MXPA06008314A - Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer - Google Patents

Abstract

Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

COMPOUNDS AND PROCEDURES FOR USE FIELD OF THE INVENTION This invention is in the field of pharmaceutical agents and refers specifically to compounds, compositions, uses and methods for treating inflammation, angiogenesis and cancer. BACKGROUND OF THE INVENTION Protein kinases represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CD6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, Fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-IR, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. The inhibition of such kinases has become an important therapeutic target. The hepatocyte growth factor receptor ("c-Met") is the only receptor tyrosine kinase that is shown to be overexpressed in a variety of cancers. c-Met typically comprises, in its native form, a 190-kDa heterodimeric transmembrane tyrosine kinase protein (a 50 kDa chain and a 145 kDa β chain linked by disulfide bonds) (Porc. Nati. Acad. Sci. United, 84: 6379-6383 (1987)). c-Met expresses mainly in epithelial cells and the stimulation of c-Met leads to dispersion, angiogenesis, proliferation and metastasis (see Cytokine and Growth Factor Reviews, 13: 41-59 (2002)). The ligand for c-Met is a hepatocyte growth factor (also known as scattering factor, HGF and SF). HGF is a heterodimeric protein secreted by cells of mesodermal origin (Nature, 327: 239-242 (1987), J. Cell Biol., 111: 2097-2108 (1990)). Various biological activities have been described for HGF through interaction with c-Met (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the c-Met Receiver, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993)). The biological effect of HGF / SF may depend in part on the target cell. HGF induces a variety of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys., Res. Comm., 122: 1450-1459 (1984); Proc. Nati. Acad. Sci. USA, 88: 415-419 (1991)). It stimulates motility and invasion of carcinoma cells, the former being involved in the migration of cells required for metastasis. HGF can also act as a "scattering factor", an activity that promotes the dissociation of vascular endothelial and epithelial cells (Nature, 327: 239-242 (1987); J. Cell Biol., 111: 2097-2108 (1990)).; EMBO J., 10: 2867-2878 (1991); Proc. Nati, Acad. Sci. United States, 90: 649-653 (1993)). Therefore, it is believed that HGF is important in tumor invasion (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)). HGF and c-Met are expressed at abnormally high levels in a wide variety of solid tumors. High levels of HGF and / or c-Met have been observed in the liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others. The role of HGF / c-Met in metastasis has been investigated in mice using cell lines transformed with HGF / c-Met (J. Mol. Med., 74: 505-513 (1996)). It has been suggested that overexpression of the c-Met oncogene plays a role in the hepatogenesis and progression of thyroid tumors derived from the follicular epithelium (Oncogene, 7: 2549-2553 (1992)). HGF is a morfogen (Development, 110: 1271-1284 (1990); Cell, 66: 697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 119: 629-641 (1992)). Recent work on the relationship between the inhibition of angiogenesis and the suppression or reversal of tumor progression shows great promise in the treatment of cancer (Nature, 390: 404-407 (1997)), especially the use of multiple inhibitors of cancer. angiogenesis compared to the effect of a single inhibitor. Angiogenesis can be stimulated by HGF, as well as by endothelial growth factor vascular (VEGF) and the basic fibroblast growth factor (bFGF). Angiogenesis, the process of branching new blood vessels from the existing vasculature and arteriogenesis, the remodeling of small vessels in larger conduit vessels are physiologically important aspects of vascular growth in adult tissues. These processes of vascular growth are required for beneficial processes such as tissue repair, wound healing, recovery of tissue ischemia and menstrual cycle. They are also required for the development of pathological conditions such as myoplasias growth, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration and certain inflammatory pathologies. The inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models. For example, the inhibition of angiogenesis by blocking the vascular endothelial growth factor or its receptor has resulted in the inhibition of tumor growth and retinopathy. In addition, the development of pathological pannus in rheumatoid arthritis involves angiogenesis and should be blocked by angiogenesis inhibitors. The ability to stimulate vascular growth has a potential utility for the treatment of pathologies induced by ischemia such as myocardial infarction, coronary artery disease, peripheral vascular disease and stroke. The branching of new vessels and / or the expansion of small vessels in ischemic tissues prevent the death of ischemic tissue and induce tissue repair. It is known that certain diseases are associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as asthma chronic, arterial atherosclerosis or after transplant, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias). The treatment of malaria and related viral diseases can also be mediated by HGF and c-Met. Elevated levels of HGF and c-Met have also been observed in non-oncological situations, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that HGF levels increase in the plasma of patients with hepatic insufficiency (Gohda et al., Supra) and in plasma (Hepatol., 13: 734-750 (1991)) or serum (J. Biochem., 109: 8-13 (1991)) of animals with experimentally induced hepatic injury. It has been shown that HGF is a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem.

Biophys. Res. Commun., 176: 45-51 (1991); Biochem. Biophys. Res. Commun., 174: 831-838 (1991); Biochem., 30: 9768-9780 (1991); Proc. Nati Acad. Sci. USA, 88: 415-419 (1991)). It has been postulated that both HGF and the c-Met proto-oncogene play a role in microglial reactions for CNS lesions (Oncogene, 8: 219-222 (1993)). In view of the role of HGF and / or c-Met in the potentiation or promotion of such diseases or pathological conditions, it would be useful to have a means to reduce or substantially inhibit one or more of the biological effects of HGF and its receptor. In this way, a compound that reduces the effect of HGF would be useful. T cells play an important role in the regulation of immune responses and are important in establishing immunity against pathogens. In addition, T cells are usually activated during autoimmune inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, type I diabetes, multiple sclerosis, Sjogren's disease, myasthenia gravis, psoriasis and lupus. Activation of T cells is also an important component of transplant rejection, allergic reactions and asthma. T cells are activated by specific antigens through the T cell receptor (TCR) that is expressed on the cell surface. This activation causes a series of intracellular signaling cascades mediated by enzymes expressed in the cell (Kane, LP et al Current Opinion in Immunol.200, 12, 242). These cascades lead to gene regulation events that lead to the production of cytokines, such as interleukin-2 (IL-2). IL-2 is an important cytokine in the activation of T cells, which leads to the proliferation and amplification of specific immune responses. One class of enzymes that is considered important in signal transduction is the enzyme kinase. Members of the SRC family of tyrosine kinases include, for example: Lck, Fyn (B), Fyn (T), Lyn, Src, Yes, Hck, Fgr and Blk (for an analysis, see: Bolen, JB, and Brugge, JS Annu, Rev. Immunol 1997, 15, 371). Studies of gene disruption suggest that inhibition of some members of the SRC family of kinases will potentially lead to a therapeutic benefit. Src (- / -) mice have abnormalities in bone remodeling or osteoporosis (Soriano, P. Cell 1991, 64, 693), suggesting that inhibition of this kinase should be useful in bone resorption diseases, such as osteoporosis. . Lck (- / -) mice have defects in the maturation and activation of T cells (Anderson, SJ et al Adv. Immunol., 1994, 56, 151), which suggests that the inhibition of this kinase should be useful in diseases of T cell-mediated inflammation. In addition, human patients have been identified with mutations that perform Lck kinase activity (Goldman, FD et al., J. Clin, Invest.1998, 102, 421). These patients have a severe combined immunodeficiency disorder (SCID). Without wishing to suggest that the compounds described in the present invention possess pharmacological activity only in by virtue of an effect in a single biological process, it is believed that the compounds modulate T cell activation by inhibiting one or more of the multiple protein kinases involved in early signal transduction steps that lead to T cell activation, for example, by inhibiting the Lck kinase. The Src family of kinases is also important for signaling current under other immune cellular receptors. Fyn, like Lck, is involved in TCR signaling in T cells (Appleby, MW et al Cell 1992, 70, 751). Hck and Fgr are involved in the signaling of the Fe receptor? which leads to the activation of neutrophils (Vicentini, L. et al., J. Immunol., 2002, 168, 6446). Lyn and Src also participate in the Fe receptor signaling? which leads to the release of histamine and other allergic mediators (Turner, H. and Kinet, J-P Nature 1999, 402, B24). These findings suggest that inhibitors of the Src kinase family may be useful for treating allergic diseases and asthma. PCT publication WO 03/000660 describes substituted phenyl compounds. Substituted quinolines are described in U.S. Patent No. 6,143,764. In WO 03/82272, substituted benzazoles are described. In WO 00/61580, benzimidazoles are described. WO 02/32872 discloses substituted quinolines. WO 00/47212 describes substituted quinazoline derivatives. WO 96/23775 discloses thioquinoline compounds.

The compounds of the present invention have not been described for the treatment of cancer. SUMMARY OF THE INVENTION A class of compounds useful in the treatment of cancer and angiogenesis is defined by Formula I E ^ XYYYY i wherein R is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and alkynyl replaced or unsubstituted; wherein R1 is selected from 5-14 membered nitrogen-containing heterocyclyl, substituted or unsubstituted, wherein A is an optionally substituted ten-membered bicyclic ring comprising at least one aromatic ring; wherein X is selected from 0, S, NR2 and CR3R4; wherein Y is selected from -NRb (CR3R4) p-, NRbC (= 0) (CR3R4) p-, -NRbC (= 0) NRb (CR3R4) p-, -NRbC (= 0) (CR3R4) pO- , -NRbC (= 0) O (CR3R4) p-, -NRC (= S) (CR3R4) p-, -NRbC (= NRa) (CR3R4) P '-NRbS02- (CR3R) p-, -0C (= 0) (CR3R4) P-, -0 (CR3R4) p-, - (CR3R4) S (= 0) t-, - (CR3R4) p-, -S (= 0) 2NRb (CR3R4) p-, -S (= 0) t (CR3R4) P-, C (= 0) (CR3R4) p-, -C (= NRa) NH (CR3R4) p-, -C (= S) NH (CR3R4) p- and C ( = 0) NH (CR3R4) p-; where Y is in any direction; wherein each of Ra and Rb is independently selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, R5R5N- (C = 0) -, and R5 - (= 0) -; wherein each of Ra and Rb is optionally substituted; wherein R2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl and R5-carbonyl; wherein each of R3 and R4 is independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R6, and alkyl substituted with R6; wherein R5 is selected from H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl; wherein R6 is selected from cyano, -OR2, -SR2, halo, -S02R2, -C (= 0) R2, -S02NR2R5, -NR5C (= 0) OR2, NR5C (= 0) NR5R2, -NR5C (= 0) R2, -C02R2, -C (= 0) NRR5 and -NR2R5; wherein p is 0, 1, 2 or 3; and wherein t is 0, 1 or 2; and pharmaceutically acceptable derivatives thereof; The invention also relates to compounds of Formula I, R is selected from H, aryl of 6-10 members, heterocyclyl of 4-10 members, cycloalkyl of 4-6 members, C? _6 alkyl, C2.6 alkenyl and C2-6 alkynyl; where R is substituted or unsubstituted; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R is phenyl or naphthyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R is a substituted or unsubstituted heterocyclyl ring selected from pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzofuryl, 2, 3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, furanyl and thienyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R is 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl and cyclohexyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R is selected from methyl, ethyl, propyl, butyl and pentyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R is selected from ethenyl and propenyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein A is selected from where R7 is selected from H, halo and C? _3 alkyl; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein A is benzothiazole; and pharmaceutically acceptable derivatives thereof; together with any of the previous and following embodiments. The invention also relates to compounds of Formula I wherein R 1 is selected from 9-10 membered bicyclic heterocyclyl; together with any of the preceding or the following embodiments.

The invention also relates to compounds of Formula I wherein R 1 is selected from 9-10 membered bicyclic heteroaryl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R 1 is wherein the T ring is selected from phenyl and 5-6 membered heteroaryl; where Z is selected from N or CH; wherein R10 is one or more substituents selected from R50-; and wherein R5 is selected from C6-C6alkyl, C6-6 haloalkyl, C6-6alkylamino-C6-6alkyl, aryl-C6-6alkyl / heterocyclycyl-C6-6alkyl, cycloalkyl-C6alkyl- 6, aryl, heterocyclyl and cycloalkyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R 1 is selected from and wherein R10 is selected from C3_3alkoxy, C3_3alkylamino-C3_3alkoxy, phenyl-C3_3alkoxy / 5-6 membered heterocyclyl_C3_3alkoxy and C4_6_alkoxyC_alkoxy? .3; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein R 1 is selected from 6,7-dimethoxy-4-quinolinyl, 6-methoxy-7- (dimethylaminopropoxy) -4-quinolinyl, 6,7-dimethoxy-4-quinazolinyl and 6-methoxy-7- (dimethylaminopropoxy) -4-quinazolinyl; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein Y is selected from -NH (CH2) P-, -NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) p0-, - NHC (= 0) O (CH2) P-, - (CH2) p-NHC (= 0) -, -NHC (= 0) NH-, -C (= 0) 0-, -NHS02- and -C ( = 0) NH (CH2) P-; and wherein p is 0, 1 or 2; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I wherein Y is selected from -NH-, -NHCH2-, -NH (CH2) 2-, -NH (CH2) 3-, -NHC (= 0) CH2-, -NHC (= 0) (CH2) 2-, NHC (= 0) -, -NHC (= 0) CH20-, -NHC (= 0) 0CH2-, -NHC (= 0) NH-, (CH2) NHC (= 0) -, -C (= 0) 0-, -NHS02- and -C (= 0) NHCH2-; With any of the above or the following embodiments. The invention also relates to compounds of Formula I wherein R is selected from ethyl, isopropyl, (CH 3) 3 CCH 2 -, ethenyl and an unsubstituted or substituted ring selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrrolidinyl, -pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro -l, 4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3 -thienyl and 2-thienyl; where A is naphthyl; where X is -O- or -CH2-; where Y is selected from -NHC (= 0) -, -NHC (= 0) (CH2) -, -NHC (= 0) (CH2) 2-, - (CH2) p-NHC (= 0) -, NHC (= 0) NH- and -NHS02-; and wherein R 1 is selected from 6,7-dimethoxy-4-quinolinyl, 6-methoxy-7- (dimethylaminopropoxy) -4-quinolinyl, 6,7-dimethoxy-4-quinazolinyl and 6-methoxy-7- (dimethylaminopropoxy) - 4-quinazolinyl; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula I and pharmaceutically acceptable salts thereof selected from N- [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -3-methyl-benzamide.; Thiophene-3-carboxylic acid [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -amide; 2-Phenyl-N- [6- (7-trifluoromethyl-quinolin-4-yloxy) -benzothiazol-2-yl] -acetamide; N- [6- (2-Methyl-pyridin-4-yloxy) -benzothiazol-2-yl] -2-phenyl-acetaraide; 4-Chloro-N- [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -benzamide; 5- ((6,7-bis (methoxy) -4-quinolinyl) oxy) -N- (4-chlorophenyl) -1,3-benzoxazol-2-amine; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) -2-thiophenecarboxamide; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3-thiophenecarboxamide; N- (6- ((7- ((3- (dimethylamino) propyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) benzamide; And N- (6- ((6- (methoxy) -7- ((3- (-morpholinyl) propyl) oxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) -3-thiophenecarboxamide . The invention also relates to compounds of Formula I ' wherein R is selected from a) substituted or unsubstituted aryl, b) substituted or unsubstituted heterocyclyl, c) substituted or unsubstituted cycloalkyl, d) substituted or unsubstituted cycloalkenyl, e) H, f) substituted or unsubstituted alkyl, g) substituted or unsubstituted alkenyl, h) substituted or unsubstituted alkynyl, i) alkylaminocarbonyl, j) aminocarbonyl, and k) cyano; wherein R1 is where the T ring is selected from phenyl and 5-6 membered heteroaryl; where Z is selected from N or CRX; where R x is selected from H, CN, NH 2, F, alkylcarbonylamino and alkylaminocarbonyl; where R10 is one or more substituents selected from H, C? -6 alkoxy, C? -6 haloalkoxy, C? -6-amino-C6-alkoxy alkoxy, aryl-C6-6 alkoxy, heterocyclyl-C-alkoxy? 6, C6-6cycloalkyl-alkoxy, heterocyclyl- (hydroxyalkoxy) C6-6, cycloalkyl- (hydroxyalkoxy) C6-6, aryl- (hydroxyalkoxy) C6-6, C6-alkoxy-alkoxy, aryloxy-alkoxy C? _6, heterocyclyloxy-C6-alkoxy, cycloalkyloxy-C6-6 alkoxy, aryloxy, heterocyclyloxy and cycloalkyloxy; where A is selected from the following: where X is selected from O, S, NR2 and CR3R4; where Y is selected from -NR (CR3R4) P-, NRC (= 0) (CR3R4) p-, -NRbC (= 0) NRb (CR3R4) p-, -NRC (= 0) (CR3R4) p0-, - NRbC (= 0) 0 (CR3R4) p-, -NRC (= S) (CR3R4) p-, -NRbC (= NRa) (CR3R4) p-, -NRbS02- (CR3R4) p-, -0C (= 0 ) (CR3R4) P-, -0 (CR3R4) p-, - (CR3R4) PS (= 0) t-, - (CR3R4) P-, -S (= 0) 2NRb (CR3R4) p-, -S ( = 0) t (CR3R4) p-, -C (= 0) (CR3R4) P-, -C (= NRa) NH (CR3R4) p-, -C (= S) NH (CR3R4) p- and -C (= 0) NRb (CR3R4) p-; where Y is in any direction; wherein each of Ra and R is independently selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, R5R5N- (C = 0) - and R5- (= 0) -; wherein each of Ra and Rb is optionally substituted; wherein R2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl and R5-carbonyl; wherein each of R3 and R4 is independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R6, and alkyl substituted with R6; wherein R5 is selected from H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl; where R6 is selected from cyano, -OR2, -SR, halo, -S02R2, -C (= 0) R2, -S02NR2R5, -NR5C (= 0) OR2, -NR5C (= 0) NR5R2, -NR5C (= 0 ) R2, -C02R2, -C (= 0) NR2R5 and -NR2R5; wherein p is 0, 1, 2 or 3; and wherein t is 0, 1 or 2; and pharmaceutically acceptable derivatives thereof; with the proviso that R is not 4-chloro-3- (1-methylpyrrolidin-2-yl) phenyl when Y is NH and A is 2,5-benzoxazolyl and when R 1 is 6,7-dimethoxyquinolinyl; with the additional proviso that R is not 4-chloro-3- (1-methylpyrrolidin-2-yl) phenyl when Y is NH and A is 2,5-benzoxazolyl and when R 1 is 6,7-dimethoxyquinazolinyl; with the additional proviso that R is not phenyl when Y is CH 2 and A is 2,5-benzimidazolyl and when R 1 is 6,7-dimethoxy-quinolinyl; with the additional proviso that Y is not -NH- or -NMe- when X is 0, S, CH2 or NH, and A is benzimidazolyl, benzoxazolyl or benzothiazolyl; and with the additional condition that R is not methyl when Y is - (CR3R4) P-, when p is 0, and A is 2, 5-indolyl. The invention also relates to compounds of Formula I 'wherein R is selected from H, aryl of 6-10 members, heterocyclyl of 4-10 members, cycloalkyl of 3-6 members, C6_6 alkyl, C2.6 alkenyl and C2_6 alkynyl; where R is substituted or unsubstituted. The invention also relates to compounds of Formula I 'wherein R is optionally substituted phenyl or optionally substituted naphthyl.

The invention also relates to compounds of Formula I 'wherein R is a substituted or unsubstituted heterocyclyl ring selected from pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydrofuryl, 2,3-dihydrothiazolyl , 2,3-dihydrobenzofuryl, 2,3-dihydro-l, 4-benzodioxinyl, 1,3-benzodioxolyl, benzisoxazolyl, benzthiazolyl, benzimidazolyl, benzothiadiazolyl, indolinyl, imidazo [1,2-a] pyridyl, isoxazolyl, isothiazolyl, oxazolyl , thiazolyl, thiadiazolyl, furanyl and thienyl. The invention also relates to compounds of Formula I 'wherein R is an unsubstituted or substituted ring selected from 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl. The invention also relates to compounds of Formula I 'wherein R is selected from 1-methyl-cyclopropyl, cyclopropyl, 2-fluorocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The invention also relates to compounds of Formula I 'wherein R is selected from methyl, trifluoromethyl, ethyl, propyl, butyl and pentyl.

The invention also relates to compounds of Formula I 'wherein R is selected from cyclohexenyl, ethenyl and propenyl. The invention also relates to compounds of Formula I 'wherein R is H. The invention also relates to compounds of Formula I' wherein R is dimethylamino. The invention also relates to compounds of Formula I 'wherein A is selected from where R7 is selected from H, halo and methyl. The invention also relates to compounds of Formula I 'wherein A is The invention also relates to compounds of Formula I 'wherein A is The invention also relates to compounds of Formula I 'wherein The invention also relates to compounds of Formula I 'wherein R1 is R10; wherein the T ring is selected from phenyl and 5-6 membered heteroaryl; where Z is selected from N or CH; wherein R10 is one or more substituents selected from R80-; and wherein R 8 is selected from C 1-6 alkyl, C? -S haloalkyl, C? _6-amino-C? -6 alkyl, aryl C? _6 alkyl, heterocyclyl C? -6 alkyl, cycloalkyl-C alkyl? -6, heterocyclyl-C? _6- (hydroxyalkyl), cycloalkyl-C? -6- (hydroxyalkyl), aryl-Ca_6- (hydroxyalkyl), C? -6-alkyl-alkoxy, aryloxy-C? -6 alkyl, heterocyclyloxy- C? _6 alkyl, cycloalkyloxy-C? -6 alkyl, aryl, heterocyclyl and cycloalkyl.

The invention also relates to compounds of Formula I 'wherein R 1 is selected from and wherein R10 is selected from C3_3alkoxy, C3_3alkylamino-C3_3alkoxy, 5-6_cyclic-C3_3alkoxy, C4_6_alkoxy-C3_3alkoxy, 5-6 heterocyclyl members- (hydroxyalkoxy) C? _3, C3_6- (hydroxyalkoxy) C? _3 cycloalkyl, C3 phenyl- (hydroxyalkoxy), C? -2-C3_3 alkoxy, C3 phenyloxy-alkoxy, 5-6 membered heterocyclyloxy-alkoxy C? _4, cycloalkyloxy-C? -3 alkoxy, 5-6 membered heterocyclyloxy and C3_6 cycloalkyloxy. The invention also relates to compounds of Formula I 'wherein R1 is selected from 6,7-dimethoxy-4-quinolinyl, 6-methoxy-7- (dimethylaminopropoxy) -4-quinolinyl, 6-methoxy-7- (4 -morpholinylpropoxy) -4-quinolinyl, 6,7-dimethoxy-4-quinazolinyl and 6-methoxy-7- (dimethylaminopropoxy) -4-quinazolinyl. The invention also relates to compounds of Formula I 'wherein Y is selected from -NH (CH2) P-, - NHC (= 0) (CH2) p-, -NHC (= 0) (CH2) p0-, -NHC (= 0) 0 (CH2) p-, - (CH2) p- NHC (= 0) -, -NHC (= 0) NH-, -C (= 0) 0-, -NHS02- and -C (= 0) NH (CH2) p-; and wherein p is O, 1 or 2. The invention also relates to compounds of Formula I 'wherein Y is selected from -NH-, -NHCH2-, -NH (CH2) 2-, -NH (CH2 ) 3-, -NHC (= 0) CH2-, -NHC (= 0) (CH2) 2-, NHC (= 0) -, -NHC (= 0) CH20-, -NHC (= 0) 0CH2-, -NHC (= 0) NH-, (CH2) NHC (= 0) -, -C (= 0) 0-, -NHS02- and -C (= 0) NHCH2-. The invention also relates to compounds of Formula I 'wherein R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 4-tert-butyl-phenyl, 2,3-dimethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3-chloro- 4- fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-chloro-3. trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) phenyl, 4-dimethylaminophenyl, 3- (4-methylpiperazin-1-ylmethyl) phenyl, 2- (4-methylpiperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [(3-dimethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidine -l-yl) -5-trifluoromethylphenyl, 2- [methyl- (l-methylpyrrolidin-3-yl) amino] -5-trifluoromethylphenyl, 2-pyrrolidinyl, l-methyl-2 pyrrolidinyl, 4-piperazinyl, 2-pyrrolyl, l-methyl-2-pyrrolyl, 5-imidazolyl, 3-pyrazolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 4-chloro -2-pyridyl, 4-methoxy-5-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 1, 3 -benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 4,5-dichloro-3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5-dimethyl-4-thiazolyl , 2-thiazolyl, 2- furanyl, 4,5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl-3-furyl, 3-furanyl, 3-thienyl, 4-methoxy-5-chloro-3-thienyl , 2-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2 -thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 5-tert. -butyl-isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 5- erc-butyl-pyrazol-3-yl and 2-methyl-benzothiazol-5-yl . The invention also relates to compounds of Formula I 'wherein X is O. The invention also relates to compounds of Formula I' selected from N- [6- (6,7-Dimethoxy-quinolin-4-yloxy) - benzothiazol-2-yl] -3-methyl-benzamide; [6- (6,7-Dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -amide of thiophene-3-carboxylic acid; 2-Phenyl-N- [6- (7-trifluoromethyl-quinolin-4-yloxy) -benzothiazol-2-yl] -acetamide; N- [6- (2-Methyl-pyridin-4-yloxy) -benzothiazol-2-yl] -2-phenyl-acetamide; 4-Chloro-N- [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -benzamide; 5- ((6,7-bis (methoxy) -4-quinolinyl) oxy) -N- (4-chlorophenyl) -1,3-benzoxazol-2-amine; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) -2-thiophenecarboxamide; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3-thiophenecarboxamide; N- (6- ((7- ((3- (dimethylamino) propyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) benzamide; and N- (6- ((6- (methoxy) -7- ((3- (4-morpholinyl) propyl) oxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3- thiophenecarboxamide. The invention also relates to compounds of Formula II wherein Xa is O or CH2; wherein Y is selected from -? H (CH2) P-, -? HC (= 0) (CH2) P-, -? HC (= 0) (CH2) pO-, - (CH2) p-? HC (= 0) -, -? HC (= 0)? H-, -? HC (= 0) 0 (CH2) p-, -C (= 0) 0-, -? HS02- and - C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3; or Y is a link if R is thienyl; wherein Z is CH or N; wherein R 'is selected from H, C? _5 alkyl, C2-4 alkenyl and an unsubstituted or substituted ring selected from phenyl, C3_6 cycloalkyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, , 3-dihydrobenzofuryl, 2,3-dihydro-l, 4-benzodioxinyl, 1,3-benzodioxolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, furanyl and thienyl; wherein R8 is selected from H, fluoro, chloro and methyl; wherein R9 is selected from H, methyl and fluoro; and wherein R10 is one or more substituents selected from 5- or 6-membered heterocyclyl-C?-C3 alkoxy, C C _2-amino-C--alkoxy alkoxy and C? _4-alkoxy; and pharmaceutically acceptable derivatives thereof; with the proviso that R is not methyl when Y is - co2-. The invention also relates to compounds of Formula II wherein Xa is O; where Ya is selected from -NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) pO-, - (CH2) P-NHC (= 0) -, NHC (= 0) NH-, -NHC (= 0) O (CH2) p-, -NHS02- and -C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3; where R 'is selected from ethyl, isopropyl, (CH 3) 3 CCH 2 -, ethenyl and an unsubstituted or substituted ring selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur- 7-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; wherein R10 is one or more substituents selected from 4-morpholinpropoxy, 1-pyrrolidinyletoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy; where R10 is attached to positions 6 and 7 of the quinolin-4-yl or quinazolin-4-yl ring; where R8 is H; and wherein R9 is H, methyl or fluoro; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula II wherein Ya is selected from -NHC (= 0) -, - NHC (= 0) (CH2) -, -NHC (= 0) (CH2) 2-, - ( CH2) p-NHC (= 0) -, NHC (= 0) NH- and -NHS02-; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula II where Ya is -NHC (= 0) - and -NHC (= 0) NH-; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula II wherein R 'is an unsubstituted or substituted ring selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur- 7-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-franyl, 3-thienyl and 2-thienyl; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula II wherein R 'is a ring selected from phenyl, cyclobutyl, cyclopentyl, ciciohexilo, 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; wherein the ring is substituted with one or two substituents selected from methoxymethylthio, 4-methylpiperazin-1-ylmethyl, trifluoromethyl, methyl, bromo, chloro, fluoro and tere-butyl; and pharmaceutically acceptable derivatives thereof; together with any of the preceding or the following embodiments. The invention also relates to compounds of Formula II wherein R8 is H; and where R9 is H or fluoro; and pharmaceutically acceptable derivatives thereof; together with any of the above or the following embodiments. The invention also relates to compounds of wherein Xa is O or CH2; wherein Ya is selected from -NH (CH2)? -3-, NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) P0-, - (CH2) p-NHC (= 0 ) -, NHC (= 0) NH-, -NHC (= 0) 0 (CH2) p- and -C (= 0) 0-; wherein Z is CH or N; wherein R 'is selected from H, C? _5 alkyl, Cx-3 haloalkyl, alkoxy-Ca-3 alkyl, C? _3-carbonyl-C? _3 alkyl, C? .5 cyanoalkyl, aminocarbonyl-C-alkyl? -5, alkyl C? -5-aminocarbonyl-C? -5 alkyl, amino-C? _5 alkyl, C? _5-amino-C? _5 alkyl, C? -5-sulfonyl-C? -5 alkyl, phenyl-C3_3alkyl, C3_6-cycloalkyl-C3-alkyl, 5-6-membered heterocyclyl-C3_3alkyl and an unsubstituted or substituted ring selected from phenyl, naphthyl, 1,3-benzodioxolyl, 2,3-dihydro -1, 4-benzodioxinyl, C3_6 cycloalkyl, C5_6 cycloalkenyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, dihydrothiazolyl, 2,3- dihydrobenzofuryl, piperidinyl, 1-methyl-oxopyridyl, tetrahydropyran-4-yl , indolinyl, imidazo [1,2- a] pyridinyl, quinolinyl, benzofuryl, benzo [1,2,5] thiadiazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, thiadiazolyl, furanyl and thienyl; wherein R8 is selected from H, fluoro, chloro and methyl; wherein R9 is selected from H, methyl and fluoro; wherein R10a is H or methoxy; and wherein R10b is selected from 4-morfolinpropoxi, 2-hydroxy-3-morpholin-4-ylpropoxy, pyrrolidin-1-yl-propoxy, 1-pyrrolidinyl-4-piperidiniloxipropoxi, (4-methylpiperazin-1-yl) propoxy 3- (4-methylpiperazin-l- yl) ropoxi, 3- (1, 2, 4-triazol-1-yl) propoxy, triazinilpropoxi, 3- (piperidin-4-yl) propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy; and pharmaceutically acceptable derivatives thereof. The invention also relates to compounds wherein R 'is selected from H, methyl, ethyl, n-butyl, isobutyl, tere-butyl, isopropyl, propyl, cyanomethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminoethyl, 2-methoxy-1-methylethyl, methoxycarbonylmethyl , methoxyethyl, methoxypropyl, methylsulfonylethyl, dimethylaminoethyl, methoxycarbonylmethyl, ethenyl, thiazol-2-yl-CH (CH3) -, phenyl- CH (CH3) -, 5-methylisoxazole-3-ylmethyl, pyrrolidin-1-ylethyl, tetrahydrofur-2 -methylmethyl, 4-methyl-2-oxo-oxazolidin-5-yl, pyrid-4-ylmethyl, pyrid-2-ylmethyl, 2-trifluoromethylpyrid-5-ylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3 ,3- trifluoropropyl, (CH3) 3CCH2-, pentafluoroethyl, CF3CH2CH2-, cyclopropylmethyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, (2-methoxyphenyl) ethyl, 1-phenylethyl, phenylethyl, cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl, 2-phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ,5-dimethyl-3-oxocyclohexenyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, 3-ethylphenyl, 2-ethylphenyl, 4- isopropylphenyl, 4-isopropyl-3-methylphenyl, 3-isopropylphenyl, 4- erc-butylphenyl, 2,3-dimethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3 , 5-difluorophenyl, 2,4,6-trifluorophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl , 2,6-dichlorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro-5-methoxyphenyl, 4-chloro-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2 -ethoxyphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-trifluoromethoxyphenyl , -trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) -phenyl, 3,5- di (trifluoromethyl) -2-methylphenyl, 4-dimethylaminophenyl, 3-dimethylaminophenyl, 3-nitrophenyl, 4- nitrophenyl, 3-cyanophenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2- methylsulfonylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4- fluorophenyl, 4- [l-isopropylpiperazinin-4-yl] phenyl, 2- [(1-methylpyrrolidin-3-yl) -N (CH 3)] - 5-trifluoromethylphenyl, 5- [1-methylpiperazin-4-ylmethyl] - 3-trifluoromethylphenyl, 5- [2-oxopyrrolidin-1-yl] -3-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-bromo-2-fluorophenyl, 2-trifluoromethoxyphenyl, 2- trifluoromethylphenyl, 4-pentafluoroethylphenyl, -fluoro-3-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2- [methylcarbonylamino] -5-trifluoromethylphenyl, 3- [1-methylpiperidin-4-yl] -5-trifluoromethylphenyl, 2- [1,1-dioxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [1-oxo-thiomorpholine- 4-yl] -5-trifluoromethylphenyl, 2- [thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [(3-dimethylaminopropyl) methylamino] -5- trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 3- (methylcarbon) ilamino) phenyl, 3- (4-methylpiperazin-1-ylmethyl) phenyl, 2- (4-methylpiperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [1- methylpiperidin 4-yloxy] -5-trifluoromethylphenyl, 2-methoxy-5-trifluoromethylphenyl, 2-methoxy-5-phenylphenyl, 2- [3,3-dimethyl-2-oxo-azetidin-1-yl] -5-trifluoromethylphenyl, 2- [morpholin-4-ylethoxy] -5-erc-butylphenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-butylphenyl, 3- [dimethylaminomethylcarbonylamino] -4-erc-butylphenyl, 2- methoxy- 5- [2-pyridylaminocarbonyl] phenyl, 2-methoxy-5- phenylaminocarbonylphenyl, 2- [methyl- (l-methylpyrrolidin-3-yl) amino] -5-trifluoromethylphenyl, 2,2-difluorobenzodioxol-4-yl, biphenyl, 2-naphthyl, 2,3-dihydro-l, 4-benzodioxin -6-yl, 7-fluoro-2,3-dihydro-l, 4-benzodioxin-6-yl, 1,3-benzodioxol-4-yl, l-isopropylpiperidin-4-yl, 2-pyrrolidinyl, l-methyl -2-pyrrolidinyl, 4-piperazinyl, 1-methylpiperidin-4-yl, 3-methyl-isothiazol-5-yl, 3-isothiazolyl, 4,5-dichloro-3-isothiazolyl, isoxazol-3-yl, 5-isoxazolyl , 4-isoxazolyl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 4,5-dimethyl-isoxazol-3-yl, 3-methyl-isoxazol-5-yl, -tert-butyl-isoxazol-3-yl, 4-bromo-5-methyl-isoxazol-3-yl, 5-oxazolyl, l-methylimidazol-5-yl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2 -methylcarbonyl-thien-3-yl, 2-methylcarbonyl-5-tert-butyl-thien-3-yl, 2-aminocarbonyl-5-tert-butyl-thien-3-yl, 4-methoxy-5-chloro-3 - thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2-thienyl , 5-chloro-2-thienyl , 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 2-furyl, 2-cyano-5-phenylfur-3 -yl, 4, 5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl-3-furyl, 3-furanyl, 1-methylpyrrol-2-yl, 2-pyrrolyl, 2-pyrazinyl, 5-methyl-2 - pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 4-methoxy-6-methylpyrimidin-2-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-pyridyl, 3-pyridyl, -pyridyl, 4- trifluoromethylpyridin-2-yl, 2-trifluoromethylpyridin-5-yl, 2-dimethylaminopyridin-5-yl, 5-chloro-2-pyridyl, 2-fluoro-3-pyridyl, 2-chloro-3-pyridyl , 2-methoxy-3-pyridyl, 2- ethoxy-3-pyridyl, 2-chloro-4-pyridyl, 2,5-dichloro-3-pyridyl, 2- (dimethylaminoethoxy) -3-pyridyl, 2-methoxy-5-pyridyl, 2-methyl-5-pyridyl, 4-chloro-2-pyridyl, 4-methoxy-5-pyridyl, 3-benzyloxypyridin-2-yl, 4-methylpyridin-2-yl, 4-ethylpyridin-2-yl, 2-chloropyridin-4-yl, 3- chloropyridin-5-yl, 3-chloropyridin-6-yl, 2-chloropyridin-5-yl, 4-chloropyridin-2-yl, l-methyl-2-oxopyrid-5-yl, tetrahydropyran-4-yl, 4, 5-dihydrothiazol-2-yl, thiazol-2-yl, 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, 4- tert-butyl-thiazol-2-yl, 5- tert-butyl-thiazol-2-yl, 5-nitrothiazol-2-yl, 5-bromothiazol-2-yl, 5- [4-chlorophenyl] -thiazol-2-yl, 4- [4-chlorophenyl] -thiazole- 2-yl, 4- [4-nitrophenyl] -thiazol-2-yl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5-dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5- tere-butyl-l, 3,4-thiadiazol-2-yl, 5-trif luoromethyl-1,3,6-thiadiazol-2-yl, 5-ethyl-l, 3,4-thiadiazol-2-yl, pyrazol-5-yl, 3-pyrazolyl, 1,3-dif-enyl-pyrazol-3-yl, 1,3-dimethyl-pyrazole-3- ilo, 5-cyano-4-tert-butyl-pyrazol-3-yl, 5-amino-3-methyl-pyrazol-1-yl, 3-methyl-1-tert-butyl-pyrazol-3-yl, 5- amino-3-tert-butyl-pyrazol-1-yl, l-ethylpyrazol-5-yl, 3-tert-butyl-pyrazol-5-yl, l-methyl-3-tert-butyl-pyrazol-5-yl, 4, 4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 7- quinolinyl, 2,3-dihydrobenzofur-7-yl, 3,3-dimethyl-l-methylcarbonylindolin-6-yl, 3, 3-dimethyl-2, 3-dihydro-indol-6-yl, 4-tert-butyl-imidazo [1,2- a] pyridin-6-yl, 3-quinolinyl, 2-benzofuryl, benzo [1.2.5] thiadiazol-4-yl, 7-methyl-benzothiazol-2-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 5,6-dimethyl-benzothiazol-2-yl, benzimidazol-2-yl, l-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzisoxazol-3-yl, 4-methoxybenzisoxazol-3-yl and 2-yl-benzothiazol-5-yl. wherein R10 is methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinyletoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy, - (4-methyl-piperazin-1-yl) propoxy, 3- (1, 2,4-triazol-1-iDpropoxy, triazinylpropoxy, 3- (piperidin-4-yl) propoxy, di-ethyloxyethoxy, dimethylaminopropoxy and methoxy. it also refers to compounds where R8 is H, and where R9 is H, methyl or fluoro The invention also relates to compounds where Ya is selected from -NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) p0-, (CH2) p-NHC (= 0) -, -NHC (= 0) NH-, -NHC (= 0) O (CH2) p-, -NHS02- and - C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3. The invention also relates to compounds where Ya is selected from -NHC (= 0) -, -NHC (= 0) (CH2) -, NHC (= 0) (CH2) 2-, - (CH2) p-NHC (= 0) -, -NHC (= 0) NH- and -NHS02- The invention also refers to compounds where? Is -NHC (= 0) - and -NHC (= 0) CH2- The invention also relates to compounds where X is O. The invention n also refers to compounds wherein R 'is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 3-isopropylphenyl, 4-er-butyl-phenyl, 2, 3-dimethylphenyl, 4- isopropyl-3-methylphenyl, 3-chloro-4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 4- trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) phenyl, 4-dimethylaminophenyl, 3- (4-methyl-piperazin-1-ylmethyl) phenyl, 2- (4-methyl-piperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [(3-dimethylaminopropyl) methylamino] -5 - trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 2- [methyl- (1-methylpyrrolidin-3-yl) amino] -5-trifluoromethylphenyl, biphenyl, 2-pyrrolidinyl, l- methyl-2-pyrrolidinyl, 4-piperazinyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 5-imidazolyl, 3-pyrazolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 2-pyridyl, 3- pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 4-chloro-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 4-methoxy-5-pyridyl, 4-pyridyl, 8- quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 4, 5 dichloro-3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 2-methyl-4- thiazolyl, 2,5-dimethyl-4-thiazolyl, 2-thiazolyl, 2-furanyl, 4,5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl-3-furyl, 3-furanyl, 3-thienyl, 4-methoxy-5-chloro-3-thienyl, 2-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2-thienyl, 3- ethoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 5-tert-butyl-isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 5- erc-butyl-pyrazole- 3-yl and 2-methylbenzothiazol-5-yl. The invention also relates to compounds of Formula III wherein Ya is selected from -NRZ (CH2) P-, NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) p0-, - (CH2) p-NHC (= 0) - , NHC (= 0) NH-, -NHC (= 0) 0 (CH2) p-, -C (= 0) 0-, -NHS02- and -C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3; wherein Z is CRX or N; wherein R 'is selected from H, C? _5 alkyl, C? _3 haloalkyl, C? _3 alkoxy C? _ jalkyl, C? -3-carbonyl-C? _3 alkyl, cyanoalkyl C? _5 / aminocarbonyl- C-5 alkyl, alkyl d-5-aminocarbonyl-C? -5 alkyl, C? _5 aminoalkyl, C? -5-amino-alkyl C? _5 alkyl, alkyl C? -5-sulfonyl-C? -5 alkyl, phenyl-C? -3 alkyl, C3-6 cycloalkyl-Cx-3 alkyl, 5-6-membered heterocyclyl-C3-alkyl, and an unsubstituted ring or substituted selected from phenyl, naphthyl, 1,3-benzodioxolyl, 2,3-dihydro-1, -benzodioxinyl, C3_6 cycloalkyl, C5-6 cycloalkenyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, dihydrothiazolyl , 2,3-dihydrobenzofuryl, piperidinyl, 1-methyl-oxopyridyl, tetrahydropyran-4-yl, indolinyl, imidazo [1,2-a] pyridinyl, quinolinyl, benzofuryl, benzo [1,2, 5] thiadiazolyl, benzothiazolyl, benzimidazolyl , benzoxazolyl, benzisoxazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, thiadiazolyl, furanyl and thienyl; wherein R8 is selected from H, fluoro, chloro and methyl; wherein R9 is selected from H, methyl and fluoro; wherein R x is selected from H, CN, NH 2, F, alkylcarbonylamino and alkylaminocarbonyl; wherein Ra is selected from H, benzyl and C? -3 alkyl; wherein R10a is H or methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinyletoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy, 3- (4-methylpiperazin-1-yl) ropoxy, 3- (1, 2, 4-triazol-1-yl) propoxy, triazinylpropoxy, 3- (piperidin-4-yl) propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy; and pharmaceutically acceptable derivatives thereof. The invention also relates to compounds wherein Z is CH; where R10a is methoxy; and wherein R 10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-β-ropoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinyl ethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy, 3- (4-methyl-piperazin-1-yl) propoxy, 3- (1,2,4-triazole-1-D-propoxy, triazinylpropoxy, 3- (piperidin-4-yl) ropoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy. it refers to compounds where R 'is selected from H, methyl, ethyl, n-butyl, isobutyl, tere-butyl, isopropyl, propyl, cyanomethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminoethyl, 2-methoxy-1-methylethyl, methoxycarbonylmethyl, methoxyethyl, methoxypropyl, methylsulfonylethyl, dimethylaminoethyl, methoxycarbonylmethyl, ethenyl, thiazol-2-yl-CH (CH3) -, phenyl- CH (CH3) -, 5-methylisoxazole-3-ylmethyl, pyrrolidin-1-ylethyl, tetrahydrofur-2-ylmethyl, 4-Methyl-2-oxo-oxazolidin-5-yl, pyrid-4-ylmethyl, pyrid-2-ylmethyl, 2-trifluoromethyl-pyrid-5-ylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- triflu oropropilo, (CH3) 3CCH2-, pentafluoroethyl, CF3CH2CH2-, cyclopropylmethyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, (2-methoxyphenyl) ethyl, 1-phenylethyl, phenylethyl, cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl, 2- phenylcyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, 5,5-dimethyl-3-oxociclohexenilo, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3, -dimetilfenilo, 3,5-dimethylphenyl, 4-ethylphenyl, 3-ethylphenyl , 2-ethylphenyl, 4-isopropylphenyl, 4-isopropyl-3-methylphenyl, 3-isopropylphenyl, 4-tert-butylphenyl, 2,3-dimethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl , 3,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,4,6-trifluorophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl , 3-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 2,6-dichlorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro-5-methoxyphenyl, -chloro-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-ethoxyphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 2 , 3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3 -trifluorometoxifenilo, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 3, 5-di (trifluoromethyl) -phenyl, 3,5- di (trifluoromethyl) -2-methylphenyl, 4-dimethylaminophenyl, 3- dimethylaminophenyl, 3-nitrophenyl , 4-nitrophenyl, 3-cyanophenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 4- [l-isopropylpiperazinin-4-yl] phenyl, 2 - [(1-methylpyrrolidin-3-yl) -N (CH 3)] -5-trifluoromethylphenyl, 5- [1- methylpiperazin-4-ylmethyl] -3-trifluoromethylphenyl, 5- [2-oxopyrrolidin-1-yl] -3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-bromo-2-fluorophenyl, 2-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 4-pentafluoroetilfenilo, -fluoro-3-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-methyl-3 -trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2- [ethylcarbonylamino] -5-trifluoromethylphenyl, 3- [1-methylpiperidin-4-yl] -5-trifluoromethylphenyl, 2- [1, 1-dioxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [1-oxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2-piperidine -l-yl-5-trifluoromethyl-phenyl, 2- [(3-dimethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 3- (meth1carbonylamino) phenyl 3- (4-methyl-piperazin-1-ylmethyl) phenyl, 2- (4-methyl-piperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [1-methyl-piperidin-4-yloxy] -5-trifluoromethyl-phenyl, 2-methoxy-5- trifluoromethylphenyl, 2-methoxy-5-phenylphenyl, 2- [3,3-dimethyl-2-oxo-azetidin-1-yl] -5-trifluoromethylphenyl, 2- [morpholin-4-ylethoxy] -5-erc-butylphenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-butylphenyl, 3- [dimethylaminomethylcarbonylamino] -4-tert-butylphenyl, 2-methoxy-5- [2-pyridylaminocarbonyl] phenyl, 2-methoxy-5-phenylaminocarbonylphenyl 2- [methyl- (l-methyl? -rolidolidin-3-yl) amino] -5-trifluoromethylphenyl, 2,2-difluorobenzodioxol-4-yl, biphenyl, 2-naphthyl, 2,3-dihydro-l, 4- benzodioxin-6-yl, 7-fluoro-2,3-dihydro-l, 4-benzodioxin-6-yl, 1,3- benzodioxol-4-yl, l-isopro-ylpiperidin-4-yl, 2-pyrrolidinyl, l-methyl-2-pyrrolidinyl, 4-piperazinyl, 1-methylpiperidin-4-yl, 3-methyl-isothiazol-5-yl, 3-isothiazolyl, 4,5-dichloro-3-isothiazolyl, isoxazol-3-yl, 5-isoxazolyl, 4-isoxazolyl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 4,5-dimethyl-isoxazol-3-yl, 3-methyl-isoxazol-5-yl, 5- erc-butyl-isoxazol-3-yl, 4-bromo-5-methyl-isoxazol-3-yl, 5- oxazolyl, l-methylimidazol-5-yl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-methylcarbonyl-thien-3-yl, 2-methylcarbonyl-5-tert-butyl-thien-3-yl, 2- aminocarbonyl-5- erc-butyl-thien-3-yl, 4-methoxy-5-chloro-3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4- methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 2-furyl, 2-cyano-5-phenyl-3-yl, 4,5-dimethyl-2-furyl, 5-methyl-2- trifluoromethyl-3-furyl, 3-furanyl, 1-methylpyrrol-2-yl, 2-pyrrolyl, 2 -pyrazinyl, 5-methyl-2-pyrazinyl, -pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 4-methoxy-6-methylpyrimidin-2-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 4-trifluoromethylpyridin-2-yl, 2-trifluoromethylpyridin-5-yl, 2-dimethylaminopyridin-5-yl, 5-chloro-2-pyridyl, 2-fluoro-3-pyridyl, 2-chloro-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 2-chloro-4-pyridyl, 2,5-dichloro-3-pyridyl, 2- (dimethylaminoethoxy) -3- pyridyl, 2-methoxy-5-pyridyl, 2-methyl-5-pyridyl, 4-chloro-2-pyridyl, 4-methoxy-5-pyridyl, 3-benzyloxypyridin-2-yl, 4-methylpyridin-2-yl, 4-Ethylpyridin-2-yl, 2-chloropyridin-4-yl, 3-chloropyridin-5-yl, 3-chloropyridin-6-yl, 2-chloropyridin-5-yl, 4-chloropyridin-2-yl, l- methyl-2-oxopyrid-5-yl, tetrahydropyran-4-yl, 4,5-dihydrothiazol-2-yl, thiazol-2-yl, 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazole- 2-yl, 4-tere-butyl-thiazol-2-yl, 5-tert-butyl-thiazol-2-yl, 5-nitrothiazol-2-yl, 5-bromothiazol-2-yl, 5- [4-chlorophenyl] ] -thiazol-2-yl, 4- [4-chlorophenyl] -thiazol-2-yl, 4- [4-nitrophenyl] -thiazol-2-yl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2, 5-dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2- ilo, 5-ethyl-l, 3, -thiadiazol-2-yl, pyrazol-5-yl, 3-pyrazolyl, 1,3-diphenyl-pyrazol-3-yl, 1,3-dimethyl-pyrazol-3-yl , 5-cyano-4- erc-butyl-pyrazol-3-yl, 5-amino-3-methyl-pyrazol-1-yl, 3-methyl-l-erc-butyl-pyrazol-3-yl, 5-amino 3-tert-butyl-pyrazol-1-yl, 1-ethylpyrazol-5-yl, 3-tert-butyl-pyrazol-5-yl, 1-methyl-3-erc-butyl-pyrazol-5-yl, 4 , 4-dimethyl-l, 2,3,4-tetrahydrate Risocynolin-7-yl, 7- quinolinyl, 2,3-dihydrobenzofur-7-yl, 3, 3-dimethyl-l-methylcarbonylindolin-6-yl, 3,3-dimethyl-2,3-dihydro-indole-6- ilo, 4-tere-butyl-imidazo [1,2-a] pyridin-6-yl, 3-quinolinyl, 2-benzofuryl, benzo [1,2,5] thiadiazol-4-yl, 7- methyl-benzothiazole-2- ilo, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 5,6-dimethyl-benzothiazol-2-yl, benzimidazol-2-yl, l-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzisoxazol-3-yl, 4-methoxybenzisoxazol-3-yl and 2-methylbenzothiazol-5-yl.

The invention also relates to compounds wherein Ya is selected from -NHC (= 0) -, -NH- and -NHC (= 0) -NH-. The invention also relates to compounds where Ya is -NHC (= 0) - or -NHC (= 0) -NH-. The invention also relates to compounds wherein R8 and R9 is H. The invention also relates to compounds wherein R is methoxy; and pharmaceutically acceptable salts thereof. The invention also relates to compounds where Ra is methyl. The invention also relates to compounds wherein Z is CH. The invention also relates to compounds selected from N- (6- ((6,7-is (methyloxy) -quinolinyl) oxy) -1-methyl-1H-indazol-3-yl) -4-chlorobenzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-liy-indazol-3-yl) -4- (trifluoromethyl) benzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1H-indazol-3-yl) -4- (methyloxy) benzamide; N- (6- ((6,7- is (methyloxy) -4-quinolinyl) oxy) -l-methyl-lH-indazol-3-yl) -3-chloro-4-fluorobenzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-li? -indazol-3-yl) -3,5-bis (trifluoromethyl) benzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1H-indazol-3-yl) -4-chloro-2-pyridinecarboxamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1H-indazol-3-yl) -3-methylbenzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1 H -indazol-3-yl) -N '- (4-methylphenyl) urea; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -N '-phenylurea; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1 H -indazol-3-yl) -3- (trifluoromethyl) benzamide; and N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1H-indazol-3-yl) -N '- (4- (methyloxy) phenyl) urea.

INDICATIONS The compounds of the present invention will be useful, but not limited, for the prevention or treatment of diseases related to angiogenesis. The compounds of the invention have kinase inhibitory activity, such as VEGFR / KDR inhibitory activity. The compounds of the invention are useful in therapy as antineoplastic agents or to minimize deleterious effects of VEGF. The compounds of the invention will be useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin (including squamous cell carcinoma); Hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma); hemopoietic tumors of the myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, eg, soft tissue and bones); tumors of the central and peripheral nervous system (including atrocytoma, neuroblastoma, glioma and schwannomas); and others tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoctantoma, follicular thyroid cancer, and Kaposi's sarcoma). Preferably, the compounds are useful for the treatment of the neoplasm selected between lung cancer, colon cancer and breast cancer. The compounds of the present invention are also useful in the treatment of cancer related indications such solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastomas, hematopoietic tumors, including leukemia and lymphoma, pleural or pericardial effusions. induced by tumor and malignant ascites. The compounds of this invention may also act as inhibitors of other protein kinases, for example, tie-2, lck, src, fgf, KDR, rum, ckit and ret, and thus may be effective in the treatment of diseases associated with other protein kinases. In addition to being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and the like. The most preferred animals include horses, dogs and cats.

As used herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

When the plural form is used for compounds, salts and the like, this also means a single compound, salt and the like. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS "Angiogenesis" is defined as any alteration of existing vascular bed or the formation of new vasculature that benefits tissue perfusion. This includes the formation of new vessels by branching endothelial cells from existing blood vessels or remodeling existing vessels to alter the size, maturity, direction, or flow properties to improve tissue blood perfusion. As used herein, "HGF" refers to the dispersion factor / hepatocyte growth factor.

This includes hepatocyte growth factor / dispersion factor, fragments of scattering factor / hepatocyte growth factor, chemical fragments synthesized from hepatocyte growth factor / dispersion factor, derivatives or mutated versions of the scattering factor / factor of hepatocytes. growth of hepatocytes, and fusion proteins comprising the dispersion factor / hepatocyte growth factor and another protein. "HGF" as used herein also includes the scattering factor / hepatocyte growth factor isolated from a species other than humans.

As used herein, "c-Met" refers to the receptor for HGF. This includes purified receptor, fragments of the receptor, chemically synthesized fragments of the receptor, derivatives or mutated versions of the receptor and fusion proteins comprising the receptor and another protein. "c-Met" as used herein also includes the HGF receptor isolated from a species other than humans. As used herein, "HGF" refers to the dispersion factor / hepatocyte growth factor.

This includes hepatocyte growth factor / dispersion factor, dispersion factor / hepatocyte growth factor fragments, chemically synthesized fragments of hepatocyte growth factor / factor, derivatives or mutated versions of the scattering factor / growth factor of hepatocytes, and fusion proteins comprising the dispersion factor / growth factor and another protein. "HGF" as used herein also includes the scattering factor / hepatocyte growth factor isolated from a species other than humans. As used herein, "c-Met" refers to the receptor for HGF. This includes purified receptor, fragments of the receptor, chemically synthesized fragments of the receptor, derivatives or mutated versions of the receptor and fusion proteins comprising the receptor and another protein. "c-Met" as used in this The document also includes the HGF receptor isolated from a species other than humans. As used herein, the terms "hepatocyte growth factor" and "HGF" refer to a growth factor that typically has a structure with six domains (finger, Kringle 1, Kringle 2, Kringle 3, Kringle 4 and serine protease domains). Fragments of HGF constitute HGF with some domains and variants of HGF that may have some of the repeated HGF domains; both are included if they still have their respective capacity to join an HGF receptor. The expressions "hepatocyte growth factor" and "HGF" include the hepatocyte growth factor of humans ("huHGF") and any non-human mammal species, and in particular rat HGF. The terms as used herein include mature forms, pre, pro-pro and pro forms, purified from a natural source, chemically synthesized or produced recombinantly. Human HGF is encoded by the cDNA sequence published by Miyazawa et al., (1989), supra, or Nakamura et al., (1989), supra. The sequences presented by Miyazawa et al. And Nakamura et al. (1989) differ by 14 amino acids. The reason for this difference is not entirely clear; polymorphism or cloning artifacts are among the possibilities. The above terms specifically cover both sequences. It will be understood that natural allelic variations exist between individuals, as demonstrated by the differences of one or more amino acids in the amino acid sequence of each individual. The terms "hepatocyte growth factor" and "HGF" specifically include the 5 huHGF delta described by Seki et al., Supra. The terms "HGF receptor" and "c-Met" when used herein refer to a cellular receptor for HGF, which typically includes an extracellular domain., a transmembrane domain and an intracellular domain, as well as variants and fragments thereof that have the ability to bind HGF. The terms "HGF receptor" and "c-Met" include the polypeptide molecule comprising the full length native amino acid sequence encoded by the gene known in various forms as pl90MET. The present definition specifically encompasses soluble forms of the HGF receptor, and the HGF receptor from natural sources, produced synthetically in vitro or obtained by genetic manipulation including recombinant DNA technology procedures. The variants or fragments of the HGF receptor or fragments preferably share at least about 65% of the sequence homology, and more preferably at least 75% of the sequence homology with any domain of the amino acid sequence of human c-Met published in Rodrigues et al., Mol. Cell. Biol., 11: 2962-2970 (1991); Park et al., Proc. Nati Acad. Sci., 84: 6379-6383 (1987); or Ponzetto et al., Oncogene, 6: 553-559 (1991).

The term "agonist" when used herein refers to or describes a molecule that can, direct or indirectly, induce, promote, or substantially improve the biological activity of HGF or the activation of the HGF receptor. The terms "cancer" and "cancerous" when used herein refer to or describe the physiological state in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to carcinoma, lymphoma, sarcoma, blastoma, and leukemia. More particular examples of cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. Although the term "cancer" as used herein is not limited to any specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers that are accompanied by high levels of HGF or c-Met expression. in the mammal. The terms "treat", "treatment" and "therapy" as used herein refer to curative therapy, prophylactic therapy and preventive therapy. The term "mammal" as used herein refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In a preferred embodiment of the invention, the mammal is a human being. Given the high levels of c-Met and HGF that are observed in hypertension, arteriesclerosis, infarction of myocardium and rheumatoid arthritis, the nucleic acid ligands will serve as useful therapeutic agents for these diseases. The term "treatment" includes therapeutic treatment as well as prophylactic treatment (to totally prevent the onset of disorders or to delay the onset of a pre-clinically evident state of disorders in individuals). A "pharmaceutically acceptable derivative" refers to any salt, ester of a compound of this invention, or any other compound which after administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis. The term "therapeutically effective" aims to qualify the amount of each agent, which will achieve the objective of improving the severity of the disorder and the frequency of incidence on the treatment of each agent by itself, while avoiding adverse side effects typically associated with therapies. alternatives. For example, effective neoplastic therapeutic agents prolong patient survival, inhibit fast proliferating cell growth associated with the neoplasm, or effect neoplasm regression.

The term "H" refers to a unit hydrogen atom. This radical can be attached, for example, to an oxygen atom to form a hydroxyl radical. When the term "alkyl" is used, only or within other terms as "haloalkyl" and "alkylamino", it includes linear or branched radicals having from one to about twelve carbon atoms. The most preferred alkyl radicals are "lower alkyl" having from one to six carbon atoms. Examples of radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, pentyl, isoamyl, hexyl, and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" includes divalent alkyl linking radicals as methylenyl and ethynyl. The term "lower alkyl substituted with R2" does not include an acetal residue. The term "alkenyl" includes straight or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. The most preferred alkenyl radicals are "lower alkenyl" radicals having from two to about six carbon atoms. The most preferred lower alkenyl radicals are radicals having from two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" include radicals that they have "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" refers to linear or branched radicals having at least one carbon-carbon triple bond and having from two to about twelve carbon atoms. The most preferred alkynyl radicals are "lower alkynyl" radicals having from two to about six carbon atoms. More lower alkynyl radicals having from two to about four carbon atoms are preferred. Examples of such radicals include propargyl, butinyl and the like.

The term "halo" means halogen atoms such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" includes radicals in which any one or more of the carbon atoms of the alkyl is substituted with halo as defined above.

Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl.

A monohaloalkyl radical, for example, may have an iodine, bromine, chlorine or fluoro atom within the radical.

The dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" includes radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloro ethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl. The term "hydroxyalkyl" includes linear or branched alkyl radicals having from one to about ten carbon atoms, either of which may be substituted with one or more hydroxyl radicals. The most preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having from one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Still more preferred are hydroxyalkyl lower radicals having from one to three carbon atoms. The term "alkoxy" includes linear or branched oxy-containing radicals and each having alkyl portions of one to about ten carbon atoms. The most preferred alkoxy radicals are "lower alkoxy" radicals having from one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Still more preferred are lower alkoxy radicals having from one to three carbon atoms. In addition, the alkoxy radicals may be substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein said rings can be joined together in a condensed manner. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. The most preferred aryl is phenyl. Said "aryl" group may have from 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, amino, alkoxy and lower alkylamino. Phenyl substituted with -0-CH2-0- forms the aryl benzodioxolyl substituent. The term "heterocyclyl" includes ring radicals containing saturated, partially saturated and unsaturated heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur and oxygen. They do not include rings that contain portions -0-0-, -O-S- or -S- S-. Said "heterocyclyl" group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino. Examples of saturated heterocyclic radicals include saturated heteromonocyclic groups of 3 to 6 members containing from 1 to 4 nitrogen atoms [for example pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; 3 to 6 membered saturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; 3 to 6 membered saturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. Examples of unsaturated heterocyclic radicals, also referred to as "heteroaryl" radicals, include 5 to 6 membered unsaturated heteromonocyclyl group containing from 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [eg, H-1, 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5 to 6 membered unsaturated heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc .; unsaturated 5 to 6 membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; 5 to 6 membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated heteromonocyclic group from 5 to 6 members containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [eg, 1,2,4-thiadiazolyl, 1,4-thiadiazolyl, 1,2,5- thiadiazolyl]. The term heterocyclyl also includes radicals in which the heterocyclic radicals are fused / fused with aryl radicals: fused and unsaturated heterocyclic group containing from 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [for example, tetrazolo [1, 5-b] pyridazinyl]; unsaturated and condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [for example benzoxazolyl, benzoxadiazolyl]; a condensed and unsaturated heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, benzothiazolyl, benzothiadiazolyl]; and unsaturated and unsaturated condensed heterocyclic group containing from 1 to 2 oxygen or sulfur atoms [for example benzofuryl, benzothienyl, 2,3-dihydro-benzo [1.4] dioxinyl and dihydrobenzofuryl]. Preferred heterocyclic radicals include fused or non-condensed radicals of five to ten. The most preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, which contains one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl. Particular examples of heterocyclyl which do not contain nitrogen include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, benzothienyl, and the like. Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydrobenzo [1.4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1, 2, 3, 4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2, 3,4,4a, 9, 9a-hexahydro-lH- 3-aza-fluorenyl, 5,6,7-trihydro-l, 2,4-triazolo [3,4-a] isoquinolyl, 3,4-dihydro-2H-benzo [1.4] oxazinyl, benzo [1.4] dioxanyl, 2, 3-dihydro -1H-l? ' -benzo [d] isothiazol-6-yl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl and the like. The term "sulfonyl", if used alone or attached to other terms such as alkylsulfonyl, refers respectively to divalent radicals -S02-. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" refer to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-S02NH2). The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" wherein the sulfamyl radicals are independently substituted with one or two alkyl radicals. The most preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having from one to six carbon atoms. Still more preferred are lower alkylaminosulfonyl radicals having from one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl and N-ethylaminosulfonyl. The terms "carboxy" or "carboxyl", if used alone or with other terms, such as "carboxyalkyl", refer to -C02H. The term "carbonyl", if used alone or with other terms, such as "aminocarbonyl", refers to - (C = 0) - The term "aminocarbonyl" refers to an amide group of formula -C (= 0)? H2 # The terms "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" refer to aminocarbonyl radicals independently substituted with one or two alkyl radicals , respectively. More "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to an aminocarbonyl radical are preferred.

The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" refer to aminocarbonyl radicals substituted, respectively, with an aryl radical, or an alkyl radical and an aryl radical. The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" include alkyl radicals substituted with heterocyclyl. The most preferred heterocyclylalkyl radicals are "5 or 6 membered heteroarylalkyl" radicals having alkyl portions of one to six carbon atoms and a 5 or 6 membered heteroaryl radical. Even more preferred are lower heteroarylalkylene radicals having alkyl portions of one to three carbon atoms. Examples include radicals such as pyridylmethyl and thienyl ethyl. The term "arylalkyl" and "aralkyl" includes alkyl radicals substituted with aryl. Preferred aralkyl radicals are "lower aralkyl" radicals having alkyl radicals attached to alkyl radicals having from one to six carbon atoms. Still more preferred are "phenylalkylenyl" attached to alkyl portions having from one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl of said aralkyl may be further substituted with halo, alkyl, alkoxy, halcoalkyl and haloalkoxy. The term "alkylthio" includes radicals containing a linear or branched alkyl radical, from one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having from one to three carbon atoms. An example of "alkylthio" is methylthio, (CH3S-). The term "haloalkylthio" includes radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of "haloalkylthio" is trifluoromethylthio. The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are independently substituted with an alkyl radical and with two alkyl radicals, respectively. The most preferred alkylamino are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Still more preferred are lower alkylamino radicals having from one to three carbon atoms. Suitable alkylamino radicals can be mono or dialkylamino such as N-methylamino, N-ethylamino, N-N-dimethylamino, N, N-diethylamino and the like. The term "arylamino" refers to amino groups that have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino may radicals can be further substituted in the aryl ring portion of the radical. The term "heteroarylamino" refers to amino groups that have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals can be further substituted on the heteroaryl ring portion of the radical. The term "aralkylamino" refers to amino groups that have been substituted with one or two aralkyl radicals. More phenyl-C 1 -C 3 -alkyl radicals, such as N-benzylamino, are preferred. The aralkylamino radicals may be further substituted in the aryl ring portion. The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" refer to amino groups that have been independently substituted with an aralkyl radical and an alkyl radical, or an aryl radical and an alkyl radical, respectively , in an amino group. The term "aminoalkyl" includes linear or branched alkyl radicals having from one to about ten carbon atoms, any of which may be substituted with one or more amino radicals. The most preferred aminoalkyl radicals are "lower aminoalkyl" radicals having from one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms. The term "alkylaminoalkyl" includes alkyl radicals substituted with alkylamino radicals. The most preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals from one to six carbon atoms. Still more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals can be mono- or dialkyl-substituted, such as N-methylaminomethyl, N, N-dimethylaminoethyl, N, N-diethylaminomethyl and the like. The term "alkylaminoalkoxy" includes alkoxy radicals substituted with alkylamino radicals. The most preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Still more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals can be mono- or dialkyl-substituted, such as N-methylaminoethoxy, N, N-dimethylaminoethoxy, N, N-diethylaminoethoxy and the like. The term "alkylaminoalkoxyalkoxy" includes alkoxy radicals substituted with alkylaminoalkoxy radicals. The most preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Still more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals can be mono- or dialkyl-substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N, N-dimethylaminoethoxyethoxy, N, N-diethylaminomethoxymethoxy and the like.

The term "carboxyalkyl" includes linear or branched alkyl radicals having from one to about ten carbon atoms, either of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having from one to six carbon atoms and a carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH2 groups. The term "halosulfonyl" includes sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl. The term "arylthio" includes aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of "arylthio" is phenylthio. The term "aralkylthio" includes aralkyl radicals as described above, attached to a divalent sulfur atom. More phenyl-C3-3-thio alkyl radicals are preferred. An example of "aralkylthio" is benzylthio. The term "aryloxy" includes optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The term "aralkoxy" includes aralkyl radicals containing oxy linked through an oxygen atom to other radicals. The most preferred aralkoxy radicals are "lower aralkoxy" radicals having optionally substituted phenyl radicals attached to the lower alkoxy radical as described above. The term "heteroaryloxy" includes optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom. The term "heteroarylalkoxy" includes oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. The most preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals attached to the lower alkoxy radical as described above. The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include cyclopentyl, cyclopropyl and cyclohexyl. The term "cycloalkylalkyl" includes alkyl radicals substituted with cycloalkyl. Preferred cycloalkylalkyl radicals are "cycloalkylalkyl lower" radicals having cycloalkyl radicals attached to alkyl radicals having from one to six carbon atoms. Even more preferred are "5-6 membered cycloalkylalkyl" attached to alkyl portions having from one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl of said radicals may be further substituted with halo, alkyl, alkoxy and hydroxy.

The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds including "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl. The term "comprising" is intended to have a broad sense, including the indicated component but without excluding other elements. The term "Formulas I-III" includes any sub-formula. The compounds of the invention have kinase inhibitory activity, such as c-Met inhibitory activity. The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, the manufacture of a medicament for the intense or chronic treatment of a disease state mediated by angiogenesis, including those previously described. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament for attenuating or preventing disorders through the inhibition of c-Met. The present invention comprises a pharmaceutical composition comprising an amount therapeutically effective of a compound of Formulas I-III together with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The present invention also comprises a method for treating disorders related to angiogenesis in a subject having or is prone to such a disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula I-III. COMBINATIONS Although the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated in the form of separate compositions that are administered at the same time or sequentially in different periods of time, or the therapeutic agents can be administered in the form of a single composition. The phrase "co-therapy" (or "combination therapy"), in the limited use of a compound of the present invention and another pharmaceutical agent, is intended to encompass the administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and also intended to encompass the co-administration of those agents in a substantially simultaneous manner, such as a single capsule that has a fixed ratio of these active agents or in multiple capsules, separated for each person. Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as radiation therapy or with cytostatic or cytotoxic agents. If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. The compounds of Formula I can also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; The compounds of the invention can be administered before, simultaneously with or after administration of the known anticancer or cytotoxic agent. Currently, conventional treatment of primary tumors consists of surgical excision followed by radiation or chemotherapy administered by IV. The typical chemotherapy regimen consists of DNA alkylating agents, DNA intercalating agents, CDK inhibitors or microtubule poisons. The doses of chemotherapy used are just below the maximum tolerated dose and therefore, dose limiting toxicities typically include nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are a large number of antineoplastic agents available for commercial use, in clinical evaluation and in pre-clinical development, which will be selected for the treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several main categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents, and a category of various agents. A first family of antineoplastic agents that can be used in combination with compounds of the present invention consists of thymidylate synthase inhibitor / antimetabolite type antineoplastic agents. Suitable antimetabolite antineoplastic agents can be selected, but without limitation, from the group consisting of 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, conjugates of cytarabine, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshito i DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyáku F0-152, isopropyl pyrrolizine, Lilly LI-188011, Lilly LY-264618, Methobenzaprim, methotrexate, Wellcome MZPES, ñorespermidine,? CI? SC-127716,? CI? SC-264880,? CI? SC-39661,? CI? SC- 612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, thiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricitin. A second family of antineoplastic agents that can be used in combination with compounds of the present invention consists of alkylating agent antineoplastic agents. Suitable alkylating agent-type antineoplastic agents may be selected, but not limited to, from the group consisting of Shionogi 254-S, analogs of aldo-phosphamide, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitan, Wakunaga CA-102, carboplatin. , carmustine, Chinoin-139, Chinoin-153, chlora bucylo, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CI-233, ciplatate, Degussa D-19-384, Sumimoto DACP ( 2, diphenylspiromustine, cytostatic diplatin, Distabamycin derivatives Erba, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine sodium phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide , mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmitKline SK & amp;; F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. A third family of antineoplastic agents that can be used in combination with compounds of the present invention consists of antineoplastic agents of antibiotic type. Suitable antibiotic-type antineoplastic agents may be selected, but not limited, from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, derivative of aeroplisinin, Ajinomoto AN-201-II, Ajinomoto AN- 3, anisomycins Nippon Soda, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMI-25067, Bristol-Myers BMI-25551, Bristol-Myers BMI-26605, Bristol-Myers BMI-27557 , Bristol-Myers BMI-28438, bleomycin sulfate, briostatin-1, Taiho C-1027, calichemycin, chromoximicin, dactinomycin, daunorrubic, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89 -A1, Kyowa Hakko DC92-B, ditrisarrubicin B, Shionogi D0B-41, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-Al, esperamycin-Alb, Erbamont FCE-21954, Fujisawa FK-973 , fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grinacamycin, herbimi cina, idarubicin, illudins, kazusamycin, kesaridodyns, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303 , menogaril, mitomycin, mitoxantrone, SmithKlinae M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI Inaternational NSC-357704, oxalisin, oxaunomycin, peplomycin, pilatin, pirarubicin, porotramycin, pirindanicin A, Tobishi RA- I, rapamycin, rhizoxin, rodrububicin, sibanomicin, siwenmicin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS -9816B, estefimicina B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, trazina, tricrozarina A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi 1-25024 and zorrubicin. A fourth family of antineoplastic agents that can be used in combination with compounds of the present invention consists of a varied family of antineoplastic agents, including agents that interact with tubulin, topoisomerase II inhibitors, topoisomerase I inhibitors, and hormonal agents, selected, but without limitation, between the group consisting of a-carotene, α-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonin, amonafide, amphetamine, amsacrine, Angiostat, anquinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3 , antineoplaston A5, antineoplaston AS2-1, Henkel APD, affinicolin glycinate, asparaginase, Avarol, bacarin, batracillin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMI-40481, boro-10 Vestar, bromofosfamide , Wellcome BW-502, Wellcome BW-773, caracemide, carmetizole hydrochloride, Ajinomoto CDAF, clorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921 , Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Clanfenur, Claviridenone, Compound ICN 1259, compound ICN 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, dateliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinalin, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel eliprabine, eliptinium acetate, Tsumura EPMTC, epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadafnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross H0-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K -76C00Na, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LI-186641, NCI (US) MAP, maricine, Merrel Dow MDL-27048 , Medco MEDR-340, merbarone, merocyanine derivatives, Methylanilinoacridine, Molecular Genetics MGI-136, Minactivine, Mitonafide, Mitochidone, Mitochondrine, Motretinide, Zenyaku Kogyo MST-16 Acids, N- (Retinoyl) Amino Acids,? isshin Flour Milling? -021, N-Actylated-Dehydroalanins, Nafazatrom, Taisho? CU-190, derived from nocodazole,? Ormosang,? CI? SC-145813,? CI? SC-361456,? CI? SC-604782,? CI? SC-95580, ocreotide, Ono O? O-112, oquizanocin, Akzo Org-10172, paclitaxel, pancratistatin, paceliptina, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, peptide ICRT D, piroxantrone, polyhaematoporphyrin, polyprotein, porphyrin Efamol, probimano, procarbazine, proglumide, protease nexin I from Invitron, Tobishi RA-700, razoxane, Sapporo Breweries RBS, P-restrictin, reteliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmitKline SK &F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, Spray, Spirocyclopropane derivatives, Spirogermanium, Unimed, SS Pharmaceutical SS-554, Strypoldinone, Stipoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukraine, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, witanolides and Yamanouchi YM-534. Alternatively, the present compounds can also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolvulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN , arsenic trioxide, BAM 002 (Novels), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleuquine, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileukine diftitox, deslorelin, dexrazoxane, dilazep, docetaxel , docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac HIT, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, combination of gimeracil / oteracil / tegafur, glycopina, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alfa, natural, interferon beta, interferon beta-la, interferon beta-Ib, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Ya kult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte interferon alpha, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, decoupled double-stranded RNA, itoguazone, mitolactol, mitoxantrone, olgra ostim, nafahrelin, naloxone + pentazocine, nartograstim, nedaplatin, niluta ida, noscapine, new erythropoiesis-stimulating protein, octreotide NSC 631570, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan sodium polysulfate, pentostatin, picibanil, pirarubicin, polyclonal rabbit antitimocito antibody, polyethylene glycol interferon-2a, sodium porphyric, raloxifene, raltitrexed, rasburicase, rhenium etidronate Re 186, retinamide RII, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofirán, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, ti alfasin, thyrotropin alfa, topotecan , tore ifeno, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoldronic acid; abarelix; AE 941 (Aeterna), both ustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexa inoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, gene therapy with HLA-B7 (Vical), granulocyte and macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetán, ilomastat, IM 862 (Cytran) , interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, MAb CA 125 (Bio ira), cancer MAb (Japan Pharmaceutical Development), MAb HER-2 and Fe (Medarex), idiotypic MAb 105AD7 (CRC Technology), idiopathic CEA MAb (Trilex), MAb LYM-1-iodine 131 (Techniclone), mucin-yttrium epithelial polymorphic 90 (Antisoma), marimastat, menogaril, mitumomab, motexafina gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P 30, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfósico acid, SRL 172 ( SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathomolybdate, taliblastine, thrombopoietin, tin ethyl etiopurpurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncosylate vaccine (New York Medical College), vaccine against viral melanoma cell lysates (Royal Newcastle Hospital), or valspodar. Alternatively, the present compounds can also be used in co-therapies with other antineoplastic agents, such as other kinase inhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors, matrix metalloprotease inhibitors.

(MMP), COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, AIDS, SOD mimetics or? Vß3 inhibitors. The present invention comprises processes for the preparation of a compound of Formula I-III. Also included in the family of compounds of Formula I-III are pharmaceutically acceptable salts of the same. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula I-III can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from the classes of organic acids aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulphonic, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic acid, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulphanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2- phenylpropionic, picric, pivalic, propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, beta-hydroxybutyric, salicylic, galactolic and galacturonic. The pharmaceutically acceptable base addition salts of compounds of Formula I-III include metal salts, such as salts prepared from aluminum, calcium, lithium, magnesium, potassium and zinc, or salts prepared from organic bases including primary amines, secondary and tertiary, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All these salts can be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I-III. When a basic group and an acid group are present in the same molecule, a compound of Formula I-III can also form internal salts. GENERAL SYNTHETIC PROCEDURES The compounds of the invention can be synthesized according to the following procedures of the Schemes 1-13, wherein the substituents are as defined for Formulas I-III, above, except where indicated. The following abbreviations are used throughout the specification: AcOH acetic acid BINAP 2,2 '-bis (diphenylphosphino) -1,1'-binaphthyl BBr3 boron tribromide BH3-THF borane-tetrahydrofuran complex BOC t-butoxycarbonyl BSA bovine serum albumin n-BuLi n-butyllithium CO monoxide carbon C202C12 or (COCÍ) 2 oxalyl chloride Cs C03 cesium carbonate CHCI3 chloroform Et20 diethyl ether DCM, CH2C12 methylene chloride DIBAL diisobutylaluminum hydride DIEA, DIPEA, Hunig's base diisopropylethylamine DMF dimethylformamide dppa diphenylphosphoryl azide DPPP 1,3-diphenylphosphino propane DMAP 4-dimethylaminopyridine EtOAc, EA ethyl acetate EtOH ethanol Et20 diethyl ether EDC, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EtNH2 ethylamine FBS fetal bovine serum g gram h hour HCl hydrochloric acid HOAt 1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole hydrate H2 hydrogen H20 water H202 hydrogen peroxide HATU O- (7-azabenzotriazol-1-yl-) N, N, N ', hexafluorophosphate N '- tetramethyluronium KOH potassium hydroxide K2C03 potassium carbonate K3P04 potassium phosphate KMn04 potassium permanganate LAH lithium aluminum hydride LiHMDS lithium bis (trimethylsilyl) -amide LiOH lithium hydroxide MgSO4 magnesium sulphate MCPBA meta-chloroperbenzoic acid MeOH, CH3OH methanol MeNH2 methylamine NH4C1 ammonium chloride NH4OH ammonium hydroxide NMP N-methylpyrrolidinone NaHC03 sodium bicarbonate NaN3 sodium azide Na2SO sulfate sodium NaOH sodium hydroxide NaH sodium hydride Na2S04 sodium sulfate NaOt-Bu tere-butoxide sodium NaHB (OAc) 3 triacetoxyborohydride sodium N2 nitrogen O / N overnight P0C13 phosphorus oxychloride Pd / C palladium carbon Pd2 (dba) 3 bis (dibenzylideneacetone) palladium Pd ( OAC) 2 palladium (II) acetate P (t-bu) 3 tri (tert-butyl) phosphine PBS phosphate buffered saline PyBop benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate TA ambient temperature S0C12 thionyl chloride TBTU 0-benzotriazol-l-il-N, N, N ',?' - tetramethyluronium tetrafluoroborate TBAI tetrabutylammonium iodide TFA trifluoroacetic acid THF tetrahydrofuran TEA, Et3N triethylamine Scheme 1 Substituted bicyclic compounds can be prepared [wherein Ya are substituted amine amines] by the procedure set forth in Scheme 1. Amine 2 [where X is O] is coupled with a quinoline derivative 1 [where LG is halo and the like] such as in the presence of KOH and Cu , in a solvent such as dry CH2C12 at a temperature above the TA, preferably above about 70 ° C, more preferably at a temperature of about 100 ° C, forming the bound compound 3. Such heating is preferably carried out with a microwave . The amine 3 can be subjected to reductive amination with aldehydes, such as in the presence of NaBH (OAc) 3, in a solvent such as dry CH2C12 to a about the temperature, forming the amides 4 of the present invention. Alternatively, amine 3 can be coupled with compounds having an acyl moiety, such as acid chlorides and carboxylic acids, such as in the presence of PyBOP and a base such as K2C03, forming the amides 4 of the present invention. Scheme 2 Alternatively, the amines 3 can be prepared by amination of a bromine derivative 5 for example a halo derivative, more preferably a bromine derivative such as in the presence of Pd and a strong base, for example LiHMDS. Preferably, Pd2 (dba) 3 is used in the presence of P (t-Bu) 3. Preferably, the reaction is maintained at approximately RT. Scheme 3 Alternatively, compounds in which Y is -C02-6 can be prepared as described in Scheme 3. A The substituted carboxylic acid ester 6 is treated with a strong base, such as NaH, preferably in a solvent such as DMF, forming the anion. Preferably the reaction temperature is about the TA. The substituted heteroaryl compounds containing nitrogen 1, such as quinazolines or substituted quinolines, are coupled with the anion, forming the compounds of the present invention 7. The reaction temperature is above the TA, preferably above about 50 ° C , more preferably at about 60 ° C.

Scheme 4 Alternatively, compounds in which Y is -C (= 0) NH-10 can be prepared as described in Scheme 4. A substituted carboxylic acid 8 can be coupled with an amine in conventional coupling chemistry, such as with EDC in the presence of a solvent such as DMF, forming the amides 9. The reaction temperature is preferably maintained at about TA. The coupling of amides 9 with nitrogen-containing heterocyclic compounds, such as quinolines and quinazolines 1, by the process described above in Scheme 1 provides compounds of the present invention [wherein Y is -C (=?) NH-].

Scheme 5 Alternatively, compounds in which Y is -C (= 0) NH-10 can be prepared as described in Scheme 5. A substituted amine 11 can be coupled with an active carbonyl compound (Y "-R) as described in Scheme 1, forming the amides 12. The coupling of the amides 12 with nitrogen-containing heterocyclic compounds, such as quinolines and quinazolines 1 by the process described in Scheme 4, provides compounds of the present invention 10 [where Y is - NHC (= 0) -].

Scheme 6 Bromonaphthyl intermediates 14 can be provided by the process described in Scheme 6. A mixture of the substituted quinoline 1 [where LG is chloro], the compound 6-bromine 13 and DMAP, in a solvent such as toluene, at a temperature above of the TA, preferably above about 100 ° C, more preferably at a temperature of about 180 ° C, forms the intermediates 14. Scheme 7 R ** tt * TH + H-Y -'- R R ^ A ^ R 15 16 17 Substituted bicyclic compounds can be prepared by the procedure indicated in Scheme 7. The coupling of the bicyclic compounds (where R is not H) 16 with intermediates 15 (where Y 'is a portion of Y, such as NH, C (= 0), etc.) provides compounds 17. Scheme 8 The ureas of the present invention 18 are prepared by the process indicated in Scheme 8. Amines 11 are treated with isocyanates, preferably an excess of isocyanate, in the presence of a base, preferably an excess of base, in a solvent such as DMF. , forming the ureas 18. Preferably, the reaction temperature is maintained at about RT. Scheme 9 Coupling, n A-COH Br-A-CH (OH) R from Grignard 21 19 dehydroxylation -Apr 24 Substituted bicyclic compounds 24 [where Y is an amide] can be prepared by the procedure set forth in Scheme 9. 6-Bromo-2-hydroxymethyl compounds 21 are prepared such as by coupling of 6- carbaldehydes 20 and activated compounds containing R 1 , such as phenylsulfinyl-substituted compounds. Preferably, the coupling is carried out in the presence of a Grignard reagent, such as phenylmagnesium bromide, in an appropriate protic solvent such as .THF. The temperature is preferably maintained at about RT. Preferably, the Grignard reagent is first added to the compound containing R1 19 prior to the addition of the carbaldehyde 20. The resulting hydroxymethyl compound 21 is dehydroxylated, such as in the presence of Zn and formic acid. The dehydroxylation is preferably carried out at a temperature above the TA, more preferably above about 50 ° C, and still preferably at approximately the reflux temperature. The resulting 6-bro-naphthyl compound 22 is aminated in a manner similar to that described in Scheme 2, forming the naphthylamine 23 and subsequently the amides 24 are formed in a manner similar to that described in Scheme 1. Scheme 10 Activated compounds containing R1 19 can be prepared as per the procedure identified in Scheme 10. The halo-substituted compounds are dehydrogenated, such as with an aqueous base, for example KOH, and then treated with a thiol compound., such as thiophenol, at a temperature above the TA, preferably above 75 ° C, more preferably at about 100 ° C. The thio compound 26 is oxidized, such as with mCPBA, at a temperature below the TA, preferably below -23 ° C, more preferably at about -78 ° C, forming the sulfinyl compounds 19. Scheme 11 reagent from einreb Br-A-CO, H »- Br-A-C0N (CH,) 0CH," Br-A-COH DIBAL 20 21 28 6-Bromonaphthyl-2-carbaldehydes 20 are prepared from carboxylic acid 27 by reducing the intermediate amide 28. The amide 28 is formed by peptide-type coupling, such as in the presence of EDC, HOBt and base, of a substituted hydroxylamine, at a temperature preferably at approximately TA. The reduction of amide 28, such as with DIBAL, in a solvent such as THF, at a temperature between -78 ° C and RT, preferably at about RT, yields the desired 6-bromonaphthalene-2-carbaldehyde 20.

Other benzothiazoles and benzoxazoles can be prepared by methods described in the literature (eg, J. Heterocycl Chem., 17 (4): 817 (1980); Tetrahedron, 42 (20): 5739 (1986); and Chem. Pharm. Bull., 43 (10): 1614 (1995)). Scheme 12 Alternatively, the compounds (wherein A are indazoles) can be prepared as described in Scheme 12. A solution of 6-fluoro-4-hydroxybenzonitrile is reacted with a hydrazine, such as methyl hydrazine a a temperature above the TA, preferably above about 50 ° C and more preferably at about 80 ° C, providing the 1H-indazol-6-ol 30. The alcohol 30 is coupled with the appropriately substituted quinolines or quinazolines (where LG is halo and the like) in the presence of a base such as cesium carbonate, forming the ethers 31. The reaction temperature is above the TA, preferably above about 50 ° C, more preferably at about 100 ° C. Other compounds of the invention can be prepared by substituting the amine 31 using chemistry such as reductive amination of aldehydes such as using NaBH (OAc) 3 at a temperature of about TA. Alternatively, a solution / suspension of Pddba3, 2- (dicyclohexylphosphino) -2'4'-6'-tri-i-propyl-1,1'-biphenyl, a base such as sodium tere-butoxide, the 1H-indazol-3-amine 31 and a halo compound, such as an aryl halide, in a solvent such as toluene to form the substituted amines 32. The reaction temperature is above the TA, preferably above about 50. ° C, more preferably at about 100 ° C. As an alternative, a solution of 1H-indazol-3-amine In a solvent such as pyridine, it is treated with a substituted acid chloride such as p-anisoyl chloride, forming the substituted amides 32. The reaction is preferably maintained at a temperature of about RT.

Alternatively, a solution of 1H-indazol-3-amine in a solvent such as benzene is treated with a substituted isocyanate, forming the substituted ureas 32.

The reaction is preferably maintained at a temperature of about RT. Scheme 13 33 34 NaOMe, The dimethoxy-quinolines can be prepared from the corresponding nitro compounds 33 by the process described in Scheme 13. The reduction of the nitro compound 33 in the amine 34, such as with H2 in the presence of a catalyst, such as Pd, by Example Pd / C, followed by treatment with a base and dimethyl ether, provides the desired quinolines 35. Various substituted quinolines and quinazolines can be prepared by the procedures described in 98/13350.

The starting compounds defined in Schemes 1-13 may also be present with functional groups in protected form if necessary and / or in the form of salts, with the proviso that a salt-forming group is present and the reaction in the form of salt is possible. If desired, a compound of Formula I can be converted to another compound of Formula I, for example an N-oxide thereof; a compound of Formula I can be converted into a salt; a salt of a compound of Formula I can be converted to the free compound or to another salt; and / or a mixture of isomeric compounds of Formula I can be separated into the individual isomers. The N-oxides can be obtained in a known manner by reacting a compound of Formula I with H202, oxone, or a peracid, for example mCPBA, in an inert solvent, for example CH2C12, or a mixture of water and an alcohol such as MeOH or EtOH, at a temperature between about -10-35 ° C, such as about 0 ° C -TA. If one or more different functional groups, for example carboxy, hydroxy, amino or mercapto, are protected or necessary to be protected in a compound of Formula I or in the preparation of compounds of Formula I, they should not take part in the reaction, are the groups that are normally used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid and sugar derivatives.

The protecting groups may be present in precursors and should protect the functional groups involved against undesired side reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis and similar reactions. It is characteristic of the protective groups that it makes them easy, ie without undesired side reactions, to be removed, typically by solvolysis, reduction, photolysis or also by enzymatic activity, for example under conditions analogous to physiological conditions, and that are not present in the final products. The specialist knows, or can easily establish, which protective groups are suitable with the reactions mentioned above and below in this document. The protection of said functional groups by such protecting groups, the protecting groups themselves and their withdrawal reactions are described for example in conventional reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry ", Plenum Press, London and New York (1973), in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York (1981), in "The Peptides", Volume 3, E.

Gross and J. Meienhofer editors, Academic Press, London and New York (1981), in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weilo, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart (1974), in H.- D. Jakubke and H. Jescheit, "Aminosáuren, Peptide, Proteine" (Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Leh ann, "Chemie der Kohlenhydrato: Monosaccharide und Derívate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart (1974). In the additional process steps, carried out as desired, the functional groups of the starting compounds that should not take part in the reaction can be present in unprotected form or can be protected for example with one or more of the protective groups mentioned above as "protective groups". Then, the protecting groups are completely or partially removed according to one of the procedures described herein. The salts of a compound of Formula I with a salt-forming group can be prepared in a manner known per se. The acid addition salts of the compounds of Formula I can be obtained in this manner by treatment with an acid or a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalide of a compound of Formula I) can also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this can be done by heating to a molten material, or for example by heating in the form of a solid at high vacuum and at elevated temperature, for example 130 to 170 ° C, one molecule of the acid being expelled for each molecule of a compound of Formula I .

Normally, the salts can be converted to free compounds, for example by treatment with suitable basic agents, for example with alkali metal carbonates, alkali metal acid carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide. All the process steps described herein can be carried out under known reaction conditions, preferably those specifically mentioned above, in the absence of or usually in the presence of solvents or diluents, preferably such as those which are inert to the reagents used and capable of dissolving them, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the form of H +, depending on the type of reaction and / or the reactants at reduced, normal temperature or elevated, for example in the range from about -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example from about -80 to about 60 ° C, at RT, about -20 to about 40 ° C or at the boiling point of the solvent used, at atmospheric pressure or in a closed container, as appropriate under pressure, and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

The salts may be present in all starting and intermediate compounds, if they contain salt-forming groups. The salts may also be present during the reaction of said compounds, provided that it is not impaired thereby. In certain cases, typically in hydrogenation processes, it is possible to achieve stereoselective reactions, allowing for example a simpler recovery of individual isomers. Solvents that can be selected as suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, for example, EtOAc, ethers, typically aliphatic ethers, eg, Et0, or cyclic ethers, eg, THF , liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH or 1-propanol, IPOH, nitriles, typically CH3CN, halogenated hydrocarbons, typically CH2C12, acid amides, typically DMF, bases, typically heterocyclic nitrogen bases, for example pyridine, carboxylic acids, typically lower alkanecarboxylic acids, eg, AcOH , carboxylic acid anhydrides, typically lower alkane anhydrides, eg, acetic anhydride, cyclic, linear or branched hydrocarbons, typically cyclohexane, hexane or isopentane, or mixtures of these solvents, eg, aqueous solutions, unless otherwise indicated another thing in the description of the procedure. Such mixtures of Solvents can also be used in the process, for example in chromatography. The invention also relates to those forms of the processes in which starting from a compound obtainable at any stage in the form of an intermediate and carrying out the missing steps, or breaking the process at any stage, or forming a material starting at the reaction conditions, or using said starting material in the form of a reactive derivative or salt, or producing a compound obtainable by the process according to the invention and processing said compound in situ. In the preferred embodiment, starting materials are those that lead to the compounds that have been described above as preferred. The compounds of Formula I, including their salts, may also be obtained in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present in the form of solvates). The new starting materials and / or intermediates, as well as the processes for the preparation thereof, are also the object of this invention. In the preferred embodiment, said starting materials are used and the reaction conditions are chosen so that the preferred compounds can be obtained. The starting materials of the invention are known, commercially available, or can be synthesized by analogy with or according to procedures that are known in the art. In the preparation of starting materials, existing functional groups that are not going to participate in the reaction should be protected, if necessary. The preferred protecting groups, their introduction and their removal have been described above or in the examples. All the remaining starting materials are known, can be prepared according to known procedures or can be obtained in the market; in particular, they can be prepared using methods that are described in the examples. The compounds of the present invention may possess, in general, one or more asymmetric carbon atoms and thus may exist in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of racemic mixtures according to conventional procedures, for example, by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the diastereomeric mixture by crystallization followed by release of the optically active bases of these salts. A different process for the separation of optical isomers involves the use of a selected chiral chromatography column optimally to maximize the separation of the enantiomers. Another available method involves the synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to release the enantiomerically pure compound. The optically active compounds of the invention can be obtained in the same way using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. The compounds of this invention may contain one or more asymmetric centers and thus may take the form of racemates and racemic mixtures, scalar mixtures, enantiomers. units, individual diastereomers and diastereomeric mixtures. All of these isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention can also be represented in multiple tautomeric forms, for example, as illustrated below: The invention expressly includes all tautomeric forms of the compounds described herein.

The compounds may also exist in isomeric forms of cis- or trans- or E- or Z- double bond. All of these isomeric forms of said compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention. Substituents on ring moieties (eg, phenyl, thienyl, etc.) can bind to specific atoms, by which they intend to bind to the atom, or they can be represented not attached to a specific atom, by which they intend to bind to any available atom that is not substituted with an atom other than H (hydrogen). The compounds of this invention may contain heterocyclic ring systems linked to another ring system. Such heterocyclic ring systems can be linked through a carbon atom or a ring system heteroatom. Alternatively, a compound of any of the formulas represented herein may be synthesized according to any of the procedures indicated herein. In the procedures indicated in this document, the steps may be performed in alternate order and may be preceded, or followed, by additional protection / deprotection steps as necessary.

The processes may further comprise the use of appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K2C03 and the like), catalysts and salt forms of the foregoing. The intermediates can be isolated or performed in situ, with or without purification. Purification procedures are known in the art and include, for example, crystallization, chromatography (liquid or gas phase and the like), extraction, distillation, trituration, reverse phase HPLC and the like. Reaction conditions such as temperature, duration, pressure and atmosphere (inert gas, environment) are known in the art and can be adjusted as appropriate for the reaction. As can be appreciated by those skilled in the art, the above synthetic schemes are not intended to comprise an extensive list of all the means by which the described and claimed compounds of this specification can be synthesized. Other procedures will be apparent to those skilled in the art. In addition, the various synthetic steps described above can be performed in an alternate sequence or order to give the desired compounds. Synthetic chemical transformations and protective group methodologies (protection and deprotection) useful for synthesizing the inhibitor compounds described herein are known in the art and include, for example, those described in R. Larock, "Comprehensive Organic Transformations ", VCH Publishers (1989), TW Greene and PGM Wuts," Protective Groups in Organic Synthesis ", 3rd edition, John Wiley and Sons (1999), L. Fieser and M. Fieser," Fieser and Fieser 's Reagents for Organic Synthesis ", John Wiley and Sons (1994), A. Katritzky and A. Pozharski," Handbook of Heterociclic Chemistry ", 2nd edition (2001), M. Bodanszky, A. Bodanszky," The Practice of Peptide Synthesis ", Springer-Verlag, Berlin Heidelberg (1984), J. Seyden-Penne, "Reductions by the Alumino- and Borohydrides in Organic Synthesis", 2nd edition, Wiley-VCH, (1997), and L. Paquette, editor, "Encyclopedia of Reagents for Organic Synthesis ", John Wiley and Sons (1995) The compounds of this invention can be modified by adding appropriate functionalities to enhance the selective biological properties Such modifications are known in the art and include those that increase the biological penetration in a biological compartment dice (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter the rate of excretion.

These detailed descriptions are within the scope, and serve as exemplification, of the General Synthetic Procedures described above which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention.

Unless otherwise indicated, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as DMF, THF, CH2C12 and toluene were obtained from the Aldrich Chemical Company.

Example (2-Chlorobenzyl) - [6- 1 (6,7-dimethoxy-quinolin-4-yloxy) benzothiazole-2-yl- ina (a) 6- (6,7-Dimethoxy-quinolin-4-yloxy) -benzothiazol-2-ylamine. To a microwave vial were added 4-chloro-6,7-dimethoxy-quinoline prepared by the procedure of Miwa, et al., (WO 03/33472) (0.300 g, 1.3 mmol), 2-amino -benzothiazole-6-ol (0.334 g, 2.0 mmol) and KOH granules (0.140 g, 2.6 mmol), followed by 4% by weight of Cu powder in 3 ml of dry CH2C12. The sealed vial was microwaved for 10 min at 100 ° C and 60 W. (Powermax, CEM). The mixture was diluted with CH2C12 and transferred to a separatory funnel. NaOH (40 ml) was added and the organic phase was extracted with 3 x extracted with 3 x CH2C12. The organic extracts were combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude compound was purified by crystallization from 10% CH2C12 / Hexanes to give the title compound as a light purple powder. EM (IEN of ion pos.) m / z: 354 (M + H). Exact mass Cale, for C18H15N303S: 353.08. (b) (2-Chloro-benzyl) - [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl-amine. To a mixture of 6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-ylamine (0.100 g, 0.28 mmol, Step a) in dry CH2C12 was added 2-chloro-benzaldehyde (1 , 5 mL, 0.4 mmol). The mixture was stirred for 10 min. NaBH (OAc) 3 (0.200 g, 0.8 mmol) was added and the mixture was stirred overnight at RT under an inert atmosphere. The mixture was quenched with water, diluted with CH2C12 and poured into a separatory funnel. The organic extracts were collected, dried over Na 2 SO 4 / filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH / CH2Cl2), giving the product as a light yellow solid. MS (ESI pos. Ion) m / z: 479 (M + H). Exact Mass Cale, for C25H20ClN3O3S: 477.09. - 4-methoxy-thiophene-3-carboxylic acid benzothiazol-2-yl] -amide To a mixture of 6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-ylamine (0.100 g, 0.28 mmol (Example 1, Step a) in dry CH2C12 was added 4-methoxy acid. -thiophene-3-carboxylic acid (0.063 g, 0.3 mmol), PyBOP (0.437 g, 1.2 mmol) and K2C03 (0, 116 g, 1.2 mmol). The mixture was stirred at RT overnight under an inert atmosphere. The mixture was quenched with water, diluted with CH2C12 and transferred to a separatory funnel. The organic extracts were collected, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH / CH2Cl2), giving the product as a rust-colored solid. MS (ESI pos. Ion) m / z: 494 (M + H). Exact Mass Cale, for C24H? 9N305S2: 493.08. 2-Methoxy-N- [6- (6-methoxy-quinolin-4-) iloxy) - benzothiazol-2-yl] -benzamide (a) Preparation of 6- (6-Methoxy-quinolin-4-yloxy) -benzothiazol-2-ylamine. The title compound was prepared according to Example 1, Step a, with 4-chloro-6-methoxy-quinoline prepared by the method of Krogstad et al. (J. Med. Chem., 41: 4918-4926 (1998)). (b) Preparation of 2-Methoxy-JST- [6- (6-methoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -benzamide. The title compound was prepared from 6- (6-methoxy-quinolin-4-yloxy) -benzothiazol-2-ylamine according to a procedure similar to that described for Example 2. The following Examples were prepared in a similar manner to the one described in Example 2.

The following were prepared in a manner similar to that described in Example 1.

The following compounds were prepared in a manner similar to that described in Example 1 or 2.

C26H24N404S 520.12 521 N- (6 - ((7 - ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -2-thiophenecarboxamide C 26 H 24? 404S 520.12 521 N- (6 - ((7 - ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3-thiophenecarboxamide 104 C29H2aN405S 576.15 577 N- (6- ((6- (methoxy) -7- ((3- (4-morpholinyl) propyl) oxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3-thiophenecarboxamide Ex. (5- (6,7-105 dimethoxy-quinolin-4-yloxy) -lff-indole-2-carboxylic acid (3-methoxy-phenyl) -amide. (a) 5- (6,7-Dimethoxy-quinolin-4-yloxy) -12α-indole-2-carboxylic acid ethyl ester. A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.8 mmol), 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.37 g, 1.8 mmol, Biosynth AG) and DMAP (0.22 g, 1.8 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180 ° C for 2 h. The mixture was cooled to RT and diluted with 30 mL EtOAc. The solution was washed twice with 10 ml of brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by column chromatography on silica gel (50% to 100% EtOAc in hexanes) to provide a white foam in the form of the desired compound. MS (ESI pos. Ion) m / z: 393 (M + H). Exact mass Cale, for C22H20N2O5: 392.40. (b) 5- (6,7-Dimethoxy-quinolin-4-yloxy) -12α-indole-2-carboxylic acid. To a solution of 5- (6,7-dimethoxy-quinolin-4-yloxy) -l-β-indole-2-carboxylic acid ethyl ester (0.2 g, 0.51 mmol, from step a) in 1 1: THF / MeOH (4 ml) was added 1.53 ml of 1 N NaOH. The reaction was stirred at RT for 16 h and then concentrated in vacuo. The remaining solution was acidified with 10% HCl to pH ~ 5. The white precipitate was collected and dried in vacuo, yielding a white solid in the form of the desired acid. MS (ESI pos. Ion) m / z: 365 (M + H). Exact Mass Cale, for C20H16N2? 5: 364.35. (c) 5- (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indole-2-carboxylic acid (3-methoxy-phenyl) -amide. To a solution of 5- (6,7-dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid (0.1 g, 0.27 punol, from step b), 3-methoxy-phenylamine (68 mg, 0.55 mmol) and DIEA (0.1 ml, 0.55 mmol) in 3 ml of DMF was added PyBOP (0.29, 0.55 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc and the resulting solution was washed with 30 mL of sat. NaHCO 3. followed by 30 ml of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (50% to 100% EtOAc / hexane), yielding an off-white solid in the form of the desired product. MS (ESI pos. Ion) m / z: 470 (M + H). Exact Mass Cale, for C27H23N305: 469.49.

Example Cyclopropylmethylamide of 106 5- (6,7-dimethoxy-quinolin-4-yloxy) -lIT-indol-2- acid carboxylic To a solution of 5- (6,7-dimethoxy-quinolin-yloxy) -lH-indole-2-carboxylic acid (1.2 g, 3.3 mmol, Example 105, Step b) and pentafluorophenol (1.21) g, 6.6 mmol, Aldrich) in 25 ml of EtOAc was added EDC (1.36 g, 6.6 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 25 mL of EtOAc and filtered to remove the white solid. The filtrate was concentrated in vacuo to give a light yellow oil. This ester was used without further purification.

To a solution of 5- (6,7-dimethoxy-quinolin-4-yloxy) -lfi-indole-2-carboxylic acid pentafluorophenyl ester (0.5 g, above) in 5 ml of THF was added cyclopropylmethylamine (0.175). g, 2.46 mmol, Aldrich) and the resulting solution was stirred at RT for 8 h. The mixture was concentrated in vacuo. The residue was diluted with 50 mL of EtOAc and washed with 20 mL of sat. NaHCO 3. followed by 20 ml of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (30% to 100% EtOAc / hexane) to give white solid as the desired product. MS (ESI pos. Ion) m / z: 418 (M + H). Dough Exacta Cale, for C24H23N304: 417.46. The following Examples were prepared in a manner similar to that described in Example 105.

Example Structure and Name Formula PM M + H lo N ° Mol 107 C26H2? N304 439, 46 440 - (6,7-Dimethoxy-quinolin-yloxy) -1H-indole-2-carboxylic acid phenylamide 108 C27H 3N3? 5 469.49 470 - (6,7-Dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid (2-methoxy-phenyl) -amide 109 C26H20ClN3O 473, 91 474 - (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indole-2-carboxylic acid (2-chloro-phenyl) -amide. 110 C26H20ClN3O 473, 91 474 - (6,7-Dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid (4-chlorofenyl) acid ester C27H23 3? 5 469.49 470 - (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indole-2-carboxylic acid (4-methoxy-phenyl) -amide 112 C26H22N40s 470.48 471 - (6,7-Dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid (6-methoxy-pyridin-3-yl) -amide. 113 C26H2oFN304 457.45 458 - (6,7-Dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid (3-fluoro-phenyl) -amide 114 C5H Q 40 440.45 441 - (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indole-2-carboxylic acid pyridin-2-ylamide 115 C23H18N404S 446.48 447 Thiazole-2-ylamide of 5- (6,7-dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid 116 C2-3H19N5O4 429.43 430 - (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indole-2-carboxylic acid (lH-pyrazol-3-yl) -amide.

The following Examples were prepared in a manner similar to that described in Example 106. 118 C25H25N304 431, 48 432 - (6,7-Dimethoxy-quinolin-4-yloxy) -1H-indole-2-carboxylic acid cyclopentylamide 119 C25H26N? 4 446.50 447 [5- (6,7-Dimethoxy-quinolin-4-yloxy) -lH-indol-2-yl] - (4-methyl-piperazin-1-yl) -methanone Example 6- ((6,7-bis (methyloxy) -4-120 quinolinyl) oxy) -1-methyl-1H-indazole-3-amino Step (a) Preparation of 3-amino-1-methyl-1-JT-indazole-6-ol A solution of 6-fluoro-4-hydroxybenzonitrile (Aldrich, 10.1 g, 73.9 mmol) in methylhydrazine (Aldrich) was stirred. , 20.0 ml, 379 mmol) at 80 ° C for 16 h. After cooling to RT, the volatile portion was removed in vacuo. The residue was triturated with DCM and MeOH. He The title compound was obtained by filtration in the form of an off-white solid. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (DCM / MeOH: from 100/0 to 95/5), giving an additional amount of the title compound as a white solid. Step (b) Preparation of 6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -l-methyl-1-J-T-indazol-3-amine. 4-Chloro-6,7-dimethoxyquinoline was stirred. (2.60 g, 11.7 mmol), 3-amino-l-methyl-lH-indazol-6-ol (Step a, 2.72 g, 16.7 mmol) and cesium carbonate (Aldrich, 16.3 g, 50.1 mmol) in DMSO (16.7 mL, Aldrich) at 100 ° C for 16 h. After cooling to RT, water was added. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried with MgSO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 0-100% of a 90: 10: 1 solution (CH2Cl2: MeOH: NH4OH) as eluent afforded the title compound as a white solid. MS (ESI, pos. Ion) m / z: 351.1 (M + 1). Masa Cale, for C19H18N403: 350.38.

Example 6- ((6, -bis (methoxy) -4-! 21-quinolinyl) oxy) -N-ethyl-l-methyl-lZ-indazole-3 - amine To a stirred solution of 6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1H-indazol-3-amine (Example 120, 140 mg, 0.40 mmol) in DCM dry (Aldrich, 4.0 ml) at RT is added acetaldehyde (Aldrich, 21.1 mg, 0.48 mmol) followed by NaHB (0Ac) 3 (Aldrich, 102 mg, 0.48 mmol). After stirring for 4 h at RT, the reaction was stopped by the addition of water. The aqueous phase was extracted with DCM. The organic phase was dried with MgSO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (DCM / acetone: from 100/0 to 60/40) afforded the title compound. MS (ESI, pos. Ion) m / z: 379.3 (M + 1). Mass Cale, for C2? H22N403: 378.43. The following compound was also isolated from the reaction mixture: The following compounds were prepared in a manner similar to the procedure indicated above: Example 128 6 - ((6,7-J-> is (Methoxy) -4-quinolinyl) oxy) -1- ethyl-N-phenyl-1H-indazol-3-amine A solution / suspension of Pd2dba3 (9.30 mg, 0.01 mmol), 2- (dicyclohexylphosphino) -2'4 '-6' -tri-i-propyl-1, 1'-biphenyl (19.5 mg , 0.04 itimol), sodium tere-butoxide (46.0 mg, 0.48 mmol), 6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1- methyl-1H-indazol-3-amine (Example 120, 119 mg, 0.34 mmol) and bromobenzene (53.4 mg, 0.34 mmol) in toluene (1 ml) was stirred at 100 ° C for 16 h. After cooling to RT, the mixture was purified by chromatography on silica gel (DCM / acetone: from 100/0 to 70/30), giving the title compound as a white solid. MS (ESI, pos. Ion) m / z: 427.3 (M + 1). Masa Cale, for C25H22N403: 426.47. The following compounds were prepared in a manner similar to the procedure indicated above: (methyloxy) benzamide To a solution of 6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -l-methyl-lH-indazol-3-amine (Example 120, 119 mg, 0.34 mmol) in pyridine ( 1 ml) was added p-anisoyl chloride (116 mg, 0.68 mmol). The reaction was stirred at RT for 16 h. The mixture was concentrated in vacuo. Trituration with MeOH and filtration afforded the title compound. MS (ESI, pos. Ion) m / z: 485.1 (M + 1). Mass Cale, for C25H22N403: 484.51. The following compounds were prepared in a similar manner to Example 132 and isolated after purification by chromatography on silica gel and / or crystallization: Example ((6,7-bis (methoxy) -4- 142 linyl) oxy) -1-methyl-ol-3-yl) -N '- (4- methylphenyl) urea To a solution of 6- ((6,7-bis (methoxy) -4-quinolinyl) oxy) -l-methyl-lH-indazol-3-amine (Example 120, 115 mg, 0.33 mmol) in benzene (1 ml) p-tolyl isocyanate (87.6 mg, 0.66 mmol) was added. The reaction was stirred at RT for 16 h. The mixture was concentrated in vacuo. Trituration with MeOH / EtOAc (1 / L) and filtration gave the title compound. MS (ESI, pos. Ion) m / z: 484.0 (M + 1). Masa Cale, for C27H25N504: 483.53. The following compounds were prepared in a similar manner to Example 142 and isolated after purification by chromatography on silica gel and / or crystallization: Example 5- < 6'7- 146 oxyquinolin-4-) benzofuran-2- xylic Step (a) Preparation of 5-hydroxybenzofuran-2-carboxylic acid A mixture of pyridine hydrochloride (15.1 g, 130 mmol) and 5-hydroxybenzofuran-2-carboxylic acid was heated at 150 ° C for 24 h. After cooling to RT, water was added. The aqueous phase was acidified to pH = 1 using 6 M aqueous HCl and then extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound. Step (b) Preparation of 5- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-2-carboxylic acid To a stirred solution of 5-hydroxybenzofuran-2-carboxylic acid (Step a, 2.00 g, 11.23 mmol) in DMSO (23 ml) at RT was added cesium carbonate (11.0 g, 33.7 mmol). The reaction was stirred for 10 min followed by the addition of 4-chloro-6, 7-dimethoxyquinoline (prepared by the procedure described in WO 03/33472) (1.75 g, 7.86 mmol). The reaction was stirred at 100 ° C for 16 h. After cooling to RT, water was added. The aqueous phase was acidified with a 6M aqueous solution of hydrochloric acid until pH = 5, filtered and the solid was suspended in EtOAc. The organic phase was extracted with a 3 M aqueous solution of sodium hydroxide. After acidification of the aqueous layer, the title compound was isolated by filtration and dried under high vacuum. The following compounds were prepared according to Example 146: Nc Structure and Name Formula Mass M + H 147 C26H19F? 2? 5 458.44 459.0 - (6,7-Dimethoxyquinolin-4-yloxy) -N- (3-fluorofenyl) benzofuran-2-carboxamide 148 C27H22? 2? 6 470.78 471.1 - (6,7-Dimethoxyquinolin-4-yloxy) -N- (3-methoxyphenyl) benzofuran-2-carboxamide 149 C26H19F? 2Os 458.44 459.0 - (6,7-Dimethoxyquinolin-4-yloxy) -N- (4-fluorophenyl) benzofuran-2-carboxamide Example 6- ((6,7-bis (methoxy) - 151 4-quinolinyl) oxy) -N- (4-chlorophenyl) -1- benzofuran-3-carboxamide Step (a) Preparation of 6-methoxybenzofuran-3 (2ff) -one. 6-Hydroxybenzofuran-3 (2H) -one (6 g, 40.0 mmol) was dissolved in DMF (80 ml) and then potassium carbonate (6.07 g, 43.97 mmol) and methyl iodide (4 g) were added. 12 ml, 65.95 mmol). The reaction was stirred at RT for 2 days. The mixture was filtered and the filtrate was concentrated in vacuo. The remaining oil was dissolved in EtOAc and washed with water. The aqueous phase was extracted again with EtOAc (2 x). The organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The remaining orange-red solid was purified by chromatography on silica gel (1: 4 EtOAc / hexane), affording 6-methoxybenzofuran- 3 (2H) -one in the form of a bright yellow crystalline solid. MS (ESI, pos. Ion) m / z: 165.1 (M + 1). Step (b) Preparation of 6-methoxybenzof ran-3-yl trifluoromethanesulfonate. 6-methoxybenzofuran-3 (2H) -one (5.6 g, 34.15 mmol) was dissolved in dichloromethane (100 ml) and then cooled to -65 ° C. N, N-diisopropylethylamine (6.84 ml, 39.27 mmol) was added dropwise via syringe, followed by the addition of trifluoromethane sulfonic anhydride (6.88 ml, 40.97 mmol). The mixture was heated slowly from -65 ° C to 0 ° C for 2.5 h. The reaction mixture was diluted with dichloromethane and then washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The remaining orange-brown liquid was purified by chromatography on silica gel (5% ethyl acetate / hexane) to give 6-methoxybenzofuran-3-yl trifluoromethanesulfonate in the form of a light orange liquid. MS (EI, pos. Ion) m / z: 296.9 (M + l). Step (c) Preparation of methyl 6-methoxybenzofuran-3-carboxylate. 6-methoxybenzofuran-3-yl trifluoromethanesulfonate (500 mg, 1.69 mmol) was added to a stainless steel high pressure reaction vessel and then dissolved in N, N-dimethylformamide (6.5 ml). Carbon monoxide gas was bubbled through the solution for 10 minutes. To the reaction mixture were added 1,3-bis (diphenylphosphino) propane (21 mg, 0.051 mmol), methanol (1.8 ml), triethylamine (342 mg, 3.38 mmol) and ethyl acetate. palladium (11 mg, 0.051 mmol), while carbon monoxide gas was continued to bubble through the mixture.

The reaction vessel was sealed and charged onto carbon monoxide (206.842 kPa (30 psi)). The reaction mixture was heated at 80 ° C for 4.5 hours. The mixture was concentrated in vacuo. The remaining orange mixture was purified by chromatography on silica gel (5% ethyl acetate / hexane), yielding methyl 6-methoxybenzofuran-3-carboxylate as light yellow solid. MS (ESI, pos. Ion) m / z: 207.1 (M + 1). Step (d) Preparation of methyl 6-hydroxybenzofuran-3-carboxylate. Methyl 6-methoxybenzofuran-3-carboxylate was dissolved (498 mg, 2.42 mmol) in dichloromethane (100 ml) and then cooled to -10 ° C. A solution of 1 M boron tribromide in dichloromethane (9.67 ml, 9.67 mmol) was slowly added via syringe. The purple reaction mixture was heated at RT for 3 h and then stirring was continued at RT for a further 4 h. The mixture was quenched slowly with 1N aqueous hydrochloric acid until it became colorless. The mixture was diluted with dichloromethane and washed with water (2 x) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The remaining orange-brown solid was purified by chromatography on silica gel (1: 4 EtOAc / hexane) to give methyl 6-hydroxybenzofuran-3-carboxylate as an off-white solid. MS (ESI, neg. Ion) m / z: 191.1 (M-1).

Step (e) Preparation of 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylic acid methyl ester. Methyl 6-hydroxybenzofuran-3-carboxylate (312 mg, 1.62 mmol) was dissolved in N, N-dimethylformamide (5 ml) and then 4-chloro-6,7-dimethoxy-quinoline (451 mg, 2.02 g) was added. mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 '-triisopropyl-1, 1-biphenyl (77 mg, 0.162 mmol), palladium acetate (36 mg, 0.162 mmol) and potassium phosphate (687 mg 3.24 mmol). The reaction mixture was stirred at 100 ° C overnight. To the mixture was added more palladium acetate (36 mg, 0.162 mmol) and the heating was continued at 100 ° C for 4 h. More 4-chloro-6,7-dimethoxyquinoline was added to the mixture. (181 mg, 0.812 mmol) and 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropyl-1,1 '-biphenyl (77 mg, 0.162 mmol) and heating was continued at 100 ° C for 2 days . The reaction mixture was filtered and the filtrate was concentrated in vacuo. The remaining orange oil was redissolved in toluene (5 ml) and DMF (1 ml) and then 4-chloro-6,7-dimethoxy-quinoline (225 mg, 1.01 mmol), 2- (dicyclohexylphosphino) -2 ', were added. 4 ', 6' -triisopropyl-1, 1'-biphenyl (38 mg, 0.080 mmol), palladium acetate (18 mg, 0.080 mol) and potassium phosphate (343 mg, 1.62 mmol). The reaction mixture was heated at 100 ° C overnight and concentrated in vacuo. The remaining orange-black oil was purified by chromatography on silica gel (1% to 2% methanol in dichloromethane), affording methyl 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylate in the form of a light yellow solid. MS (ESI, pos. Ion) m / z: 380.1 (M + 1). Step (f) Preparation of 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylic acid. Methyl 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylate (102 mg, 0.269 mmol) was dissolved in dioxane (1.6 ml) and water (0.5 ml) and then hydroxide was added. aqueous sodium 2 N (141 μl). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and then diluted with water. The aqueous phase was extracted with ethyl acetate. The aqueous phase was acidified with 1 N aqueous hydrochloric acid (282 μl) and the precipitate was collected, washed with water and dried under high vacuum to give 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylic acid as a light yellow solid (65 g). mg). MS (ESI, pos. Ion) m / z: 366.1 (M + 1). Step (g) Preparation of N- (4-chlorophenyl) -6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxamide. To a reaction tube were added 6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxylic acid (31 mg, 0.085 mmol) and 2- (lH-benzotriazol-1-yl) -1 tetrafluoroborate. , 1,3,3-tetramethyluronium (41 mg, 0.127 mmol) and then dissolved in DMF (0.6 ml). To the reaction mixture was added 4-chloroaniline (13 mg, 0.102 mmol), followed by N, N-diisopropylethylamine (22 mg, 0.17 mmol) and stirring was continued for 2 days. The mixture was concentrated in vacuo. The remaining orange oil was purified by chromatography on silica gel (1% to 2% methanol in dichloromethane) to give N- (4-chlorophenyl) -6- (6,7-dimethoxyquinolin-4-yloxy) benzofuran-3-carboxamide as a solid yellow (5 mg). EM (IE ?, pos. Ion) m / z: 475.1 (M + l). Masa Cale, for C26H19C1? 205: 474.89. Example 6- ((6,7-bis (Methoxy) -154-quinolinyl) oxy) -N- (3-methylphenyl) -1- benzofuran-3 carboxamide Prepared as described above in Example 151. EM (IE, pos. Ion) m / z: 455, 1 (M + l). Masa Cale, for C27H22? 205: 454, 48.

Table 1 ? e R1 153. pyridin-4-yl 154. 4-pyrimidinyl 155. quinazolin-4-yl 156. 6,7-dimethoxyquinazolin-4-yl Table 2 N ° Although the pharmacological properties of the compounds of Formulas I-III vary with the structural change, in general, the activity possessed by the compounds of Formulas I-III can be demonstrated in vivo.

The pharmacological properties of the compounds of this invention can be confirmed by a variety of in vitro pharmacological assays. The exemplified pharmacological tests shown below have been carried out with the compounds according to the invention and their salts. The compounds of the present invention showed inhibition of c-Met kinase at doses lower than 20 μM. BIOLOGICAL ASSAY The effectiveness of the compounds of the invention as inhibitors of VEGFR and / or GF related activity is demonstrated below. C-Met receptor assay Cloning, Expression and Purification of the c-Met Kinase Domain A PCR product is generated which includes residues 1058-1356 of c-Met (c-Met kinase domain) from the human liver QuickClone ™ cDNA (Invitrogen) using the direct primer 5 '-ATTGACGGATCCATGCTAAATCCAGAGCTGGTCCAGGCA-3' (SEQ ID NO: 1) and the reverse primer 5 '~ ACAACAGAATTCAATACGGAGCGACACATTTTACGTT-3' (SEQ ID NO: 2). The PCR product is cloned into the modified pFastBacl expression vector (which carries the glutathione S-transferase gene from S. japonicum immediately upstream of the multiple cloning site) using conventional molecular biology techniques. The kinase fusion domain gene GST-c-Met (GST-Met) is transposed into full-length baculovirus DNA using the BacToBac ™ system (Invitrogen). High5 cells become infected with the recombinant baculovirus for 72 hours at 27 ° C. Infected cells are collected by centrifugation and the pellet is stored at -80 ° C. The pellet is resuspended in buffer A (50 mM HEPES, pH 8.0, 0.25 M NaCl, 10 mM 2-mercaptoethanol, 10% glycerol (w / v), 0.5% protease inhibitor cocktail (v / v) (Sigma P8340)), is stirred at 4 ° C until homogeneous, and the cells are disrupted by microfluidization (Microfluidics) at 10,000 psi (68,947.57 kPa). The resulting lysate is centrifuged at 5,000 x g for 90 minutes at 4 ° C, the supernatant is adsorbed in 10 ml of glutathione sepharose ™ 4B (Amersham) by the batch process. The suspension is stirred gently overnight at 4 ° C. The glutathione resin is collected by centrifugation and washed 3 times with 40 ml of buffer A by the batch process. The resin is washed 3 times with buffer B (buffer A adjusted to 0.1 M NaCl, less protease inhibitors). The protein is eluted with buffer B containing 25 mM reduced glutathione. The eluted fractions are analyzed by SDS-PAGE and concentrated to < 10 ml (-10 mg / ml total protein). The concentrated protein is separated by size exclusion chromatography Superdex ™ 200 (Amersham) in buffer C (25 mM Tris, pH 7.5, 0.1 M NaCl, 10 M 2-mercaptoethanol, 10% glycerol). The fractions are analyzed by SDS-PAGE and the appropriate fractions are pooled and concentrated to ~ 1 mg / ml. The protein is dispensed in aliquots and stored at -80 ° C.

Alternative purification of human GST-cMET from Baculovirus cells Baculovirus cells are disrupted in 5x (volume / weight) of lysis buffer (50 mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10% glycerol plus Complete Protease Inhibitors (Roche (No. 10019600), 1 tablet per 50 ml of buffer) The used cell suspension is centrifuged at 100,000 xg (29,300 rpm) in a Beckman ultracentrifuge Ti45 rotor for 1 h. The supernatant is incubated with 10 ml of Glutathione Sepharose 4B from Amersham Biosciences (No. 27-4574-01) The incubation is carried out overnight at a cold temperature (approximately 8 ° C). The resin and the supernatant were poured into a disposable column of appropriate size and the flow was collected through the supernatant. The resin is washed with 10 column volumes (100 ml) of Buffer of Lysis The GST-cMET is eluted with 45 ml of 10 mM Glutathione (Sigma No. G-4251) in Lysis Buffer. The elution is collected as 15 ml fractions. The aliquots of the elution fractions are run on SDS-PAGE (12% Tris Glycine gel, Invitrogen No. EC6005BOX). The gel is stained with 0.25% Coomassie Blue stain. The fractions with GST-cMET are concentrated with a 20 ml Vivaspin concentrator (No. VS2002, limit 10.00 PM) to a final volume of less than 2.0 ml. The concentrated solution of GST-cMET is applied to a Superdex 75 16/60 column (Amersham Biosciences No. 17-1068-01) equilibrated with 25 mM Tris, pH 7.54, 100 mM NaCl, 10 mM mercaptoethanol, 10 g glycerol. %. The GST-cMET is eluted with an isocratic run of the previous buffer, with the eluent collected in 1.0 ml fractions. Fractions with significant DO280 readings are run on another 12% Tris Glycine gene. The maximum tubes with GST-cMET are pooled and the D028o is read with the column buffer indicated above as white buffer. The phosphorylation of CST-cMET is done by incubating the protein for 3 h at RT with the following final concentration a) 100 mM ATP (Sigma No. A7699) 25 M b) MgCl21.0 M (Sigma No. M-0250) 100 mM c) 200 mM sodium orthovanadate (Sigma No. 15 mM S-6508) d) Tris-HCl 1.0 M, pH 7.00 (manufacture 50 mM own) e) H20 f) GST-cMET 0.2 - 0.5 mg / ml After incubation, the solution is concentrated in a 20 ml Vivaspin concentrator at a volume of less than 2.00 ml. The solution is applied to the same Superdex 75 16/60 column used previously after rebalancing. The CST-cMET is eluted as described above. The elution fractions corresponding to the first peak eluted in the chromatogram are run on a 12% Tris Glycine gel, as above, to identify the fractions with CST-cMET. The fractions are pooled and the DO280 is read with the column buffer used as blank. A kinase reaction buffer is prepared as follows: Per 1 1 60 mM HEPES, pH Stock solution 16.7 ml ml 7.4 1 MX NaCl 50 mM Stock solution 100 X 10 ml 5 M MgCl2 20 M Stock solution 50 X 20 ml 1 M MnCl2 5 mM Stock solution 200 X 5 ml 1 M When the test is carried out, it is added freshly prepared: DTT 2 M Stock solution 1 500 X M BSA 0.05% Stock solution at 100 X 5% Na3OV4 0.1 mM Stock solution 1000 X 0.1 M 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% BSA, 0.05% Tween 20, 5 mM EDTA. Freshly prepared SA-APC is added (PJ25S Phycolink Streptavidin-Allophycocyanin Conjugate, Prozyme Inc.) and Eu- PT66 (PT66 anti-phosphorotyrosine antibody labeled with Eu-W1024, AD0069, Lot 168465, Perkin-Elmer Inc.) to reach the final concentration: Final concentration of Eu PT66 0.1 nM Final concentration of SA-APC 11 nM Procedures: 1 Dilute the enzyme GST-cMet (P) in kinase buffer as shown below: Prepare the working solution of GST-cMET (P) 8 nM (7.32 μM to 8 nM, 915 X, 10 μL to 9 15 ml). In a 96-well transparent plate [Costar No. 3365] add 100 μl in eleven columns, in one column add 100 μl of kinase reaction buffer alone. 2. Preparation of the assay plate: Use Biomek FX to transfer 10 μl of 8 nM GST-cMet (P) enzyme, 48.4 μl of kinase reaction buffer, 1.6 μl of compound (in DMSO) (concentration starting at 10 mM, 1 mM and 0.1 mM, sequential dilution 1: 3 to reach 10 test points) in a 96-well transparent costar plate [Costar No. 3365], mix several times. Then incubate the plate at RT for 30 min. 3. Prepare the working solution of Gastrin and ATP in the kinase reaction buffer as shown below: Prepare 4 μM Gastrin and 6 μM ATP working solution. Per 10 ml Gastrin stock solution (500 μM to 4 μM, 125 80 μl 4 μM X) Stock solution of ATP 16 (1000 μM to 16 μM, 160 μL μM 62.5 X) ATP and Gastrina work to the assay plate to start the reaction, incubate the plate at RT for 1 h. 4. Transfer 5 μl of the reaction product at the end of 1 h in 80 μl of HTRF buffer on a white plate [Costar No. 3356], read on Discover after 30 min of incubation. Summary of the test status: KM ATP * 6 μM [ATP] - 4 μM M 3, 8 μM Gastrin / p (EY) [gastrin] - l μM [enzyme] - 1 nM KM of ATP, KM of gastrin for various enzymes was determined by the HTRF and HTRF / 33P labeling procedures. Examples 1, 2, 4-31, 90-93 and 96 showed activity with IC50 values of less than 0.5 μM Auto-phosphorylation assay based on c-Met cells Human PC3 and mouse CT26 cells are obtained from ATCC. The cells were cultured in a culture medium containing RPMI 1640, penicillin / streptomycin / glutamine (IX) and 5% FBS. 2 x 10 4 cells were cultured per well in medium in a 96-well plate and incubated at 37 ° C overnight. Cells were maintained without serum replacing culture media with basic medium (DMEM with low glucose + 0.1 BSA, 120 μl per well) at 37 ° C for 16 h. The compounds (1 mM and 0.2 mM) in 100% DMSO were serially diluted (1: 3) 3333 times in a 96-well plate, diluting 1: 3 with DMSO from column 1 to 11 (the columns 6 and 12 do not receive the compound). Compound samples (2.4 μl per well) were diluted with basic medium (240 μl) in a 96-well plate. The cells were washed once with basic medium (GIBCO, DMEM 11885-076) then the compound solution (100 μl) was added. The cells were incubated at 37 ° C for 1 h. A solution (2 mg / ml) of CHO-HGF (7.5 μl) was diluted with 30 ml of basic medium to give a final concentration of 500 ng / ml. This medium containing HGF (120 μl) was transferred to a 96-well plate. The compounds (1.2 μl) were added to the medium containing HGF and mixed well. The media / HGF / compound mixture (100 μl) was added to the cells (final concentration of HGF-250 ng / ml) then incubated at 37 ° C for 10 minutes. A cell lysate buffer (20 ml) containing 1% Triton X-100, 50 mM Tris, pH 8.0, 100 mM NaCl, inhibitor was prepared. protease (Sigma, No. P-8340) 200 μl, Roche protease inhibitor (Complete, No. 1-697-498) 2 tablets, phosphatase II inhibitor (Sigma, No. P-5726) 200 μl, and a Sodium vanadate solution (containing 900 μl of PBS, 100 μl of 300 mM NaV03, 6 μl of H202 (30% stock solution) and stirred at RT for 15 min) (90 μl). The cells were washed once with ice cold IX PBS (GIBCO, No. 14190-136), then lysis buffer (60 μl) was added and the cells were incubated on ice for 20 minutes. The IGEN assay was performed as shown below: Dynabeads M-280 streptavidin beads were preincubated with biotinylated antihuman HGFR (240 μl of anti-human HGFR (R & D system, BAF527 or BAF328) at 100 μg / ml + 360 μl of beads (IGEN No. 10029 + 5.4 μl of buffer - PBS / 1% BSA / 0.1% Tween20) rotating for 30 min at RT Antibody beads (25 μl) were transferred to a 96-well plate. Wells were transferred further to cell lysate solution (25 μl), and the plate was shaken at RT for 1 h. Anti-phosphotyrosine 4G10 (Upstate 05-321) (19.7 μl antibody + 6 ml IX PBS) was added. ) (12.5 μl) to each well, then incubated for 1 h at RT ORIG labeled anti-mouse IgG (ORIGIN No. 110087) (24 μl antibody + 6 ml buffer) was added to each well (12 , 5 μl), then incubated at RT for 30 min, and PBS (175 μl) was added to each well and electrochemiluminescence was read by an IGEN M8. A 4-parameter adjustment equation in XLFit. Then, the IC50 values are determined using the Grafit software.

Examples 46, 82, 96, 102 and 104 showed activity in PC93 cells with IC50 values of less than 1.0 μM. Examples 36, 46, 71, 82, 89, 96, 100-102 and 104 showed activity in CT26 cells with IC50 values of less than 1.0 μM. HUVEC Proliferation Assay Human umbilical vein endothelial cells in the form of cryopreserved cells collected from a group of donors were purchased from Clonetics, Inc. These cells, in step 1, were thawed and expanded in complete medium EBM-2 to step 2 or 3. The cells were trypsinized, washed in DMEM + 10% FBS + antibiotics, and centrifuged at 1000 rmp for 10 minutes. min. Before centrifugation of the cells, a small amount is collected for a cell count. After centrifugation, the medium is discarded, and the cells are resuspended in the appropriate volume of DMEM + 10% FBS + antibiotics to achieve a concentration of 3 x 10 5 cells / ml. Another cell count is performed to confirm the cell concentration. The cells are diluted to 3 x 10 4 cells / ml in DMEM + 10% FBS + antibiotics, and 100 μl of cells are added to a 96-well plate. The cells are incubated at 37 ° C for 22 h. Before the completion of the incubation period, the dilutions of the compound are prepared. Serial dilutions of five times and five points are prepared in DMSO at concentrations 400 times higher than the desired final concentrations. 2.5 μl of each dilution is diluted additionally compounded in a total of 1 ml of DMEM + 10% FBS + antibiotics (400x dilution). The medium containing 0.25% DMSO is also prepared for the 10 μM sample of the compound. At the time point 22 h, the medium is removed from the cells, and 100 μl of each compound dilution is added. The cells are incubated at 37 ° C for 2-3 h.

During the preincubation period of the compound, the growth factors are diluted to the appropriate concentrations. Solutions of DMEM + 10% FBS + antibiotics are prepared, containing VEGF or bFGF in the following concentrations: 50, 10, 2, 0.4, 0.08, and 0 ng / ml. For cells treated with compound, solutions of VEGF at 550 ng / ml or bFGF at 220 ng / ml are prepared for final concentrations of 50 ng / ml or 20 ng / ml, respectively, since they will be added to the cells (110 μl of final volume) 10 μl of each. In the appropriate period of time after adding the compounds, the growth factors are added. VEGF is added to one group of plates, while bFGF is added to another group of plates. For the growth factor control curves, the media in wells B4-G6 of plates 1 and 2 are replaced with media containing VEGF or bFGF in the various concentrations (50-0 ng / ml). The cells are incubated at 37 ° C for a further 72 h. At the end of the 72 h incubation period, the medium is removed, and the cells are washed 2 times with PBS. After the second wash with PBS, the plates are gently tapped to remove excess PBS, and the cells are Place at -70 ° C for at least 30 min. The cells are thawed and analyzed using the fluorescent dye CyQuant (Molecular Probes C-7026), following the manufacturer's recommendations. The plates are read on a Victor / Wallac 1420 workstation at 485 nm / 530 nm (excitation / emission). The starting data is collected and analyzed using a 4-parameter fit equation in XLFit. Then, the IC50 values are determined. Examples 132, 134-140, 142, 144 and 145 inhibited the proliferation of VEGF-stimulated HUVEC at a level below 500 nM. Tumor model Tumor cells of human glioma (U87MG cells, ATCC) are expanded in culture, harvested and injected subcutaneously in nude female mice 5-8 weeks of age (CD1 nu / nu, Charles River Labs) (n = 10). Subsequent administration of the compound by an oral probe or by IP (10 -100 mpk / dose) begins at any time point from day 0 to day 29 after exposure of the tumor cell and continues generally once or twice at day while the experiment lasts. The evolution of tumor growth is continued by measurements of three-dimensional caliber and recorded as a function of time. The initial statistical analysis is carried out by analysis of repeated measures of variance (RMANOVA), followed by the post hoc Scheffe test for multiple comparisons. The vehicle alone (captisol, or similar) is the control negative. The compounds of the present invention will be active at doses less than 100 pk. FORMULATIONS A class of pharmaceutical compositions comprising the active compounds of Formula I-II is also encompassed within this invention, together with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein). as "vehicle" materials) and, if desired, other active ingredients. The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route, and in a dose effective for the desired treatment. The compounds and compositions of the present invention can be administered, for example, orally, mucosally, topically, rectally, pulmonarily, such as by spraying for inhalation or parenterally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients, adjuvants and vehicles. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy procedures to produce medicinal agents for administration to patients, including humans and other mammals.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably carried out in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, they may contain an amount of active ingredient of about 1 to 2000 mg, preferably about 1 to 500 mg. A suitable daily dose for a human or other mammal can vary widely depending on the condition of the patient and other factors, but, again, can be determined using standard procedures. The amount of compounds that is administered and the dosage regimen for treating a disease state with the compounds and / or compositions of this invention depends on various factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration and the particular compound used. In this way, the dosage regimen can vary widely, but can be determined in a conventional manner using conventional procedures. A daily dose of about 0.01 to 500 mg / kg, preferably between 0.01 and about 50 mg / kg, and more preferably about 0.01 and about 30 mg / kg of weight bodily. The daily dose can be administered in one to four doses per day. For therapeutic purposes, the active compounds of this invention are combined in a customary manner with one or more adjuvants appropriate for the indicated route of administration. If administered per os, the compounds can be administered with lactose, sucrose, powdered starch, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of acids phosphoric and sulfuric, gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol, and then, can be compressed or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation that can be provided in a dispersion of the active compound of hydroxymethylpropyl cellulose. In the case of psoriasis or other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area 2 to 4 times a day. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the skin, (eg, liniments, lotions, ointments, creams or pastes) or drops suitable for administration to the eye, ear or nose. A suitable topical dose of the active ingredient of a compound of the invention is from 0.1 mg to 150 mg administered from a four, preferably one to two times a day. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, although preferably not more than 5% w / w, and more preferably from 0.1% to 1% of the formulation. When formulated in an ointment, the active ingredients may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of the polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof . The topical formulation may desirably include a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs. The compounds of this invention can also be administered by a transdermal device. The preferably transdermal administration will be performed using a reservoir type patch and porous membrane or a variety of solid matrix. In any case, the active agent is administered continuously from the reservoir or microcapsules through a membrane in the adhesive permeable of the active agent, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as a membrane. The oil phase of the emulsions of this invention can be constituted from known ingredients in a known manner. Although the phase may simply comprise an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or both, a fat and an oil. Preferably, a hydrophilic emulsifier is included together with the lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier or emulsifiers with or without the stabilizer or stabilizers constitute the so-called emulsifying wax, and the wax together with the oil and the fat constitute the so-called emulsifier ointment base which forms the oily dispersed base of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art. The choice of oils or greases suitable for the formulation is based on achieving the cosmetic properties desired, since the solubility of the active compound in most oils that are likely to be used in pharmaceutical emulsion formulations is much lower. In this way, the cream should preferably be a non-greasy, non-dyed and washable product with a suitable consistency to avoid leakage of the tubes or other containers. Mono or dibasic straight or branched chain alkyl esters such as di-isodipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palimitate or a mixture of branched chain esters. They can be used alone or in combination depending on the required properties. Alternatively, lipids with high melting points such as white soft paraffin and / or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops in which the active ingredients are dissolved or suspended in a suitable vehicle, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly of about 1.5% w / w. Formulations for parenteral administration may be in the form of non-aqueous sterile isotonic injection solutions or suspensions. These solutions and suspensions can be prepared from powders or sterile granules using one or more of the mentioned carriers or diluents for use in the formulations for oral administration or for using other suitable dispersing agents or humectants and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and / or various buffers. In the pharmaceutical art, other adjuvants and modes of administration are well known and quite well known. The active ingredient can also be administered by injection in the form of a composition with suitable carriers including saline, dextrose or water, or with cyclodextrin (ie, Captisol), co-solvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e. Tween 80). The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any white fixed oil, including synthetic mono- or diglycerides, may be employed. In addition, fatty acids such as acid oleic find use in the preparation of injectable agents. For pulmonary administration, the pharmaceutical composition can be administered in the form of an aerosol or with an inhaler including the dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter or polyethylene glycols which are solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum and release the drug. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. The tablets and pills can be further prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring and perfuming agents. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes that are obvious to a person skilled in the art are intended to be within the scope and nature of the invention as defined in the appended claims. From the above description, one skilled in the art can easily determine the essential characteristics of this invention, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and states. Ueptable toxicological effects are not expected when the compounds of the present invention are administered in accordance with the present invention. All references, patents, applications and publications mentioned are hereby incorporated by reference in their entirety, as if they were described in this document.

Claims (52)

NOVELTY OF THE INVENTION Having described the invention as above, the content of the following CLAIMS is declared as property

1. A compound of Formula I ' X. r. RJ A 'R wherein R is selected from a) substituted or unsubstituted aryl, b) substituted or unsubstituted heterocyclyl, c) substituted or unsubstituted cycloalkyl, d) substituted or unsubstituted cycloalkenyl, e) H, f) substituted or unsubstituted alkyl , g) substituted or unsubstituted alkenyl, h) substituted or unsubstituted alkynyl, i) alkylaminocarbonyl, j) aminocarbonyl, and k) cyano; where R1 is to) wherein the T ring is selected from phenyl and 5-6 membered heteroaryl; where Z is selected from N or CRX; where R x is selected from H, CN, NH 2, F, alkylcarbonylamino and alkylaminocarbonyl; wherein R10 is one or more substituents selected from C6-C6 alkoxy, C6-6 haloalkoxy, Ci-6-alkylamino C6-alkoxy, aryl-alkoxy L-6, heterocyclyl-C6-6 alkoxy, cycloalkyl-alkoxy C? _6, heterocyclyl- (hydroxyalkoxy) C? _6, cycloalkyl- (hydroxyalkoxy) C? _6, aryl- (hydroxyalkoxy) C? -6, Cx-6-alkoxy, aryloxy-C? -6 alkoxy, heterocyclyloxy-alkoxy C? -6, cycloalkyloxy-C? _6 alkoxy, aryloxy, heterocyclyloxy and cycloalkyloxy; wherein A is selected from the following: wherein X is selected from 0, S, NR2 and CR3R4; wherein Y is selected from -NRb (CR3R4) P-, NRbC (= 0) (CR3R4) p-, -NRbC (= 0) NRb (CR3R4) p-, -NRbC (= 0) (CR3R4) p0- , -NRC (= 0) 0 (CR3R4) p-, -NRbC (= S) (CR3R4) p-, -NRbC (= NRa) (CR3R4) p-, -NRbS02- (CR3R) p-, -0C (= 0) (CR3R4) p-, -0 (CR3R) p-, - (CR3R4) pS (= 0) t-, - (CR3R4) P-, -S (= 0) tNRb (CR3R4) p-, -S (= 0) t (CR3R4) p-, -C (= 0) (CR3R4) P-, -C (= NRa) NH (CR3R4) p-, - C (= S) NH (CR3R4) p- and -C (= 0) NH (CR3R) p-; where Y is in any direction; wherein each of Ra and R is independently selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, R5R5N- (C = 0) - and R5- (= 0) -; wherein each of Ra and Rb is optionally substituted; wherein R2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl and R5-carbonyl; wherein each of R3 and R4 is independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6; wherein R5 is selected from H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl; wherein R6 is selected from cyano, -OR2, -SR2, halo, -S02R2, -C (= 0) R2, -S02NR2R5, -NR5C (= 0) OR2, NR5C (= 0) NR5R2, -NR5C (= 0) R2, -C02R2, -C (= 0) NR2R5 and -NR2R5; wherein p is 0, 1, 2 or 3; and wherein t is 0, 1 or 2; and pharmaceutically acceptable derivatives thereof; with the proviso that R is not 4-chloro-3- (1-methylpyrrolidin-2-yl) phenyl when Y is NH and A is 2,5-benzoxazolyl and when R 1 is 6,7-dimethoxyquinolinyl; with the additional proviso that R is not 4-chloro-3- (1-methylpyrrolidin-2-yl) phenyl when Y is NH and A is 2,5-benzoxazolyl and when R 1 is 6,7-dimethoxyquinazolinyl; with the additional proviso that R is not phenyl when Y is CH 2 and A is 2,5-benzimidazolyl and when R 1 is 6,7-dimethoxy-quinolinyl; with the additional proviso that Y is not -NH- or -NMe- when X is O, S, CH2 or NH, and A is benzimidazolyl, benzoxazolyl or benzothiazolyl; and with the additional proviso that R is not methyl when Y is - (CR3R4) p-, when p is 0, and A is 2, 5-indolyl.

2. Compound of claim 1 wherein R is selected from H, aryl of 6-10 members, heterocyclyl of 4-10 members, cycloalkyl of 3-6 members, alkyl d-6, alkenyl C2_6 and alkynyl C2-6; where R is substituted or unsubstituted.

3. The compound of claim 1 wherein R is optionally substituted phenyl or optionally substituted naphthyl.

4. The compound of claim 1 wherein R is a substituted or unsubstituted heterocyclyl ring selected from pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydrofuryl, 2,3-dihydrothiazolyl, 2, 3-dihydrobenzofuryl , 2, 3-dihydro-l, 4- benzodioxinyl, 1, 3-benzodioxolyl, benzisoxazolyl, benzthiazolyl, benzimidazolyl, benzothiadiazolyl, indolinyl, imidazo [1, 2-a] pyridyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, thiadiazolyl, furanyl and thienyl.

5. Compound of claim 1 wherein R is an unsubstituted or substituted ring selected from 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4- isoxazolyl, 3-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl.

6. Compound of claim 1 wherein R is selected from 1-methyl-cyclopropyl, cyclopropyl, 2-fluorocyclopropyl, 2-phenylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

7. The compound of claim 1 wherein R is selected from H, methyl, ethyl, rt-butyl, isobutyl, tere-butyl, isopropyl, propyl, cyanomethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminoethyl, 2-methoxy-1-methylethyl, methoxycarbonylmethyl, methoxyethyl, methoxypropyl, methylsulfonylethyl, dimethylaminoethyl, methoxycarbonylmethyl, ethenyl, thiazol-2-yl-CH (CH3) -, phenyl- CH (CH3) -, 5-methylisoxazole-3-ylmethyl, pyrrolidin-1-ylethyl, tetrahydrofur-2- ilmethyl, 4-methyl-2-oxo-oxazolidin-5-yl, pyrid-4-ylmethyl, pyrid-2-ylmethyl, 2-trifluoromethylpyrid-5-ylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3, 3- trifluoropropyl, (CH3) 3CCH2-, pentafluoroethyl, CF3CH2CH2-, cyclopropylmethyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, (2-methoxyphenyl) ethyl, 1-phenylethyl and phenylethyl.

8. The compound of claim 1 wherein R is selected from cyclohexenyl, 5,5-dimethyl-3-oxocyclohexenyl, ethenyl and propenyl.

9. Compound of claim 1 wherein R is H.

10. Compound of claim 1 wherein R is dimethylamino.

11. Compound of claim 1 wherein A is selected from wherein R7 is selected from H, halo and methyl; and pharmaceutically acceptable derivatives thereof.

1 . Compound of claim 1 wherein A is

13. Compound of claim 1 wherein A is

1 . Compound of claim 1 wherein

15. Compound of claim 1 wherein R1 is ; wherein the T ring is selected from phenyl and 5-6 membered heteroaryl; where Z is selected from N or CH; wherein R10 is one or more substituents selected from R80-; and wherein R 8 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-amino-C 1-6 alkyl, aryl C 1-6 alkyl, heterocyclyl-6 alkyl, cycloalkyl C 6 alkyl, heterocyclyl- (hydroxyalkyl)? -6, cycloalkyl- (hydroxy) C? _6, aryl- (hydroxyalkyl) C? C 6 alkoxyalkyl l? -6, aryloxy-alkyl C? _6 alkyl heterocyclyloxy-C? -6, cicloalquiloxi- C? -6 alkyl, aryl, heterocyclyl and cycloalkyl.

16. Compound of claim 1 wherein R1 is selected from and wherein R10 is selected from C3_3alkoxy, C3_3alkylamino-Cx-3alkoxy, 5-6-membered heterocyclyl-C3_3alkoxy, C4_6-cycloalkyl-C3_3alkoxy, 5-6 membered heterocyclyl- (hydroxyalkoxy) C? -3, C3_6- (hydroxyalkoxy) C? -3 cycloalkyl, phenyl- (hydroxyalkoxy) C1-3, C? _2-alkoxy C? _3 alkoxy, phenyloxy-C? -3 alkoxy, 5-6 heterocyclyloxy? C1-C4 alkoxy, C3 cycloalkyloxy-alkoxy, 5-6 membered heterocyclyloxy and C3_6-oxy cycloalkyl.

17. Compound of claim 1 wherein R1 is selected from 6,7-dimethoxy-4-quinolinyl, 6-methoxy-7- (dimethylaminopropoxy) -4-quinolinyl, 6-methoxy-7- (4-morpholinylpropoxy) -4- quinolinyl, 6,7-dimethoxy-4-quinazolinyl, and 6-methoxy-7- (dimethylaminopropoxy) -4-quinazolinyl.

18. Compound of claim 1 wherein Y is selected from -NH (CH2) P-, -NHC (= 0) (CH2) p-, NHC (= 0) (CH2) P0-, -NHC (= 0) (CH2) P-, - (CH2) p-NHC (= 0) -, NHC (= 0) NH-, -C (= 0) 0-, -NHS02- and -C (= 0) NH (CH2) p-; and where p is 0, 1 or 2.

19. Compound of claim 1 wherein Y is selected from -NH-, -NHCH2-, -NH (CH2) 2-, -NH (CH2) 3-, -NHC (= 0) CH2-, -NHC (= 0 ) (CH2) 2-, -NHC (= 0) -, -NHC (= 0) CH20-, -NHC (= 0) 0CH2-, -NHC (= 0) NH-, - (CH2) NHC (= 0) ) -, -C (= 0) 0-, -NHS02- and -C (= 0) NHCH2-.

20. Compound of claim 1 wherein R is selected from cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl, 2-phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5,5-dimethyl-3-oxocyclohexenyl, phenyl, 4-methylphenyl, 3- methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, 3-ethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-isopropyl-3-methylphenyl, 3-isopropylphenyl, 4-methyl. butylphenyl, 2,3-dimethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3, 5-difluorophenyl, 2,4,6-trifluorophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4- dimethoxyphenyl, 2,6-dichlorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro-5-methoxyphenyl, 4-chloro-2-methoxyphenyl, 2,4- dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-ethoxyphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) -phenyl, 3,5-di (trifluoromethyl) -2- methylphenyl, 4-dimethylaminophenyl, 3-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 4- [l-isopropylpiperazinin-4-yl] phenyl, 2- [(1-methylpyrrolidin-3-yl) -N (CH 3)] - 5-trifluoromethylphenyl, 5- [1-methyl-piperazin-4-ylmethyl] -3- trifluoromethylphenyl, 5- [2-oxopyrrolidin-1-yl] -3-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-bromo-2-fluorophenyl, 2-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 4-pentafluoroethylphenyl, -fluoro-3- trifluorome tilphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2- [methylcarbonylamino] -5-trifluoromethylphenyl, 3- [1- methylpiperidine] -4-yl] -5-trifluoromethylphenyl, 2- [1,1-dioxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [1-oxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2 - [(3-dimethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 3- (methylcarbonylamino) phenyl, 3- (4-methylpiperazin-1-ylmethyl) phenyl, 2- (4-methylpiperazin-1-ylmethyl) phenyl, -piperidin-l-yl-5-trifluoromethyl-phenyl, 2- [1-methylpiperidin-4-yloxy] -5-trifluoromethylphenyl, 2-methoxy-5-trifluoromethylphenyl, 2-methoxy-5-phenylphenyl, 2- [3, 3-dimethyl-2-oxo-azetidin-1-yl] -5-trifluoromethylphenyl, 2- [morpholin-4-ylethoxy] -5-erc-butylphenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5- erc -butylphenyl, 3- [dimethylamino-ethylcarbonylamino] -4-tert-butylphenyl, 2-methoxy-5- [2-pyridylaminocarbonyl] phenyl, 2-methoxy-5-phenylaminocarbonylphenyl, 2- [methyl- (1-methylpyrrolidin-3-yl) ) amino] -5-trifluoromethylphenyl, 2,2-difluorobenzodioxol-4-yl, biphenyl, 2-naphthyl, 2,3-dihydro-l, 4-benzodioxin-6-yl, 7-fluoro-2,3-dihydro- 1, 4-benzodioxin-6-yl, 1,3-benzodioxol-4-yl, l-isopropylpiperidin-4-yl, 2-pyrrolidinyl, l-methyl-2-pyrrolidinyl, 4-piperazinyl, 1-methylpiperidin-4 ilo, 3-methyl-isothiazol-5-yl, 3-isothiazolyl, 4 , 5-dichloro-3-isothiazolyl, isoxazol-3-yl, 5-isoxazolyl, 4-isoxazolyl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 4,5-dimethyl -isoxazol-3-yl, 3-methyl-isoxazol-5-yl, 5-tert-butyl-isoxazol-3-yl, 4-bromo-5-methyl-isoxazol-3-yl, 5-oxazolyl, l-methylimidazole -5-yl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-methylcarbonyl-thien-3-yl, 2-methylcarbonyl-5-tert-butyl-thien-3-yl, 2-aminocarbonyl-5-tert. -butyl-thien-3-yl, 4-methoxy-5-chloro-3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2 -thienyl, 3-ethoxy-2-thienyl, 3- chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 2-furyl, 2-cyano-5-phenylfur-3-yl, 4,5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl-3-furyl, 3-furanyl, 1-methylpyrrol-2-yl, 2-pyrrolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 4-methoxy-6-methylpyrimidin-2-yl, 4-chloro-2-methylthiopyrimidin- 6-yl, 2-pyridyl, 3-pyridyl, 4-? Iridyl, 4-trifluoromethyl-pyridin-2-yl, 2-trifluoromethyl-pyridin-5-yl, 2-dimethylaminopyridin-5-yl, 5-chloro-2-pyridyl, -fluoro- 3-pyridyl, 2-chloro-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 2-chloro-4-pyridyl, 2,5-dichloro-3-pyridyl, 2 - (dimethylaminoethoxy) -3-pyridyl, 2-methoxy-5-pyridyl, 2-methyl-5-pyridyl, 4-chloro-2-pyridyl, 4-methoxy-5-pyridyl, 3-benzyloxypyridin-2-yl, -methylpyridin-2-yl, 4-ethylpyridin-2-yl, 2-chloropyridin-4-yl, 3-chloropyridin-5-yl, 3-chloropyridin-6-yl, 2-chloropyridin-5-yl, 4-chloropyridin -2-yl, l-methyl-2 -oxopyrid-5-yl, tetrahydropyran-4-yl, 4,5-dihydrothiazol-2-yl, thiazol-2-yl, 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl , 4- tert-butyl-thiazol-2-yl, 5- er-butyl-thiazol-2-yl, 5- nitrothiazol-2-yl, 5-bromothiazol-2-yl, 5- [4-chlorophenyl] -thiazole -2-yl, 4- [4-chlorophenyl] -thiazol-2-yl, 4- [4- nitrophenyl] -thiazol-2-yl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5-dimethyl -4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, ethyl-l, 3,4-thiadiazol-2-yl, pyrazol-5-yl, 3-pyrazolyl, 1,3-diphenyl-pyrazol-3-yl, 1,3-dimethyl- pyrazol-3-yl, 5-cyano-4- erc-butyl-pyrazol-3-yl, 5-amino-3-methyl-pyrazol-1-yl, 3-methyl-l-erc-butyl-pyrazole-3 ilo, 5-amino-3-tert-butyl-pyrazol-1-yl, l-ethylpyrazol-5-yl, 3-tert-butyl-pyrazol-5-yl, l-methyl-3-tert-butyl-pyrazole- 5-yl, 4,4-dimethyl-l, 2,3,4-tetrahydroisoquinolin-7-yl, 7-quinolinyl, 2,3-dihydrobenzofur-7-yl, 3, 3-dimethyl-1-methylcarbonylindolin-6- ilo, 3, 3-dimethyl-2, 3-dihydro-indol-6-yl, 4-tert-butyl-imidazo [1,2- a] pyridin-6-yl, 3-quinolinyl, 2-benzofuryl, benzo [ 1.2.5] thiadiazol-4-yl, 7-methyl-benzothiazol-2-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 5,6-dimethyl-benzothiazole-2 ilo, benzimidazol-2-yl, l-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzisoxazol-3-yl, 4-methoxybenzisoxazol-3-yl and 2-methyl-benzothiazol-5-yl; and pharmaceutically acceptable derivatives thereof.

21. Compound of claim 1 wherein X is O.

22. Compound of claim 1 and pharmaceutically acceptable salts thereof selected from N- [6- (6,7-Dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -3-methyl-benzamide; [6- (6,7-Dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -amide of thiophene-3-carboxylic acid; 2-Phenyl-N- [6- (7-trifluoromethyl-quinolin-4-yloxy) -benzothiazol-2-yl] -acetamide; N- [6- (2-Methyl-pyridin-4-yloxy) -benzothiazol-2-yl] -2-phenyl-acetamide; 4-Chloro-N- [6- (6,7-dimethoxy-quinolin-4-yloxy) -benzothiazol-2-yl] -benzamide; 5- ((6,7-bis (methoxy) -4-quinolinyl) oxy) -? - (4-chlorophenyl) -1,3-benzoxazol-2-amine; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -2-thiophenecarboxamide; N- (6- ((7- ((2- (dimethylamino) ethyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -1,3-benzothiazol-2-yl) -3-thiophenecarboxamide; N- (6- ((7- ((3- (dimethylamino) propyl) oxy) -6- (methoxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) benzamide; and N- (6- ((6- (methoxy) -7- ((3- (-morpholinyl) propyl) oxy) -4-quinolinyl) oxy) -l, 3-benzothiazol-2-yl) -3-thiophenecarboxamide .

23. A compound of claim 1 wherein Xa is O or CH2; wherein already Is selected from -? H (CH2) x_3-,? HC (= 0) (CH2) P-, -? HC (= 0) (CH2) pO-, - (CH2) P-? HC ( = 0) -,? HC (= 0)? H-, -? HC (= 0) 0 (CH2) p- and -C (= 0) 0-; wherein Z is CH or?; wherein R 'is selected from H, alkyl d_5, haloalkyl d-3, alkoxy C? _3-alkyl C? _3 # alkoxy Cx_3-carbonyl-alkyl d_3, cyanoalkyl d_5, aminocarbonyl- alkyl d-5, alkyl d-5-aminocarbonyl-alkyl d-5, aminoalkyl Ci-s, alkyl C? _5-amino-alkyl Cx-S, alkyl C1-5-sulfonyl-alkyl C? _5, phenyl-alkyl C ? -3, C3-6 cycloalkyl-d-3 alkyl, 5-6 membered heterocyclyl-C1-3 alkyl and an unsubstituted or substituted ring selected from phenyl, naphthyl, 1,3-benzodioxolyl, 2,3-dihydro-? 1,4-benzodioxinyl, C3-6 cycloalkyl, C5-cycloalkenyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, dihydrothiazolyl, 2,3-dihydrobenzofuryl, piperidinyl, 1-methyl-oxopyridyl, tetrahydropyran 4-yl, indolinyl, imidazo [1,2-a] pyridinyl, quinolinyl, benzofuryl, benzo [1.2.5] thiadiazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, thiadiazolyl, furanyl and thienyl; wherein R8 is selected from H, fluoro, chloro and methyl; wherein R9 is selected from H, methyl and fluoro; wherein R10a is H or methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy , 3- (4-methylpiperazin-1-yl) propoxy, 3- (1, 2,4-triazol-1-yl) propoxy, triazinylpropoxy, 3- (piperidin-4-yl) propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy; and pharmaceutically acceptable derivatives thereof.

24. Compound of claim 23 wherein R 'is selected from H, methyl, ethyl, n-butyl, isobutyl, tere-butyl, isopropyl, propyl, cyanomethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminoethyl, 2-methoxy-1-methylethyl, methoxycarbonylmethyl , methoxyethyl, methoxypropyl, methylsulfonylethyl, dimethylaminoethyl, methoxycarbonylmethyl, ethenyl, thiazol-2-yl-CH (CH3) -, phenyl-CH (CH3) -, 5-methylisoxazol-3-ylmethyl, pyrrolidin-1-ylethyl, tetrahydrofur-2 -methylmethyl, 4-methyl-2-oxo-oxazolidin-5-yl, pyrid-4-ylmethyl, pyrid-2-ylmethyl, 2-trifluoromethylpyrid-5-ylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3 , 3- trifluoropropyl, (CH3) 3CCH2-, pentafluoroethyl, CF3CH2CH2-, cyclopropylmethyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, (2-methoxyphenyl) ethyl, 1-phenylethyl, phenylethyl, cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl , 2-phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5,5-dimethyl-3-oxocyclohexenyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methyl nyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, 3-ethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-isopropyl-3-methylphenyl, 3-isopropylphenyl, 4-erc-butylphenyl, 2, 3-dimethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3, 5 difluorophenyl, 2,4,6-trifluorophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 2, 6- dichlorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro-5-methoxyphenyl, 4-chloro-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-ethoxyphenyl, 4- hydroxyphenyl, 2-hydroxyphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) -phenyl, 3,5-di (trifluoromethyl) -2-methylphenyl, 4-dimethylaminophenyl, 3-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3- cyanophenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 4- [l-isopropylpiperazinin-4-yl] phenyl, 2- [(1-methylpyrrolidin -3-yl) -N (CH3)] -5-trifluoromethylphenyl, 5- [1- methylpiperazin-4-ylmethyl] -3-trifluoromethylphenyl, 5- [2-oxopyrrolidin-1-yl] -3-trifluoromethylphenyl, 2- chloro-4- trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-bromo-2-fluorophenyl , 2-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 4-pentafluoroethylphenyl, -fluoro-3-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2- [methylcarbonylamino] - 5-trifluoromethylphenyl, 3- [1-methylpiperidin-4-yl] -5-trifluoromethylphenyl, 2- [1,1-dioxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [1-oxo-thiomorpholin-4] -yl] -5-trifluoromethylphenyl, 2- [thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [(3- di ethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 3- (methylcarbonylamino) phenyl, 3- (4-methylpiperazin-1-ylmethyl) phenyl, 2- (4-methylpiperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [1-methylpiperidin-4-yloxy] -5-trifluoromethylphenyl, 2-methoxy-5-trifluoromethylphenyl , 2-methoxy-5-phenylphenyl, 2- [3,3-dimethyl-2-oxo-azetidin-1-yl] -5-trifluoromethylphenyl, 2- [morpholin-4-ylethoxy] -5-erc-butylphenyl, -methoxy-5-fluorophenyl, 2-methoxy-5-tert-butylphenyl, 3- [dimethylaminomethylcarbonylamino] -4-erc-butylphenyl, 2-methoxy-5- [2-pyridylaminocarbonyl] phenyl, 2-methoxy-5-phenylaminocarbonylphenyl, 2- [Methyl- (1-methylpyrrolidin-3-yl) amino] -5-trifluoromethylphenyl, 2,2-difluorobenzodioxol-4-yl, biphenyl, 2-naphthyl, 2,3-dihydro-1,4-benzodioxin-6 - ilo, 7-fluoro-2,3-dihydro-l, 4-benzodioxin-6-yl, 1,3-benzodioxol-4-yl, l-isopropylpiperidin-4-yl, 2-pyrrolidinyl, l-methyl-2 -pyrrolidinyl, 4-piperazinyl, 1 -methylpiperidin-4-yl, 3-methyl-isothiazol-5-yl, 3-isothiazolyl, 4,5-dichloro-3-isothiazolyl, isoxazol-3-yl, 5-isoxazolyl, 4-isoxazolyl, 5-methyl-isoxazole -3-yl, 3,5-dimethyl-isoxazol-4-yl, 4,5-dimethyl-isoxazol-3-yl, 3-methyl-isoxazol-5-yl, 5-tert-butyl-isoxazol-3-yl , 4-bromo-5-methyl-isoxazol-3-yl, 5-oxazolyl, l-methylimidazol-5-yl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-methylcarbonyl-thien-3-yl, 2 -methylcarbonyl-5-tert-butyl-thien-3-yl, 2-aminocarbonyl-5-butyl-thien-3-yl, 4-methoxy-5-chloro-3-thienyl, 3-methyl-2-thienyl , 5-methyl-2-thienyl, 5-methylthio- 2-thienyl, 5-methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2- thienyl, 4-methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 2-furyl, 2-cyano-5-phenyl-3-yl, 4,5-dimethyl-2-furyl, 5- methyl-2-trifluoromethyl-3-furyl, 3-furanyl, 1-methylpyrrol-2-yl, 2-pyrrolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4- pyrimidinyl, 4-methoxy-6-methylpyrimidin-2-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-trifluoromethylpyridin-2-yl, 2-trifluoromethylpyridin- 5-yl, 2-dimethylaminopyridin-5-yl, 5-chloro-2-pyridyl, 2-fluoro-3-pyridyl, 2-chloro-3-pyridyl, 2-methoxy-3-pyridyl, 2- ethoxy-3- pyridyl, 2-chloro-4-pyridyl, 2,5-dichloro-3-pyridyl, 2- (dimethylaminoethoxy) -3-pyridyl, 2-methoxy-5-pyridyl, 2-methyl-5-pyridyl, 4-chloro- 2-pyridyl, 4-methoxy-5-pyridyl, 3-benzyloxypyridin-2-yl, 4-methylpyridin-2-yl, 4-ethylpyridin-2-yl, 2-chloropyridin-4-yl, 3-chloropyridin- 5- ilo, 3-chloropyridin-6-yl , 2-chloropyridin-5-yl, 4-chloropyridin-2-yl, 1-methyl-2-oxopyrid-5-yl, tetrahydropyran-4-yl, 4,5-dihydrothiazol-2-yl, thiazol-2-yl , 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, 4- tert-butyl-thiazol-2-yl, 5- erc-butyl-thiazol-2-yl, 5- nitrothiazole -2-yl, 5-bromothiazol-2-yl, 5- [4-chlorophenyl] -thiazol-2-yl, 4- [4-chlorophenyl] -thiazol-2-yl, 4- [4- nitrophenyl] -thiazole -2-yl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5-dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-tert-butyl-l, 3,4-thiadiazole -2-yl, 5-trifluoromethyl-1,3,6-thiadiazol-2-yl, 5-ethyl-l, 3,4-thiadiazol-2-yl, pyrazole-5- ilo, 3-pyrazolyl, 1,3-diphenyl-pyrazol-3-yl, 1,3-dimethyl-pyrazol-3-yl, 5-cyano-4- erc-butyl-pyrazol-3-yl, 5-amino- 3-methyl-pyrazol-1-yl, 3-methyl-1-tert-butyl-pyrazol-3-yl, 5-amino-3-tert-butyl-pyrazol-1-yl, 1-ethylpyrazol-5-yl, 3-tert-butyl-pyrazol-5-yl, l-methyl-3-tert-butyl-pyrazol-5-yl, 4,4-dimethyl-l, 2,3,4-tetrahydroisoquinolin-7-yl, 7- quinolinyl, 2,3-dihydrobenzofur-7-yl, 3,3-dimethyl-l-methylcarbonylindolin-6-yl, 3,3-dimethyl-2,3-dihydro-indol-6-yl, 4-tert-butyl- imidazo [1,2-a] pyridin-6-yl, 3-quinolinyl, 2-benzofuryl, benzo [1,2,5] thiadiazol-4-yl, 7-methyl-benzothiazol-2-yl, 6-ethoxy-benzothiazole- 2-yl, 6-fluoro-benzothiazol-2-yl, 5,6-dimethyl-benzothiazol-2-yl, benzimidazol-2-yl, l-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzisoxazole- 3-yl, 4-methoxybenzisoxazol-3-yl and 2-methylbenzothiazol-5-yl; and pharmaceutically acceptable derivatives thereof.

25. Compound of claim 23 wherein R10a is methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy, - (4-methylpiperazin-1-iDpropoxy, 3- (1, 2,4-triazol-1-yl) propoxy, triazinylpropoxy, 3- (piperidin-4-yl) propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy, and pharmaceutically acceptable derivatives of the same.

26. Compound of claim 23 wherein R8 is H; and wherein R9 is H, methyl or fluoro; and pharmaceutically acceptable derivatives thereof.

27. Compound of claim 23 wherein Ya is selected from -NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) pO-, - (CH2) P-NHC (= 0) -, - NHC (= 0) NH-, -NHC (= 0) 0 (CH2) p-, -NHS02- and -C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3; and pharmaceutically acceptable derivatives thereof.

28. Compound of claim 23 wherein Ya is selected from -NHC (= 0) -, -NHC (= 0) (CH2) -, -NHC (= 0) (CH2) 2-, - (CH2) p-NHC (= 0) -, -NHC (= 0) NH- and -NHS02-; and pharmaceutically acceptable derivatives thereof.

29. Compound of claim 23 wherein Ya is -NHC (= 0) - and -NHC (= 0) CH2-; and pharmaceutically acceptable derivatives thereof.

30. Compound of claim 23 wherein X is O; and pharmaceutically acceptable derivatives thereof.

31. Compound of claim 23 wherein R 'is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 3-isopropylphenyl, 4-erc-butylphenyl, , 3-dimethylphenyl, 4-isopropyl-3-methylphenyl, 3-chloro-4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2- fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 4-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-chloro-3- trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) phenyl, 4-dimethylaminophenyl, 3- (4-methylpiperazin-1-ylmethyl) phenyl, 2- (4-methylpiperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [(3-dimethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 2- [ methyl- (1-methylpyrrolidin-3-yl) amino] -5-trifluoromethylphenyl, biphenyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-piperazinyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 5- imidazolyl, 3-pyrazolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-pyrimidinyl, 2-pyridyl, 3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 4-chloro-2 -pyridyl, 4-trifluoromethyl-2-pyridyl, 4-methoxy-5-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-l, 4-benzodioxin-5 -yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 4,5-dichloro-3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5 -dimethyl-4-thiazolyl, 2-thiazolyl, 2- furanyl, 4,5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl-3- furyl, 3-furanyl, 3-thienyl, 4-methoxy-5-chloro-3-thienyl, 2-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5-methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4- methoxy-5-bromo-3-thienyl, 4-methoxy-3-thienyl, 5-tert-butyl-isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazole-4- ilo, 5- tert -butyl-pyrazol-3-yl and 2-methylbenzothiazol-5-yl.

32. A compound of claim 1 wherein Y is selected from -NRZ (CH2) -, NHC (= 0) (CH2) P-, -NHC (= 0) (CH2) pO-, - (CH2) p-NHC (= 0) -, NHC (= 0) NH-, -NHC (= 0) 0 (CH2) p-, -C (= 0) 0-, -NHS02- and C (= 0) NH (CH2) p-; where p is 0, 1, 2 or 3; wherein Z is CRX or N; wherein R 'is selected from H, alkyl d_5, haloalkyl C? _3, alkoxy d_3-alkyl Cx_3, alkoxy d-3? carbonyl-C? _3 alkyl, cyanoalkyl C? _5, aminocarbonylalkyl C? -5, alkyl d-? 5-aminocarbonyl-C?-5 alkyl, C?-5 aminoalkyl, C d-5 alkyl-5-amino-alkyl Cx-5 alkyl sulfonyl-C 1-5 alkyl, phenyl-d-3 alkyl, C 3-6 cycloalkyl-C 1 -C 3 alkyl, 5-6 membered heterocyclyl-C 3 alkyl, and an unsubstituted or substituted ring selected from phenyl, naphthyl, 1, 3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, dihydrothiazolyl, 2,3-dihydrobenzofuryl , piperidinyl, 1-ethyl-oxopyridyl, tetrahydropyran-4-yl, indolinyl, imidazo [1,2-a] pyridinyl, quinolinyl, benzofuryl, benzo [1,2,5] thiadiazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, isoxazolyl, isothiazolyl , oxazolyl, thiazolyl, thiadiazolyl, furanyl and thienyl; wherein R8 is selected from H, fluoro, chloro and methyl; wherein R9 is selected from H, methyl and fluoro; wherein R x is selected from H, CN, NH 2, F, alkylcarbonylamino and alkylaminocarbonyl; wherein Ra is selected from H, benzyl and alkyl d_3; wherein R10a is H or methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy , 3- (4-methyl-piperazin-1-yl) -propoxy, 3- (1, 2, 4-1-azole-1-yl) -propoxy, triazinyl-propoxy, 3- (piperidin-yl) -propoxy, dimethylamino-ethoxy, dimethylaminopropoxy and methoxy; and pharmaceutically acceptable derivatives thereof.

33. Compound of claim 32 wherein Z is CH; where R10 is methoxy; and wherein R10b is selected from 4-morpholinpropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-yl-ropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl) propoxy , 3- (4-methylpiperazin-1-yl) propoxy, 3- (1,2,4-triazol-1-yl) propoxy, triazinylpropoxy, 3- (piperidin-4-yl) propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy; and pharmaceutically acceptable salts thereof.

34. Compound of claim 32 wherein R 'is selected from H, methyl, ethyl, n-butyl, isobutyl, tere-butyl, isopropyl, propyl, cyanomethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminoethyl, 2-methoxy-1-methylethyl, methoxycarbonylmethyl , methoxyethyl, methoxypropyl, methylsulfonylethyl, dimethylaminoethyl, methoxycarbonylmethyl, ethenyl, thiazol-2-yl-CH (CH3) -, phenyl-CH (CH3) -, 5-methylisoxazol-3-ylmethyl, pyrrolidin-1-ylethyl, tetrahydrofur-2 -methylmethyl, 4-methyl-2-oxo-oxazolidin-5-yl, pyrid-4-ylmethyl, pyrid-2-ylmethyl, 2-trifluoromethylpyrid-5-ylmethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3 , 3- trifluoropropyl, (CH3) 3CCH2-, pentafluoroethyl, CF3CH2CH2-, cyclopropylmethyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, (2-methoxyphenyl) ethyl, 1-phenylethyl, phenylethyl, cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl , 2- phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5,5-dimethyl-3-oxocyclohexenyl, phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, 3- ethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-isopropyl-3-methylphenyl, 3-isopropylphenyl, 4-erp-butylphenyl, 2,3-dimethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4- difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,4,6-trifluorophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl , 3-chlorophenyl, 2-chlorophenyl, -methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 2,6-dichlorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro-5-methoxyphenyl, 4- chloro-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-ethoxyphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 2, 3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-tr ifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-di (trifluoromethyl) -phenyl, 3,5-di (trifluoromethyl) -2-methylphenyl, 4-dimethylaminophenyl, 3-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-methylthiophenyl, 3-methylsulfonylphenyl, 2-methylsulfonylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 4- [l-isopropylpiperazinin-4-yl] phenyl, - [(1-methylpyrrolidin-3-yl) -N (CH 3)] - 5-trifluoromethylphenyl, 5- [1- methylpiperazin-4-ylmethyl] -3-trifluoromethylphenyl, 5- [2-oxopyrrolidin-1-yl] - 3-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-bromo-2-fluorophenyl, 2-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 4-pentafluoroetilfenilo, -fluoro-3-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-methyl-3 -trifluorometilfenilo, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2- [methylcarbonylamino] -5-trifluoromethylphenyl, 3- [1-methylpiperidin-4-yl] -5-trifluoromethylphenyl, 2- [1, 1-dioxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [1-oxo-thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2- [thiomorpholin-4-yl] -5-trifluoromethylphenyl, 2-piperidine -l-yl-5- trifluoromethyl-phenyl, 2 - [(3-dimethylaminopropyl) methylamino] -5-trifluoromethylphenyl, 2- (3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethylphenyl, 3- (methylcarbonylamino) phenyl , 3- (4-methyl-piperazin-1-ylmethyl) phenyl, 2- (4-methyl-piperazin-1-ylmethyl) phenyl, 2-piperidin-1-yl-5-trifluoromethyl-phenyl, 2- [1- methylpiperidin-4-] iloxy] -5-trifluoromethylphenyl, 2-methoxy-5-trifluoromethylphenyl, 2-methoxy-5-fe nylphenyl, 2- [3,3-dimethyl-2-oxo-azetidin-1-yl] -5-trifluoromethylphenyl, 2- [morpholin-4-ylethoxy] -5-erc-butylphenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-tert-butylphenyl, 3- [dimethylaminomethylcarbonylamino] -4- erc-butylphenyl, 2-methoxy-5- [2-pyridylaminocarbonyl] phenyl, 2-methoxy-5- fenilaminocarbonilfenilo, 2- [methyl- (l methylpyrrolidin-3- yl) amino] -5-trifluoromethylphenyl, 2, 2-difluorobenzodioxol- 4-yl, biphenyl, 2-naphthyl, 2,3-dihydro-l, 4-benzodioxin-6- yl, 7-fluoro- 2,3-dihydro-l, 4-benzodioxin-6-yl, 1,3- benzodioxol-4-yl, l-isopropylpiperidin-4-yl, 2-pyrrolidinyl, l-methyl-2-pyrrolidinyl, 4-piperazinyl, 1-methylpiperidin-4-yl, 3-methyl-isothiazol-5-yl, 3- isothiazolyl, 4,5-dichloro-3-isothiazolyl, isoxazol-3-yl, 5-isoxazolyl, 4-isoxazolyl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 4, 5-dimethyl-isoxazol-3-yl, 3-methyl-isoxazol-5-yl, 5- erc-butyl-isoxazol-3-yl, 4-bromo-5-methyl-isoxazol-3-yl, 5-oxazolyl, 1-methylimidazol-5-yl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-methylcarbonyl-thien-3-yl, 2-methylcarbonyl-5-tert-butyl-thien-3-yl, 2-aminocarbonyl- 5- erc-butyl-thien-3-yl, 4-methoxy-5-chloro-3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methylthio-2-thienyl, 5- methylsulfonyl-2-thienyl, 3-ethoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 3-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methoxy- 5-bromo-3-thienyl, 4-methoxy-3-thienyl, 2-furyl, 2-cyano-5-phenyl-3-yl, 4,5-dimethyl-2-furyl, 5-methyl-2-trifluoromethyl- 3-furyl, 3-furanyl, 1-methylpyrrol-2-yl, 2-pyrrolyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 4-pyrimidinyl, 2,6-dimethoxy-4-pyrimidinyl, 4-methoxy-6-methylpyrimidin-2-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4- trifluoromethylpyridine-2-yl, 2-trifluoromethylpyridine-5-yl, 2-dimethylaminopyridin-5-yl, 5-chloro-2-pyridyl, 2-fluoro- 3- pyridyl, 2-chloro-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 2-chloro-4-pyridyl, 2,5-dichloro-3-pyridyl, 2- (dimethylaminoethoxy) - 3-pyridyl, 2-methoxy-5-pyridyl, 2-methyl-5-pyridyl, 4-chloro-2-pyridyl, 4-methoxy-5-pyridyl, 3-benzyloxypyridin-2-yl, 4-methylpyridin-2- ilo, -ethylpyridin-2-yl, 2-chloropyridin-4-yl, 3-chloropyridin-5-yl, 3-chloropyridin-6-yl, 2-chloropyridin-5-yl, 4-chloropyridin-2-yl, l-methyl -2-oxopyrid-5-yl, tetrahydropyran-4-yl, 4,5-dihydrothiazol-2-yl, thiazol-2-yl, 5-methyl-thiazol-2-yl, 4,5-dimethyl-thiazole-2 -yl, 4-tert-butyl-thiazol-2-yl, 5- erc-butyl-thiazol-2-yl, 5-nitrothiazol-2-yl, 5-bromothiazol-2-yl, 5- [4-chlorophenyl] -thiazol-2-yl, 4- [4-chlorophenyl] -thiazol-2-yl, 4- [4-nitrophenyl] -thiazol-2-yl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2,5 -dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-tert-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl , 5-ethyl-l, 3,4-thiadiazol-2-yl, pyrazol-5-yl, 3-pyrazolyl, 1,3-diphenyl-pyrazol-3-yl, 1,3-dimethyl-pyrazol-3-yl , 5-cyano-4- erc-butyl-pyrazol-3-yl, 5-amino-3-methyl-pyrazol-1-yl, 3-methyl-l-erc-butyl-pyrazol-3-yl, 5-amino -3-tert-butyl-pyrazol-1-yl, l-ethylpyrazol-5-yl, 3- tert-butyl-pyrazol-5-yl, l-methyl-3-tert-butyl-pyrazol-5-yl, 4,4-dimethyl-l, 2,3,4 -tetrahydroisoquinolin-7-yl, 7- quinolinyl, 2,3-dihydrobenzofur-7-yl, 3, 3-dimethyl-l-methylcarbonylindolin-6-yl, 3,3-dimethyl-2,3-dihydro-indole-6 -yl, 4-tert-butyl-imidazo [1,2-a] pyridin-6-yl, 3-quinolinyl, 2-benzofuryl, benzo [1,2,5] thiadiazol-4-yl, 7-methyl-benzothiazol-2 -yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 5,6-dimethyl-benzothiazol-2-yl, benzimidazol-2-yl, l-methyl-benzimidazol-2-yl , benzoxazol-yl, benzisoxazol-3-yl, 4-methoxybenzisoxazol-3-yl and 2-methylbenzothiazol-5-yl; and pharmaceutically acceptable derivatives thereof.

35. Compound of claim 32 wherein Ya is selected from -NHC (= 0) -, -NH- and -NHC (= 0) -NH-; and pharmaceutically acceptable salts thereof.

36. Compound of claim 32 wherein Ya is -NHC (= 0) - or -NHC (= 0) -NH-; and pharmaceutically acceptable salts thereof.

37. Compound of claim 32 wherein R8 and R9 is H; and pharmaceutically acceptable salts thereof.

38. The compound of claim 32 wherein R 10b is methoxy; and pharmaceutically acceptable salts thereof.

39. The compound of claim 32 wherein Ra is methyl; and pharmaceutically acceptable salts thereof.

40. Compound of claim 32 wherein Z is CH; and pharmaceutically acceptable salts thereof.

41. Compound of claim 32 and pharmaceutically acceptable salts thereof selected from N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -4 -chlorobenzamide; N- (6- ((6,7-bi (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -4- (trifluoromethyl) benzamide; N. (6_ ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -4- (methyloxy) benzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lr-indazol-3-yl) -3-chloro-4-fluorobenzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lJI-indazol-3-yl) -3,5-bis (trifluoromethyl) benzamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1 H -indazol-3-yl) -4-chloro-2-pyridinecarboxamide; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-1 H -indazol-3-yl) -3-methylbenzamide; N- (6- ((6,7-bi (methyloxy) -quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -N '- (4-methylphenyl) urea; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -N '-phenylurea; N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -3- (trifluoromethyl) benzamide; and N- (6- ((6,7-bis (methyloxy) -4-quinolinyl) oxy) -1-methyl-lH-indazol-3-yl) -N '- (4- (methyloxy) phenyl) urea.

42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of claims 1-41.

43. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of cancer.

44. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of diseases related to angiogenesis.

45. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of neoplasia.

46. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of ophthalmological conditions.

47. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of cell proliferation.

48. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for reducing blood flow in a tumor.

49. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for reducing the size of a tumor.

50. The use of a compound according to any of claims 1-41 or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition according to claim 42 for preparing a medicament for the treatment of diabetic retinopathy.

51. A compound as defined in any of claims 1-41 or a pharmaceutically acceptable derivative thereof for use in a therapeutic treatment procedure.

52. The use of claim 43 comprising a combination with a compound selected from antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents and various agents.