically acceptable solvate, hydrate, tautomer or sai thereof, wherein R is -OH or -NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra , -S03Ra or -S02NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R? is hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein R c and d are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C?-alkyl, amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORe , -COORe, -CONReRf, -N (R?) CORß > -S02Re, -S03Re or -S02NReRf; or a 5- to 7-membered monocyclic or 8- to 10-membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-α-6 alkyl, amino, halogen , hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Re, -S02Re, -S03Re or -S02NReRf) wherein Re and Rf are independently hydrogen, alkyl, cycloalkyl , aryl, aralkyl, heteroaralkyl or heteroaryl. Even another embodiment of the invention is directed to the compounds of formula IV: rv or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRaRb, -S02Ra or -P03RaRb, wherein Ra and R are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino , halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONRcRd, -NHCORcRd, -NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R-i is hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein Re and Rf are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C-? -4 alkyl, amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3 , -CORg, -COORg, -CONRgRn, -N (R?) CORg, -S02Rg, -S03Rg or -S02NRgRh; or a 5- to 7-membered monocyclic or 8- to 10-membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-α-6 alkyl, amino, halogen , hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORg, -COORg, -CONRgRn, -NHCORgRh, NHS02Rg, -S02Rg, -S03Rg or -S02NRgRh, wherein Rg and Rh are independently hydrogen, alkyl, cycloalkyl , aryl, aralkyl, heteroaralkyl or heteroaryl. The compounds of formulas I and III are especially potent inhibitors of VEGFR-2 (KDR), c-fms, c-met and protein tyrosine kinases tie-2. It is expected that the compounds of formulas II and IV have similar inhibitory potencies. In a further embodiment, the invention relates to methods for preparing the compounds of formulas I, II, III and IV. The invention also relates to methods for inhibiting tyrosine kinase protein activity in a mammal by administering a therapeutically effective amount of at least one compound of Formulas I, II, III or IV.

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to the novel compounds of the formula or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -OH or -NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; a 5 to 6 membered monocyclic or bicyclic 8 to 10 membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-? 6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra, - S03Ra or -S02NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R1 is hydrogen, alkyl, hydroxy or alkoxy; R 2 is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R3 is a direct bond or C? -6 alkyl, C?? 6 alkoxy, C?? 6 thioalkyl, C?? 6 hydroxyalkyl or C1.6 carboxyalkyl; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C? -4 alquiloalkyl, amino, aminoalkyl, halogen, hydroxy, -CF 3, alkoxy, aryloxy, arylalkoxy, -OCF 3, -CORc, -COORc, -CONRcRd, -N (R?) CORCl -S02Rc, -S03Rc or -S02NRcRd; a 5 to 7 membered monocyclic or bicyclic 8 to 10 membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-? 6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONReRd, -NHCORcRd, NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd; or -CORc, -COORc or -CONRcRd, wherein Re and Rd are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. In another embodiment, the invention is directed to the novel compounds of Formula II: II or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRaRb, -S02Ra or -P03RaR, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; Ai is a 5-6 membered monocyclic or bicyclic 8- to 10-membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C? -6 alkyl, amino, alkylamino , halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORC) -COORc, -CONRcRd, -NHCORcRd, -NHS02RC, -S02Rc, -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; hydrogen, alkyl, hydroxy or alkoxy; R 2 is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R3 is a direct bond or C1-6 alkyl, C-? 6 alkoxy, C? -6 thioalkyl, C-? -6 hydroxyalkyl or C? -6 carboxyalkyl; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C ?4 alkyl, amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, - CORe, -COORe, -CONReRf, -S02Re, -S03Re or -S02NReRf; a 5- to 7-membered monocyclic or bicyclic 8- to 10-membered monocyclic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Ra, -S02Ra, -S03Ra or -S02NRaRb; or -CORe, -COORe or -CONReRf, where Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. In yet another embodiment, the invention is directed to the novel compounds of Formula III: III or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -OH or -NHORg, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ai is a 5-6 membered monocyclic or bicyclic 8- to 10-membered monocyclic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra , -S03Ra or -S02NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ri is hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein R c and R d are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1 -C, amino, aminoalkyl, halogen, hydroxy, -CF 3, alkoxy, aryloxy, arylalkoxy, -OCF 3, -CORe, -COORe, -CONReRf, -N (R?) CORe, -S02Re, -S03Re or -S02NReRf; or a 5- to 7-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, halogen , hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Re, -S02Re, -S03Re or -S02NReRf, wherein Re and Rf are independently hydrogen, alkyl, cycloalkyl , aryl, aralkyl, heteroaralkyl or heteroaryl. Even another embodiment of the invention is directed to the compounds of Formula IV: TV or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRgRb, -S02Ra or -P03RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; A- \ is a 5-6 membered monocyclic or bicyclic 8- to 10-membered monocyclic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C? -6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORe, -CONRcRd, -NHCORcRd, -NHS02Rc, -S02Rc , -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein Re and Rf are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C-? alkyl. , amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORg, -COORg, -CONRgRh, -S02Rg, -S03Rg or -S02NRgRh; or a 5- to 7-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, halogen , hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORg, -COORg, -CONRgRn, -NHCORgRh, NHS02Rg, -S02Rg, -S03Rg or -S02NRgRh, wherein Rg and Rh are independently hydrogen, alkyl, cycloalkyl , aryl, aralkyl, heteroaralkyl or heteroaryl. The preferred compounds of Formula I are those wherein wherein Ra and Rb are independently -H, -alkyl of C -? - 6, -C02-alkyl, -C02-CH2CH2NH2) -CO- (CH2) 1-4-C02H or - (CH2) 1-4-C02H; R2 is -H, -Me, -Et, wherein R c is alkyl; R3 is -CH2-, -CH2CH2-, -CH (CH3) -, -C (CH3) 2-, -CH (CH2OH) - or -CH (CH2CH2COOH) -; and A2 is wherein X is O or S. Particular preferred compounds of Formula I include, but are not limited to, 4- (Benzothiazol-6-ylamino) -6- (ethyl-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (methyl-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (benzylamino) - [1, 3,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylamino) - [1, 3,5] triazin-2-ol; (S) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylamino) - [1, 3,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; (S) -4- (Benzothiazol-6-ylamino) -6- (meth1l-1-phenylethylamino) - [1, 3,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (ethyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; (S) -4- (Benzothiazol-6-ylamino) -6- (ethyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (methyl-2-phenylethylammon) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (ethyl-2-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-chloro-benzamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-amyl) -6- (2-fluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(pyridin-3-ylmethyl) -amino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,6-difluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [methyl- (2-pyridin-2-yl-ethyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylammon) -6- [pyridin-2-ylmethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (1-benzyl-pyrrolidin-3-yl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-fluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-chloro-6-methyl-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N'-methyl-N'-phenyl-hydrazino) - [1, 3,5] triazin-2-ol; 4- (benzothiazol-6-ylamino) -6 - [(pyridin-4-ylmethyl) -amino] - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- (2-pyridin-3-yl-ethylamino) - [1, 3,5] triazin-2-ol; 4-Benzothiazol-6-ylamino) -6- (1-phenyl-propylamino) - [1, 3,5] triazin-2-ol; 4-Benzothiazol-6-ylamino) -6- (2-pyridin-2-yl-ethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-naphthalen-1-yl-ethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-hydroxymethyl-phenylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (quinolin-5) -ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (4-hydroxy-naphthalen-1-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1 H -indazol-6-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(1 H-ndazoI-6-yl) -methylamino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1 H -indazol-6-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (6-hydroxy-naphthalen-1-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-hydroxy-phenylamino) - [1, 3,5] triazin-2-oI; 4- (Benzothiazol-6-ylamino) -6- [2- (2-hydroxyethyl) -phenylamino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (5-thiophen-2-yl-2H-pyrazol-3-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-2H-pyrazol-3-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,4-d-fluoro-benzyl amino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-phenylamino- [1, 3,5] triazin-2-ol; 4- (1 H-ldazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-hydroxy-1-phenylethylamino) - [1, 3,5] triazin-2-oI; 4- (1 H-ldazol-5-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-7-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(furan-2-yl-methyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(thiophen-2-yl-methyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(furan-3-ylmethyl) -amino- [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(thiophen-3-yl-methyl] -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (benzyl-pyrrolidin-3-ylamino) - [1, 3,5] triazin-2-ol; 3-. { [4- (Benzothiazol-6-ylamino) -6-hydroxy- [1, 3,5] triazin-2-yl] -benzylamino} -propan-1,2-diol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (3-morpholin-4-ylpropyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-. { benzyl- [3- (4-methyl-piperazin-1-yl) -propyl] -amino} - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (3-dimethylamino-propyl) -arnino] - [1, 3,5] triazin-2-ol; 4- (BenzothiazoI-6-ylamino) -6- [benzyl- (2-piperazin-1-ylethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylammon) -6- [benzyl- (2-morpholin-4-ylethyl) -amino] - [1, 3,5] triazin-2-yl; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (2-dimethylamino-ethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (2-Amino-benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (1-Methyl-1-phenylethylammon) -6- (quinolin-6-ylammon) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6- (N-ethylbenzylamino) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-lamino) -6- (N-methylbenzylamino) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; N- [4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-yl] -hydroxylamine; 4- (Benzothiazol-6-ylamino) -6 - [(4-fluoro-3-trifluoromethylbenzyl) amino] - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6 - [(4-fluoro-3-trifluoromethylbenzyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (ethyl- (pyridin-2-ylmethyl) amino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N-benzylisopropylammon) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (etl- (2-fluorobenzyl) amino] - [1, 3,5] trizin-2-ol; 4- (Benzothiazol-6-ylammon) ) -6- [benzyl- (2,2,2-trifluoroethyl) amino] - [1, 3,5] triazin-2-ol; 3 - [[4- (Benzothiazol-6-ylamino) -6 -hydroxy- [1, 3,5] triazin-2-yl] - (1-phenylethi) amino] propan-1,2-diol; 4- (Benzothiazol-6-ylamino) -6- (ethyl- (pyridine- 2-methylmethyl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N- (2-fluorobenzyl) isopropylamino) - [1, 3,5 ] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [ethyl- (1 H -indazol-6-yl) amino] - [1, 3,5] triazin-2-ol; (Benzothiazol-6-ylamino) -6- { Benzyl- [2- (3 H -amidazol-4-yl) ethyl] amino.} - [1, 3,5-triazin-2-ol; - (Benzothiazol-6-ylamino) -6-. {2-fluorobenzyl- [2- (3H-imidazol-4-yl) ethyl] amino.} - [1, 3,5] tr¡az¡n- 2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (3-imidazol-1-yl-propyl) amino] - [1, 3,5] triazin-2-ol, 4-acid { [4- (Benzothiazol-6-ylamino) -6-hydroxy- [1, 3,5] triazin-2-yl] -benzylamino} butyric acid; 4- (Benzothiazol-6-ylamino) -6- {(2-piperazin-1-ethyl) -quinolin-5-ylamino}. - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-. { benzyl- [2- (3H-imidazol-4-yl) ethyl] amino} - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N-benzylpropylamino) - [1, 3,5] triazin-2-ol and pharmaceutically acceptable salts thereof. It is expected that the preferred compounds of Formula II have similar or identical substituents Ri, R2, R3, Ai and A2, as compared to preferred compounds of Formula I. Preferred compounds of Formula III include 4- (Benzothiazole-6 -ylamino) -6- (2-methyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-benzyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-lamino) -6- (2,6-dimethyl-piperidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,5-dimethyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-phenyl-thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-methyl-p-peridin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (morpholin-4-yl) - [1, 3,5] triazin-2-ol and pharmaceutically acceptable salts thereof. It is expected that preferred compounds of Formula IV have similar or identical substituents Ri, R2, R3, Ai and A2, as compared to preferred compounds of Formula III. A further embodiment of the invention relates to a novel method (Scheme 2, below) for preparing the compounds of Formulas I and III, wherein R is -OH, comprising the steps of: a) displacing one of three groups scrollable in the positions 2-, 4- and 6-, respectively, of a 1, 3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2- (4-methoxybenzyloxy) - [1, 3,5] triazine; b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2- (4-methoxybenzyloxy) - [1, 3,5] triazine; and c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino- (2-hydroxy) - [1, 3] , 5] triazine. To prepare the compounds of Formulas II and IV, an additional step to steps a) -c) would be required as follows: d) adding an acylation, sulfonation or phosphorylation agent to 4,6-diamino- ( 2-hydroxy) - [1, 3,5] triazine to give a 4,6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2 -0-sulfonyl) - [1, 3,5] triazine or 4,6-diamino- (2-0-phosphoryl) - [1, 3,5] triazine, respectively. Another embodiment of the invention relates to a novel method (Scheme 3, below) for preparing the compounds of Formulas I and III, wherein R is -OH, comprising the steps of: aa) displacing one of three displaceable groups in positions 2-, 4- and 6, respectively, of a 1, 3, 5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino- [1, 3,5] triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino- [1, 3,5] triazine; and ce) displacing the third displaceable group with reactive grade TFA to give a 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine. To prepare the compounds of formulas I and III, wherein R is -NHOH, hydroxylamine hydrochloride was used instead of water to displace the third displaceable group in step ce) of scheme 3. The -OH attached to the hydroxylamine nitrogen then could be optionally derived in an appropriate manner, as defined by Ra. To prepare the compounds of Formulas II and IV, an additional step to steps aa) -cc) would be needed in the following manner: dd) adding an acylating agent, sulfonation or phosphorylation to the 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine to give a 4,6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4.6 -diamino- (2-0-sulfonyl) - [1, 3,5] triazine or a 4,6-diamino- (2-0-phosphoryl) - [1, 3,5] triazine, respectively. A preferred movable group in steps a) -c) and aa) -cc) above is chlorine. Preferred amines (i) and (i) include 6-aminobenzothiazole and cumyl amine. Examples of acylating agents include, but are not limited to, acetic anhydride and butyryl chloride. Examples of sulfonating agents include, but are not limited to, methanesulfonyl chloride and p-toluenesulfonyl chloride. Examples of phosphorylating agents include, but are not limited to, phosphoryl chloride. The invention also relates to methods for inhibiting protein tyrosine kinase activity in a mammal, by administering a therapeutically effective amount of at least one compound of formulas I, II, III or IV.

The invention is considered to include the enantiomeric, diastereomeric and tautomeric forms of all compounds of Formulas I, II, III and IV, as well as their racemic mixtures. In addition, some of the compounds represented by Formulas I, II, III and IV are prodrugs, ie, derived from an active drug that possesses superior delivery capabilities and therapeutic value, as compared to the active drug. The prodrugs are transformed into active drugs by chemical or enzymatic methods in vivo.

I. Definitions The term "alkyl" refers to straight and branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, and includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl , secondary butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. The term "cycloalkyl" refers to a ring composed of 3 to 8 carbon atoms. Optionally, alkyl substituents may be present in the ring. Examples include cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylcyclopentyl and cyclohexyl. The term "heterocyclyl" refers to a non-aromatic ring composed of 3 to 7 carbon atoms and at least one heteroatom selected from N, O or S. Optionally, alkyl substituents may be present in the ring. Examples include tetrahydrofuryl, dihydropyranyl, 2,5-dimethylpiperidyl, morpholinyl and piperazinyl. The term "heterocyclylalkyl" refers to a C? _6 alkyl group that contains a heterocyclyl substituent. Examples include dihydropyranylethyl and 2-morfoiinylpropyl. The term "hydroxyalkyl" refers to at least one hydroxyl group attached to any carbon atom together with an alkyl chain. The term "aminoalkyl" refers to at least one primary or secondary amino group attached to any carbon atom together with an alkyl chain. The term "polyalkoxyalkyl" refers to long-chain alkoxy compounds and includes polyethylene glycols of discrete or monodisperse sizes. The term "thioalkyl" refers to at least one sulfur group attached to any carbon atom together with an alkyl chain. The sulfur group can be in any oxidation state and includes sulfoxides, sulfones and sulfates. The term "carboxyalkyl" refers to at least one carboxylate group attached to any carbon atom together with an alkyl chain. The term "carboxylate group" includes carboxylic acids and esters of alkyl, cycloalkyl, aryl or aralkyl carboxylate. The term "heteroaromatic" or "heteroaryl" refers to 5- to 7-membered or bicyclic monocyclic ring systems of 8 to 10 members, any ring of which may consist of one to four heteroatoms selected from N, O or S , where the nitrogen and sulfur atoms can exist in any allowed oxidation state. Examples include benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl and thienyl. The term "heteroaralkyl" refers to an alkyl group of C 6 -6 having a heteroaryl substituent. Examples include furylethyl and 2-quinolinylpropyl. The term "heteroatom" refers to a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen and sulfur atoms may exist in any permitted oxidation state. The term "alkoxy" refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy. The term "aryl" refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring, and optionally substituted with 1-3 substituents selected from alkoxy, alkyl, halogen, hydroxy and heteroaryl. Examples include benzene, biphenyl and naphthalene.

The term "aralkyl" refers to an alkyl group of C-α-6 containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl. The term "acyl" refers to the group -C (0) Ra, wherein Ra is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. An "acylating agent" adds the group -C (0) Ra to a molecule. The term "sulfonyl" refers to the group -S (0) 2Ra, wherein Ra is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. A "sulfonation agent" adds the group -S (0) 2Ra to a molecule. The term "phosphoryl" refers to the group -P (0) 2ORa, wherein Ra is H, alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. A "phosphorylating agent" adds the P (0) 2ORa group to a molecule.

II. Therapeutic Uses The compounds of Formulas I, II, III and IV represent potent novel inhibitors of the protein tyrosine kinases and may be useful in the prevention and treatment of disorders resulting from the actions of these kinases. The invention also provides methods for inhibiting a tyrosine kinase protein, comprising contacting the tyrosine kinase protein with an effective inhibitory amount of at least one of the compounds of Formulas I, II, III or IV. Proteins tyrosine kinases that can be inhibited include, but are not limited to VEGFR-2 (KDR), c-fms, c-met and tie-2 kinases. In various embodiments of the invention, the protein tyrosine kinases inhibited by the compounds of Formulas I, II, III or IV are located in cells, in a mammal or in vitro. In the case of mammals, which includes humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formulas I, II, III or IV is administered. The invention further provides methods for treating cancer in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable composition of at least one compound of Formulas I, II, III or IV. Examples of cancers include, but are not limited to, breast cancer, colon cancer, stomach cancer, hairy cell leukemia, and non-small lung carcinoma. In one embodiment of the invention, an effective amount of at least one compound of the formulas I, II, III or IV is administered, in combination with an effective amount of a chemotherapeutic agent. The invention also provides methods for treating vascular diseases, eye diseases and restenosis in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formulas I, II, III or IV.

When employed as inhibitors of the protein tyrosine kinase, the compounds of the invention can be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g in Unitary or divided daily doses. The dosage administered will be affected by factors such as the route of administration, health, weight and age of those who receive it, the frequency of treatment and the presence of concurrent and unrelated treatment. The compounds of Formulas I, II, III and IV can be formulated in pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Examples of carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Examples of excipients that may also be components of the formulation include fillers, binders, disintegrants and lubricants. The pharmaceutically acceptable salts of the compounds of the formulas I, II, III and IV include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorrate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.

The base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts and salts with amino acids, such as arginine. Also, groups containing basic nitrogen can be quatemized with, for example, alkyl halides. The pharmaceutical compositions of the invention can be administered by any means that fulfills its intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular administration. Alternatively or concurrently, the administration can be by oral route. Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, eg, water-soluble salts, acid solutions, alkaline solutions, water-dextrose solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

III. Preparation methods The compounds of the formulas I, II, III and IV can be prepared by conventional solid phase support methodology or by means of a novel synthesis of the solution phase. Scheme 1 is representative of the solid phase support steps used to produce compounds of formulas I and III, wherein R is -OH: SCHEME 1 (Re (O (D) As shown in Scheme 1, the Wang resin was treated with excess cyanuric chloride in the presence of a base to obtain the [1, 3,5] triazine ether bound to resin (A). Then, the resin (A) was treated with a primary or secondary alkyl or aromatic amine (RRNH) to produce the 4-amino- [1, 3,5] triazine ether bound to resin (B). Then, the resin (B) was treated with a primary or secondary amine (R "R" NH) to provide the 4,6-diamino- [1, 3,5] triazine ether bound to resin (C). Rupture of the 4,6-diamino- [1, 3,5] triazine binding from the resin with trifluoroacetic acid (TFA) yielded 4,6-diamino- (2-hydroxy) - [1, 3 , 5] triazine (D) in solution as its TFA salt. To prepare the compounds of Formulas II and IV, 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine (D) was treated with an acylating, sulfonating or phosphorylating agent to provide an antibacterial agent. , 6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2-0-sulfonyl) - [1, 3,5] triazine or a 4,6 -diamino- (2-O-phosphoryl) - [1, 3,5] triazine, respectively.

The novel solution phase syntheses of the compounds of Formulas I, II, III and IV normally proceed by one of two routes. In the first route, as represented by Scheme 2, cyanuric chloride was treated with 4-methoxybenzyl alcohol to provide a 4,6-dichloro-2- (4-methoxybenzyloxy) - [1, 3,5] triazine, which then it is treated with primary or secondary alkyl or aromatic amine (RR'NH), followed by another primary or secondary alkyl or aromatic amine (R "R" 'NH) to provide, after concomitant loss of the protective group O-4-methoxybenzyl , a 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine of Formulas I and III, wherein R is -OH. To prepare the compounds of Formulas II and IV, the 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine was further treated with an acylating, sulfonating or phosphorylating agent to provide a 4.6 -diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2-0-sulfonyl) - [1, 3,5] triazine or a 4,6-diamino - (2-0-phosphoryl) - [1, 3,5] triazine, respectively.

SCHEME 2 In another novel solution phase route to the compounds of Formulas I, II, III and IV, as represented by Scheme 3, cyanuric chloride was treated sequentially with primary or secondary alkyl or aromatic amines (RR'NH and R " R '"NH), to provide a 6-chloro-2,4-diamino- [1, 3,5] triazine which was treated with reactive grade trifluoroacetic acid to provide, after neutralization, a compound of 4.6- diamino- (2-hydroxy) - [1, 3,5] triazine of Formulas I and III, where R is -OH. To prepare the compounds of Formulas I and III, wherein R is -NHORa, 6-chloro-2,4-diamino- [1, 3,5] triazine was treated with hydroxylamine instead of TFA in the final step of scheme III. To prepare the compounds of Formulas II and IV, 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine (D) was further treated with an acylating, sulfonation or phosphorylation to provide a 4,6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2-0-sulfonyl) - [1, 3,5] triazine or a 4,6-diamino- (2-0-phosphoryl) - [1, 3,5] triazine, respectively.

SCHEME 3 The approach of Scheme 2 to prepare the protein kinase inhibitors of Formulas I, II, III and IV, is ideal for acid sensitive compounds, since each step in the synthesis occurs under basic conditions. The final step of the route of Scheme 3 is superior to similar conversions reported in the literature, because it is carried out under very sensitive reaction conditions of room temperature and reaction times of less than 15 minutes.

Experimental The following examples have an illustrative, but not limiting, purpose of the invention. The following reagents were used in the examples: Wang resin, a solid support, sold by Polymer Labs, Amherst, MA. Cyanuric chloride, trichloro [1, 3,5] triazine, sold by Aldrich Chemical Company, Milwaukee, Wl. Diisopropylethylamine (DIEA), trifluoroacetic acid (TFA) and all anhydrous solvents, such as tetrahydrofuran (THF) and dichloromethane (DCM), were purchased from Aldrich Chemical Co (Milwaukee, Wl) and used as they are, without further purification . The amines for use as substituents on the triazine ring were purchased from various chemical suppliers, including Aldrich, Lancaster, TCI, Maybridge and Acros, and were used as they are, without further purification or were synthesized according to standard procedures in the literature .

I. General procedure for supported solid phase synthesis (Scheme 1): A solution of cyanuric chloride (22.8g, 122 mmol) in 180 mL of anhydrous tetrahydrofuran (THF) was added in one portion to Wang resin (12g, 20 mmol) ) under a nitrogen atmosphere. The resulting suspension was exhausted at room temperature (ta) for 15 min. Diisopropylethylamine (DIEA) (21.6 mL, 122 mmol) was added slowly with a syringe to the mixture, followed by stirring the suspension at room temperature for 18 h. The suspension was filtered and the resin washed sequentially with THF and dichloromethane (DCM). The resin was then dried under vacuum to yield 15g of a light yellow resin (A) (100% yield based on the original weight and charge of 1.7 mmoles / g). To the resin (A) was added a solution of a primary or secondary aromatic alkylamine (100 mmol) in 150 mL of anhydrous THF under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for 18 h, filtered, and the resin was washed sequentially with THF, DCM, methanol (MeOH) and DCM. The resin was then dried under vacuum to produce a dark yellow resin (B) (100% yield based on the original weight and charge of 1.7 mmoles / g). The resin (B) (0.17 mmole) was divided into equal portions in several bottles. To each flask was added 2 mL of a different amine solution (0.25 M) in dioxane and 100 μl of DIEA, and the bottles were sealed and the resins were heated and shaken at 90 degrees for 16 h. After allowing them to cool to room temperature, the bottles were opened and the resin in each bottle was filtered separately and washed sequentially with MeOH and DCM. Each resin (C) was then dried under vacuum. For each resin portion (C) in a vial, 2mL of 5-50% trifluoroacetic acid (TFA) / DCM was added. The bottles were sealed and allowed to stand at room temperature with occasional manual agitation for 3 h. The bottles were opened and the resin in each bottle was filtered and washed separately with a 0.5 mL portion of TFA / DCM. The filtrates and washings were collected for each flask and concentrated in vacuum for 12 h. Each of the resulting compounds (D) was analyzed by LC / MS and 1H-NMR.

EXAMPLE 1 4- (Ben-2-thiazol-6-ylamino) -6- (N-ethylbenzylamino) -f1, 3,51-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 250 mg (82%). MS: 379 (M + 1). LC / MS purity: 97%. 1 H-NMR (300 MHz, DMSO-d 6): d 9.4 (d, 1 H); 8.2 (s, 1 H); 8.0 (d, 1 H); 7.5 (d, 1 H); 7.4 (m, 5H); 4.8 (s, 2H); 3.6 (m, 2H); 1.1 (t, 3H).

EXAMPLE 2 4- (Benzothiazol-6-ylamino) -6- (benzylaminoH1, 3,51triazin-2-ol The procedure followed was that described for scheme 1. The yield was 104 mg (88%). MS: 351 (M + 1). LC / MS purity: 98%.

EXAMPLE 3 (R) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylamino) -ri, 3,51-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 116 mg (96%). MS: 365 (M + 1). LC / MS purity: 98%.

EXAMPLE 4 (S) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylammon) -f1,3,51-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 114 mg (95%). MS: 365 (M + 1). LC / MS purity: 99%.

EXAMPLE 5 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylaminoHI, 3,51-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 104 mg (85%). MS: 379 (M + 1). LC / MS purity: 97%.

EXAMPLE 6 4- (Benzothiazol-6-ylamino) -6-rmethyl- (2-pyridyl-2-ylethyl) amino1-ri, 3,51 triaz? 'N-2-ol The procedure followed was that described for Scheme 1. The yield was 9.91 mg (> 80%). MS: 380 (M + 1). LC / MS purity: 94%.) EXAMPLE 7 4- (1-methyl-1-phenylethylamino) -6- (quinolin-6-ylaminoH, 3,51-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 6.4 mg (> 80%). MS: 373 (M + 1). LC / MS purity: 87%.

EXAMPLE 8 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-pyrrolidin-1-yl) -f1,3,5-triazin-2-ol The procedure followed was that described for scheme 1. The yield was 13 mg (80%). MS: 391 (M + 1). LC / MS purity: 88%.

EXAMPLE 9 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-thiomorpholin-4-yl) -ri, 3,51 riazin-2-ol The procedure followed was that described for Scheme 1. The yield was 9.1 mg (> 80%). MS: 423 (M + 1). LC / MS purity: 97%.

EXAMPLE 10 4- (BTnzothiazol-6-ylamino) -6- (3-phenyl-thiomorpholin-4-yl) -ri, 3,51-triazin-2-ol The procedure followed was that described for Scheme 1. The yield was 14 mg (> 80%). MS: 423 (M + 1). LC / MS purity: 87%.

EXAMPLE 11 3- (Benzothiazol-6-ylamino) -5-f (1 H -indazol-6-yl) -methylamino-1-phenol The procedure followed was that described for scheme 1. The yield was 34 mg (79%). MS: 391 (M + 1). LC / MS purity: 99%.

II. Example of procedure for solution phase synthesis (Scheme 2): EXAMPLE 12 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) -f1, 3,51-triazin-2-ol A solution of cyanuric chloride (456 mg, 2.48 mmol), 4-methoxybenzyl alcohol (557 mg, 4.03 mmol), and DIEA (371 mg, 2.9 mmol) in THF (8 mL) was stirred for 15 min. The resulting cloudy suspension was diluted with H20 (100 mL) and the reaction was extracted with DCM (2x20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc, 1: 1) yielded 2,4-dichloro-6- (4-methoxybenzyloxy) - [1, 3,5] triazine (256 mg, 1.25 mmol). A solution of 2,4-dichloro-6- (4-methoxybenzyloxy) - [1, 3,5] triazine (613 mg, 2.15 mmol), cumyl amine (285 mg, 2.11 mmol) and DIEA (267 mg, 2.07 mmol) in THF (13 mL) was stirred at room temperature for 5 minutes. The resulting cloudy suspension was diluted with H20 (150mL), and extracted with DCM (2x30 mL). The combined organic layers were dried over MgSO, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc, 85:15) yielded [4-chloro-6- (4-methoxybenzyloxy) - [1, 3,5] triazin-2-yl] - (1-methyl-1) phenylethyl) amine (512 mg, 1.33 mmol). A solution of [4-chloro-6- (4-methoxybenzyloxy) - [1, 3,5] triazin-2-yl] - (1-methy1-1-phenylethyl) amine (50 mg, 0.13 mmol) ), 6-aminobenzothiazole (25 mg, 0.16 mmol) and DIEA (18 mg, 0.14 mmol) in THF (2 mL) was prepared in a sealed tube and heated to 120 ° C in a microwave reactor (Personal Chemistry, Synthesizer Smith) for 90 min. Chromatography on silica gel (DCM: MeOH, gradient 19: 1, 9: 1) yielded 4- (benzothiazol-6-yl-amino) -6- (1-methyl-1-phenylethylamino) - [1, 3, 5] triazin-2-ol (3 mg, 8x10"3 mmol) MS: 379 (M + 1) LC / MS purity: 97%.

III. Example of Procedure for solution phase synthesis (Scheme 3): EXAMPLE 13 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) -H, 3.51triazin-2-ol A solution of cyanuric chloride (737 mg, 4.0 mmol) in THF (10 mL) was treated with 6-aminobenzothiazole (533 mg, 3.5 mmol) and DIEA (0.70 mL, 4.0 mmol). After 30 minutes of stirring, the resulting suspension was poured into 800 mL of H20 and 100 mL of DCM. The reaction was partitioned and the organic layer was dried over MgSO4) filtered and concentrated. Without further purification, the resulting benzothiazole-6-yl- (4,6-dichloro- [1, 3,5] triazin-2-yl) -amine was dissolved in THF (12 mL), and treated with cumyl amine ( 450 mg, 3.3 mmol), followed by DIEA (0.7 mL, 4.0 mmol). After 10 minutes of stirring, the reaction was poured into 250 mL of H20 and 20 mL of DCM. The reaction was partitioned and the aqueous layer was extracted with an additional 20 L of DCM. The combined organic layers were dried over MgSO, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc, 2: 1) gave 308 mg of N- (benzothiazol-6-yl) -6-chloro-N '- (-methyl-1-phenylethyl) - [1, 3, 5] triazine-2,4-diamine. MS: 397 (M + 1). LC / MS purity: 100%. A solution of N- (benzothiazol-6-yl) -6-chloro-N- (1-methyl-1-phenylethyl) - [1, 3,5] triazine-2,4-d-amines (5.4 mmoles) is dissolved in 50 mL of DCM and 5 mL of TFA, and treated with 5 mL of H20. The reaction was allowed to stir at room temperature for 48 h to provide 4- (benzothiazol-6-yl-amino) -6- (1-methyl-1-phenylethylamino) - [1, 3, 5] triazin-2-ol as the salt tri-TFA. MS: 379 + 3 TFA (M + 1). LC / MS purity: 100%.

EXAMPLE 14 N-r4-Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylaminoHI, 3,51-triazin-2-yl-hydroxylamine The procedure followed was that described for scheme III, except for the final step. The displacement of the chlorine in the triazine ring with TFA reagent was replaced by the following step: A solution of hydroxylamine hydrochloride (69 mg, 1.0 mmol) in ethanol (10 mL) and DIEA (1 mL) was treated with N- ( benzothiazol-6-yl) -6- (chloro-N '- (1-methyl-1-phenylethyl) - [1, 3, 5] triazine-2,4-diamine (95 mg, 0.24 mmol). heated at 75 ° C for 16 hrs. After cooling to room temperature, the solution was evaporated on celite (10g) and chromatographed on silica gel (95/5 DCM / MeOH) to give 15 mg (0.04 mmoles) of N - [4- (benzothiazol-6-yl-amino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-yl] -hydroxylamine, MS 393 (M + 1). LC / MS purity: 100%, 1 H-NMR (300 MHz, acetone-d 6): d 9.0 (s, 1 H), 7.2-8.0 (m, 8H), 1.8 (s, 6H).

IV. Comparative examples EXAMPLE 15 N- (Benzothiazol-6-yl) -N '- (1-methyl-1-phenylethyl) -H, 3,51-triazine-2 A6-triamine SCHEME 4 The Knorr resin (350 mg, 0.25 mmol) was treated with a 20% piperidine solution in DMF and stirred for 120 minutes. The resin was rinsed three times alternately with DCM (10 mL) and MeOH (10 mL). The resin was swollen again with DCM (1.5 mL) and treated with a solution of N-benzothiazol-6-yl-6-chloro-N '- (1-methyl-1-phenylethyl) - [1, 3,5] triazine-2,4-diamine (100 mg, 0.25 mmol) in DMF (2.5mL). The stirred suspension was heated to 110 ° C in a sealed flask for 16 hrs. The breaking of the resin was carried out with 50/50 (v / v) TFA / DCM. The resulting solution was concentrated, dissolved in MeOH and chromatographed on a TLC preparation plate, using (DCM: MeOH, 9: 1) to give 1.5 mg of N- (benzothiazol-6-yl) -N '- ( 1-methyl-1-phenylethyl) - [1, 3, 5] triazine-2,4,6-triamine as its TFA salt. MS: 378 (M + 1). LC / MS purity: 87%.

EXAMPLE 16 N- (Benzothiazol-6-yl) -N '- (1-methyl-1-phenylethyl), 3,51-triazine-2,4-diamine SCHEME S A solution of N- (benzothiazol-6-yl) -6-chloro-N '- (1-methyl-1-phenylethyl) - [1, 3,5] triazine-2,4-dia Na (100 mg, 0.25 mmol) in MeOH (3 mL) was treated with ammonium formate (350 mg, 5.2 mmol) and 5% Pd / C (43 mg, 0.25 mmol) and heated at 65 ° C for 16 h. hrs. Chromatography of the resulting mixture (DCM: MeOH, 9: 1) gave the free base of N- (benzothiazol-d-yl) -N '- (1-methyl-1-phenylethyl) - [1, 3,5] triazine-2,4-diamnan. The material was dissolved in 50/50 (v / v) TFA DCM (1 mL) and concentrated to give 2.9 mg of the TFA salt. MS: 363 (M + 1). LC / MS purity: 100%.

EXAMPLE 17 N- (Benzothiazol-6-yl) -6-methoxy-N '- (1-methyl-1-phenylethyl-H, 3,51-triazine-2,4-diamine SCHEME ß A solution of 2,4-dichloro-6-methoxy- [1, 3,5] triazine (328 mg, 2 mmol), and 6-aminobenzothiazole (300 mg, 2 mmol) in THF (10 mL) was treated with DIEA (0.36 mL, 2 mmol) and stirred for 1 hr. The resulting suspension was poured into H20 (50 mL) and DCM (50 mL) and divided. The aqueous layer was washed with 50 mL of DCM and the combined organic layers were dried over MgSO, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc 2: 1) gave N- (benzothiazol-6-yl) - (4-chloro-6-methoxy- [1, 3,5] triazin-2-yl) -amine (130 mg, 0.44 mmol). A solution of 1- (6-amino-benzothiazolyl) -3-chloro-5-methoxytriazine (130 mg, 0.44 mmoies) in dioxane (10 mL) was treated with cumyl amine (65 mg, 0.48 mmol) and DIEA (89 mg). , 0.69 mmole) and heated to reflux for 16 hrs. The reaction was cooled to room temperature, poured into H20 (50 mL) and extracted with DCM (2x50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc, 1: 1) gave 110 mg of N- (benzothiazol-6-yl) -6-methoxy-N '- (1-methyl-1-phenylethyl) - [ 1, 3,5] triazine-2,4-diamine. MS: 393 (M + 1). LC / MS purity: 99%.

EXAMPLE 18 N- (Benzothiazol-6-in-6-benzyloxy-N'-f 1 -methyl-1-phenylethyl-3 .3-triazine-2,4-diamine SCHEME 7 A solution of cyanuric chloride (1.0 g, 5.4 mmol) in THF (50 mL) at -30 ° C was treated with benzyl alcohol (550 mg, 5.12 mmol) and DIEA (1.0 mL, 5.8 mmol). The reaction was allowed to warm to room temperature for more than 4 hrs. The yellow reaction mixture was poured into 150 mL of H20 and 20 mL of DCM. The reaction was partitioned and the organic layer was dried over MgSO4, filtered and concentrated in diatomaceous earth. Chromatography on silica gel (hexanes: EtOAc, 9: 1) gave 2-benzyloxy-4,6-dichloro- [1, 3,5] triazine (620 mg, 2.42 mmol). A solution of 2-benzyloxy-4,6-dichloro- [1, 3,5] triazine (256 mg, 1.0 mmol) in THF (10 mL) was treated with cumyl amine (138 mg, 1.02 mmol), followed by DIEA (133 mg, 1.04 mmol). The reaction was allowed to stir at room temperature for 3 hours, and was diluted with H20 (120mL), and extracted with DCM (3x30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Chromatography on silica gel (hexanes: EtOAc, 9: 1) gave (4-benzyloxy-6-chloro- [1, 3, 5] triazin-2-yl) - (1-methyl-1-phenylethyl) -amine (83 mg, 0.23 mmol). A solution of (4-benzyloxy-6-chloro- [1,3,5] triazin-2-yl) - (1-methyl-1-phenylethyl) -amine (80 mg, 0.22 mmol), 6-aminobenzothiazole (50 mg, 0.33 mmol), and DIEA (33 mg, 0.26 mmol) in THF (1.75 mL) was heated at 120 ° C in the microwave for 12 hrs. The reaction was concentrated and chromatographed on silica gel (hexanes: EtOAc, 1: 1) gave N- (benzothiazol-6-yl) -6-benzyloxy-N '- (1-methyl-1-phenylethyl) - [ 1, 3,5] triazine-2,4-diamine (60 mg, 0.13 mmol).

MS: 469 (M + 1). LC / MS purity: 100%.

V. Results Two in vitro tests were performed to measure the inhibitory potency of the tyrosine kinase protein by the compounds selected from Formulas I and III. It is expected that the compounds of the Formulas I and IV behave as typical prodrugs, since the power measurements will be better reflected by in vivo studies.

KDR Enzyme Assay A fluorescence polarization competition immunoassay was used to determine the potency of the compound for KDR. The assay was performed in 96-well black microplates (LJL BioSystems). The pH regulator of the assay that was used was 100 mM HEPES, pH 7.5, 1 mM DTT, 0.01% (v / v) Tween 20. The compounds were diluted in test pH buffer containing 4% DMSO just before the test. To each cavity 5μl of compound was added, followed by the addition of 3μl of a mixture containing 33.3 μM ATP (Sigma), 33.3 μg / ml poly (E4, Y) (Sigma), and 16.7 mM MgCl2 in pH buffer of test. The kinase reaction was initiated by adding 2μl of 8nM KDR in the pH buffer of the assay. The final concentrations in the assay were 1.6 nM KDR, 10 μM ATP, 10 μg / m! poly (E4, Y), 5mM MgCl2, 2% DMSO. The control reactions were performed on each plate: in positive and negative control cavities the pH regulator of the assay (made 4% in DMSO) was replaced by the compound; in addition, the positive control cavities did not receive KDR.

Plates were incubated at room temperature for 5 minutes. At the end of the incubation, the reaction was quenched with 1.2 μl of 50 mM EDTA. After a 5 minute incubation, each cavity received 10μl of a 1: 1: 3 mixture of anti-phosphotyrosine antibody, 10X, PTK green radioactive marker, 10X (vortex), FP dilution regulator, respectively (all of PanVera, cat. # P2837). The plate was covered, incubated for 30 minutes at room temperature and the fluorescence polarization was read on an ANALYST ™ HT Assay Detection System (LJL Biosystems, Sunnyvale, CA). The instrument settings were: 485 nm excitation filter; 530 nm emission filter; height Z: half of the cavity; G factor: 0.93. Under these conditions, the fluorescence polarization values for positive and negative controls were -260 and -110, respectively, and were used to define 100% inhibition and 0% of the KDR reaction. The IC50 values reported are the averages of three independent measurements.

Test based on KDR cells. To determine the effect of test compounds on KDR function in cells, the activation of VEGF-stimulated MAP kinase in human umbilical vein endothelial cells (HUVEC), which express endogenous Flk-1 (KDR), was examined. HUVEC was grown for confluence in an EMB-2 endothelial cell medium (Biowhittaker Inc., Walkersville, MD) at 37 ° C and 5% C02. The confluent, quiescent HUVECs were treated with the test compounds 30 minutes before stimulation with VEGF 25ng / ml for 10 minutes at 37 ° C. These cells were then used in pH regulator of HNTG (50mM HEPES, 150mM NaCl, 1% triton-X-100, 1.5mM MgCl2, 10% glycerol, 10mM NaF, 1mM EDTA, 10mM sodium pyrophosphate, 1uM PMSF and 250uM NaV04 ). The cellular ones (40ug of total protein) were separated by SDS-PAGE and transferred to nitrocellulose. The immunoblots were probed with a polyclonal antibody to phosphorylated MAP kinase (Cell Signaling Technologies, Woburn, MA) and secondary antibody conjugated to alkaline phosphatase (Biorad Labs, Hercules, CA). Immunoblot detection was performed by measuring the fluorescent product of the alkaline phosphatase reaction with the substrate 9H- (1,3-dichloro-9,9-dimethiclacridin-2-one-7-yl) phosphate, diammonium salt (phosphate DDAO) (Molecular Probes, Eugene, OR) using a Molecular Dynamics Typhoon Imaging System (Molecular Dynamics, Sunnyvale, CA). Quantification of DDAO phosphate signal and IC50 determinations were made with Molecular Dynamics ImageQuant software As shown in Table 1, 4- (benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) ) - [1, 3, 5] triazin-2-ol (Examples 5, 12 and 13) was one of the most potent inhibitors of the tyrosine kinase protein that was tested. Analogous example 2 without branching in R3 was less active than examples 3 and 4, of which each had mono-methyl substitution in R3. The R-enantiomer (Example 3) was more potent than the corresponding S-enantiomer (Example 4). Examples 9 and 10 are examples of inhibitors powerful represented by Formula III. Example 14 is an example of a potent inhibitor which is a hydroxylamine of Formula I. Examples comparative 15-18, wherein the hydroxy group of one of the most potent compounds (represented by Examples 5, 12 and 13) was replaced by -NH2, -H, -OCH3 and -OCH2Ph, respectively, showed a decrease in the inhibition.

TABLE 1 A: < 1 μM B: > 1 μM and < 15 μM C: > 15 μM and < 50 μM D: > 50 μM N. D. = Not available

Claims (44)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of Formula I: I or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: R is -OH or -NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-α-6 alkyl, amino, alkylamino , halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra, -S03Ra or -S02NRaRb, wherein Ra and R are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R1 is hydrogen, alkyl, hydroxy or alkoxy; R 2 is hydrogen, alkyl, carboxyalkyo, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R3 is a direct bond or C1-6 alkyl, C-? 6 alkoxy, C? -6 thioalkyl, C-? 6 hydroxyalkyl or C? -6 carboxyalkyl; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1 - alkyl, amino, aminoalkyl, halogen, hydroxy, -CF 3, alkoxy, aryloxy, arylalkoxy, -OCF 3, -CORc , -COORc, -CONRcRd) -N (R?) CORc, -S02Rc, -S03Rc or -S02NRcRd; a 5 to 7 membered monocyclic or 8 to 10 membered bicyclic monocyclic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with Ci-β, amino, halogen, hydroxy, alkoxy alkyl , aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONRcRd, -NHCORcRd, NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd; or -CORc, -COORc or -CONRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
2. 2. A compound of Formula II: II or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRaRb, -S02Ra or -P03RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; Ai is a 5- to 6-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C 1-6 alkyl, amino, alkylamino, halogen , hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONReRd, -NHCORcRd, -NHS02Rc, -S02Rc, -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ri is hydrogen, alkyl, hydroxy or alkoxy; R 2 is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl; R 3 is a direct bond or C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 1-6 hydroxyalkyl or C 1-6 carboxyalkyl; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, - CORe, -COORe, -CONReRf, -NÍR ^ CORe, -S02Re, -S03Re or -S02NReRf; a 5 to 7 membered monocyclic or bicyclic 8 to 10 membered monocyclic heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may optionally be substituted with C-α-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Ra, -S02Ra, -S03Ra or -S02NRaRb; or -CORe, -COORe or -CONReRf, where Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. 3. - A compound of Formula III: ip or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -OH or -NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ai is a 5 to 6 membered monocyclic or bicyclic 8 to 10 membered monocyclic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C 1-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryioxy, arylalkoxy, -CF3, -OCF3, -CORa, -COORa, -CONRaRb, -NHCORaRb, -NHS02Ra, -S02Ra, - S03Ra or -S02NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R-i is hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein R c and R d are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C-- 4 alkyl, amino, aminoalkyl, halogen, hydroxy, -CF 3, alkoxy, aryloxy, arylalkoxy, -OCF 3, -CORe, -COORe, -CONReRf, -N (R?) CORe, -S02Re, -S03Re or -S02NReRf; or a 5- to 7-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C?-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3, -OCF3, -CORe, -COORe, -CONReRf, -NHCOReRf, NHS02Re, -S02RT, -S03Re or -S02NReRf, wherein Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. 4. A compound of Formula IV: IV or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R is -CORa, -CONRaRb, -S02Ra or -P? 3RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl; Ai is a 5-6 membered monocyclic or bicyclic 8- to 10-membered monocyclic ring having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C? -6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, aryloxy, arylalkoxy, -CF3, -OCF3, -CORc, -COORc, -CONRcRd, -NHCORcRd, -NHS02Rc, -S02Rc > -S03Rc or -S02NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl; Ri is hydrogen, alkyl, hydroxy or alkoxy; and R2 is wherein Re and Rf are independently hydrogen or alkyl; X is N, O or S; and A2 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C? -4 alquiloalkyl, amino, aminoalkyl, halogen, hydroxy, -CF 3, akoxy, aryloxy, arylalkoxy, -OCF 3, -CORg, -COORg, -CONRgRn, -N (R?) CORg, -S02Rg, -S03Rg or -S02NRgRh; or a 5- to 7-membered monocyclic or bicyclic 8- to 10-membered heteroaromatic ring, having one to four heteroatoms selected from N, O or S, and may be optionally substituted with C-? 6 alkyl, amino, halogen , hydroxy, alkoxy, aryloxy, arylalkoxy, -CF3 | -OCF3, -CORg, -COORg, -CONRgRh, -NHCORgRh, NHS02Rg, -S02Rg, -S03Rg or -S02NRgRh, wherein Rg and Rh are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. 5. The compound according to claim 1, further characterized in that Ai is: wherein Ra and Rb are independently -H, -alkyl of d-6, -C02-alkyl or -C02CH2CH2NH2, RI is -H; R2 is -H, -Me, -Et, wherein R c is alkyl; R3 is -CH2-, -C2CH2-, -CH (CH3) -, -C (CH3) 2-, -CH (CH2OH) - or -CH (CH2CH2COOH) -; and A2 is wherein X is O or S. 6. The compound according to claim 1, further characterized in that it is one of: 4- (Benzothiazol-6-ylamino) -6- (ethyl-benzylamino) - [1, 3, 5] triazin-2-ol; 4- (Benzothiazoi-6-ylamino) -6- (methyl-benzylamino) - [1,3,5-Triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (benzylamino) -1,4,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylamino) -1,4,5] triazin-2-ol; (S) -4- (Benzothiazol-6-ylamino) -6- (1-phenylethylamino) -1,4,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (methyl-1-phenylethylamino) -1,4,5] triazin-2-oI; (S) -4- (Benzothiazol-6-ylamino) -6- (methyl-1-phenylethylamino) -1,4,5] triazin-2-ol; (R) -4- (Benzothiazol-6-ylamino) -6- (ethyl-1-phenylethylamino) -1,4,5] triazin-2-ol; (S) -4- (Benzothiazol-6-ylamino) -6- (ethyl-1-phenylethylamine) -1,4,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) -1,4,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylammon) -6- (methyl-2-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- (ethyl-2-phenylethylammon) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- (2-chloro-benzamino) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- (2-fluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6 - [(pyridin-3-ylmethyl) -amino) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- (2,6-difluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylammon) -6- [methyl- (2-pyridin-2-yl-ethyl) amino] - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylamino) -6- [pyridin-2-ylmethyl) -amino] - [1, 3,5] triazin-2-ol; 4- Benzothiazol-6-ylammon) -6- [benzyl- (1-benzyl-pyrrolidn-3-yl) -amino] - [1, 3,5] triazin- 2- ol; 4- (Benzothiazol-6-ylammon) -6- (3-fluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-chloro-6-methyl-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-e-ylaminoJ -? - ÍN'-methyl-N'-phenyl-hydrazinoJ-fl. S ^ Jtriazin ^ -ol; 4- (benzothiazol-6-ylammon) -6 - [(pyridine) n-4-ylmethyl) -amino] - [1, 3,5] triazin-2-ol; 4-benzothiazol-6-ylamino) -6- (2-pyridin-3-yl) -ethylamino) - [1, 3,5] triazin-2-ol; 4-Benzothiazol-6-ylamino) -6- (1-phenyl-propylamino) - [1, 3,5] triazin-2-ol; 4-Benzothiazol-6-ylamino) -6- (2-pyridin-2-yl-ethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-naphthalen-1-yl-ethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-hydroxymethyl-phenylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (quolin-5-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (4-hydroxy-naphthalen-1-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1 H -indazol-6-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(1 H -indazol-6-yl) -methylamino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (1-methyl-1 H -indazol-6-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (6-hydroxy-naphthalen-1-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-hydroxy-phenylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [2- (2-hydroxyethyl) -phenylamino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (5-thiophen-2-yl-2H-pyrazol-3-ylammon) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-2H-pyrazol-3-ylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,4-d-fluoro-benzylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-phenylamino- [1, 3,5] triazin-2-ol; 4- (1 H-ldazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-hydroxy-1-phenylethyllamine) - [1, 3,5] triazin-2-ol; 4- (1 H-ldazol-5-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-7-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(furan-2-yl-methyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(thiophen-2-yl-methyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(furan-3-ylmethyl) -amino- [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6 - [(thiophen-3-yl-methyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (benzyl-pyrrolidin-3-ylamino) - [1, 3,5] triazin-2-ol; 3-. { [4- (Benzothiazol-6-ylamino) -6-hydroxy- [1, 3,5] triazin-2-yl] -benzylamino} -propan-1,2-diol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (3-morpholin-4-ylpropyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-. { benzyl- [3- (4-methyl-piperazin-1-yl) -propyl] -amino} - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamine) -6- [benzyl- (3-dimethylamino-propyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (2-piperazin-1-ylethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (2-morpholin-4-ylethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [benzyl- (2-dimethylamino-ethyl) -amino] - [1, 3,5] triazin-2-ol; 4- (2-Amino-benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3, 5] triazin-2-ol; 4- (1-Methyl-1-phenylethylamine) -6- (quinolin-6-ylammon) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6- (N-ethylbenzylamino) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6- (N-methylbenzylamino) - [1, 3,5] triazin-2-ol; 4- (Quinolin-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3, 5] triazin-2-ol; N- [4- (Benzothiazol-6-ylamino) -6- (1-methyl-1-phenylethylamino) - [1, 3,5] triazin-2-yl] -hydroxylamine; 4- (Benzothiazol-6-ylamino) -6 - [(4-fluoro-3-trifluoromethylbenzyl) amino] - [1, 3,5] triazin-2-olr. ; 4- (Quinolin-6-ylamino) -6 - [(4-fluoro-3-trifluoromethylbenzyl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (ethyl- (pyridin-2-ylmethyl) amino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N-benzyl isopropylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylammon) -6- (ethyl- (2-fluorobenzyl) amino] - [1, 3,5] trizin-2-ol; 4- (benzothiazol-6-ylamino) - 6- [benzyl- (2,2,2-trifluoroethyl) amino] - [1, 3,5] triazin-2-ol; 3 - [[4- (Benzothiazol-6-ylamino) -6-hydroxy- [1 , 3,5] triazin-2-yl] - (1-phenylethyl) amino] propan-1,2-diol; 4- (Benzothiazol-6-ylamino) -6- (ethyl- (pyridin-2-ylmethyl) amino] ) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N- (2-fluorobenzyl) isopropylamino) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- [ethyl- (1 H -indazol-6-yl) amino] - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylam No) -6-. (Benzyl- [2- (3H-imidazol-4-yl) ethyl] amino.} - [1, 3,5] triazin-2-ol; 4- (Benzothiazole- 6-ylamino) -6- {2-fluorobenzK2- (3H-amidozol-4-yl) ethyl] amino.} - [1, 3,5] triazin-2-ol; 4- (Benzothiazole -6-ylamino) -6- [benzi- (3-imidazol-1-yl-propyl) amino] - [1, 3,5] triazin-2-ol, 4- [{[4- (Benzothiazole- 6-ylamino) -6-hydroxy- [1, 3,5] triazin-2-yl] -benzylaminojbutyric acid, 4- (Benzothiazol-6-ylamino) -6-. {(2-piperazin-1-ylethyl) - quinolin-5-ylamino.} - [1, 3,5] t riazin-2-ol; 4- (Benzothiazol-6-ylamino) -6-. { benzyl- [2- (3H-imidazol-4-yl) ethyl] amino} - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (N-benzylpropylamino) - [1, 3,5] triazin-2-ol and pharmaceutically acceptable salts thereof. 7. The compound according to claim 3, further characterized in that it is one of: 4- (Benzothiazol-6-i! Amino) -6- (2-methyl-pyrrolidin-1-yl) - [1, 3, 5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-benzyl-pyrroidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,6-dimethyl-piperidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2,5-dimethyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-pyrrolidin-1-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-phenyl-thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (2-phenyl-thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (thiomorpholin-4-yl) - [1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (3-methyl-piperidin-1-ylH1, 3,5] triazin-2-ol; 4- (Benzothiazol-6-ylamino) -6- (morpholine-4-) il) - [1, 3,5] triazin-2-ol and pharmaceutically acceptable salts thereof 8. A pharmaceutical composition comprising a compound as described in any of claims 1 to 4 and a pharmaceutically carrier acceptable 9. A pharmaceutical composition comprising a compound as described in claim 5 and a pharmaceutically acceptable carrier 10. A pharmaceutical composition comprising a compound as claimed in claim 6 or 7 and a pharmaceutically acceptable carrier. pharmaceutically acceptable carrier 11.- A method for preparing the compounds of Formulas I and III, wherein R is -OH, the method comprises the steps of: a) moving one of three displaceable groups in positions 2-4. and 6-, respectively, of a 1, 3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2- (4-methoxybenzyloxy) - [1, 3, 5] triazine; b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2- (4-methoxybenzyloxy) - [1, 3,5] triazine; and c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino- (2-hydroxy) - [1 , 3,5] triazine. 12. A method for preparing the compounds of Formulas II and IV, the method comprises the steps of: a) moving one of three displaceable groups in positions 2-, 4- and 6-, respectively, of a ring 1, 3,5-triazine with 4-methoxybenzyl alcohol to give a 2- (4-methoxybenzyloxy) - [1, 3,5] triazine; b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2- (4-methoxybenzyloxy) - [1, 3,5] triazine; and c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino- (2-hydroxy) - [1, 3] , 5jtriazine; and d) adding an acylation, sulfonation or phosphorylation agent to 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine to give 4,6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2-0-sulfonii) - [1, 3,5] triazine or a 4,6-diamino- (2-0-phosphoryl) - [ 1, 3,5] triazine, respectively. 13. The method according to claim 11 or 12, further characterized in that the displaceable groups are chloros. 14. A method for preparing the compounds of Formulas I and III, wherein R is -OH, the method comprises the steps of: aa) moving one of three displaceable groups in positions 2-, 4- and 6, respectively , of a 1, 3, 5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino- [1, 3,5] triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino- [1, 3,5] triazine; and c) displacing the third displaceable group with water under acidic conditions to give a 4,6-diamino- (2-hydroxy) - [1, 3,5] triazine. 15. A method for preparing the compounds of Formulas I and III, wherein R is -NHOH, the method comprises the steps of: aa) displacing one of three displaceable groups in positions 2-, 4- and 6-, respectively, of a 1, 3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino- [1, 3,5] triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino- [1, 3,5] triazine; and ce) displacing the third displaceable group with hydroxylamine under acidic conditions to give a 4,6-diamino - ([1, 3,5] triazin-2-yl) -hydroxylamine. 16. A method for preparing the compounds of Formulas II and IV, the method comprising the steps of: aa) moving one of three displaceable groups in positions 2-, 4- and 6-, respectively, of a ring 1, 3,5-triazine with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino- [1, 3,5] triazine; bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino- [1, 3,5] triazine; and c) displace the third displaceable group with water under acidic conditions to give a 4,6-diamino- (2-hydroxyH1, 3,5) triazine, and dd) add an acylating agent, sulfonation or phosphorylation at 4.6 -diamino- (2-hydroxy) - [1, 3,5] triazine to give a 4,6-diamino- (2-0-acyl) - [1, 3,5] triazine, a 4,6-diamino- (2-0-sulfonyl) - [1, 3,5] triazine or a 4,6-diamino- (2-0-phosphori!) - [1, 3,5] triazine, respectively. 17. The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for inhibiting the activity of the protein tyrosine kinase. 18. The use of at least one compound as described in claim 5, for preparing a medicament for inhibiting the protein tyrosine kinase activity. 19. The use of at least one compound as described in claim 6 or 7, to prepare a medicament for inhibiting the protein tyrosine kinase activity. 20. A method for inhibiting the activity of the protein tyrosine kinase in vitro, which comprises contacting the kinase with at least one compound as described in any of claims 1 to 4. 21.- A method for inhibit the activity of the protein tyrosine kinase in vitro, which comprises contacting the kinase with at least one compound as described in claim 5. 22.- A method for inhibiting the activity of the protein tyrosine kinase in vitro , which comprises contacting the kinase with at least one compound as described in claim 6 or 7. 23.- A method for inhibiting the activity of the protein tyrosine kinase in cells, which comprises contacting the kinase with at least one compound as described in any of claims 1 to 4. 24.- A method for inhibiting the protein tyrosine kinase activity in cells, which comprises contacting the kinase with at least one compound as described in claim 5. 25.- A method for inhibiting the protein tyrosine kinase activity in cells, comprising contacting the kinase with at least one compound such as which is described in claim 6 or 7. 26.- The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for inhibiting the activity of the protein tyrosine kinase in a mammal. 27. The use of at least one compound as described in claim 5, for preparing a medicament for inhibiting the activity of the protein tyrosine kinase in a mammal. 28. The use of at least one compound as described in claim 6 or 7, for preparing a medicament for inhibiting the activity of the protein tyrosine kinase in a mammal. 29. The use claimed in any of claims 17 to 19, wherein the protein tyrosine kinase is VEGFR-2 (KDR), c-fms, c-met or tie-2. 30. - The use claimed in any of claims 26 to 28, wherein the protein tyrosine kinase is VEGFR-2 (KDR), c-fms, c-met or tie-2. 31. The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for treating cancer in a mammal. 32. The use of at least one compound as described in claim 5, for preparing a medicament for treating cancer in a mammal. 33. The use of at least one compound as described in claim 6 or 7, for preparing a medicament for treating cancer in a mammal. 34. The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for treating vascular diseases in a mammal. 35.- The use of at least one compound as described in claim 5, for preparing a medicament for treating vascular diseases in a mammal. 36.- The use of at least one compound as described in claim 6 or 7, for preparing a medicament for treating vascular diseases in a mammal. 37. - The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for treating ocular diseases in a mammal. 38.- The use of at least one compound as described in claim 5, for preparing a medicament for treating ocular diseases in a mammal. 39.- The use of at least one compound as described in claim 6 or 7, for preparing a medicament for treating ocular diseases in a mammal. 40.- The use of at least one compound as described in any of claims 1 to 4, for preparing a medicament for treating restenosis in a mammal. 41. The use of at least one compound as described in claim 5, for preparing a medicament for treating restenosis in a mammal. 42. The use of at least one compound as described in claim 6 or 7, for preparing a medicament for treating restenosis in a mammal. 43.- A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound as described in claims 1 to 7. 44. The dosage form according to claim 43, further characterized in that it is adapted for parenteral or oral administration.