MXPA06000177A - Triazolotriazine compounds and uses thereof - Google Patents

Abstract

The present invention relates to compounds of the Formula (I), and their pharmaceutically acceptable salts. These compounds modulate the activity of c-Met and are therefore expected to be useful in the prevention and treatment of c-Met related disorders such as cancer.

Description

COMPOUNDS OF TRIAZOLOTRIAZINA AND ITS USES BACKGROUND OF THE INVENTION The following is offered only as a basic information and it is not admitted that it is prior art to the present invention. Protein kinases (PK) are enzymes that catalyze the phosphorylation of the hydroxy groups of the tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering: cell growth, differentiation and proliferation, that is, virtually all aspects of cell life depend in one way or another on PK activity. Moreover, abnormal PK activity has been linked to host disorders, ranging from life-threatening diseases, such as psoriasis, to extremely virulent diseases such as glioblastoma (brain cancer). PKs can be broken down into two classes: protein tyrosine kinases (PTK) and serine-threonine kinases (STK). One of the aspects that stand out in the first place of the PTK activity is its involvement with the growth factor receptors. The growth factor receptors are cell surface proteins. When a growth factor ligand is attached, the growth factor receptors become the active form that interacts with proteins on the inner surface of the cell membrane. This leads to the phosphorylation of the receptor tyrosine residues and other proteins, and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules which, in turn, carry out numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic repercussions to the extracellular microenvironment, etc. For a more complete discussion, see Schlessinger and Ullrich, Neuron 9: 303-391 (1992), which is incorporated by reference, including the drawings, as if presented in full herein. Growth factor receptors with PTK activity are known as receptor tyrosine kinases (RTKs). They comprise a large family of transmembrane receptors with diverse biological activities. Currently, at least nineteen (19) different subfamilies of RTK have been identified. An example of these is the subfamily called the "HER" RTKs, which include the EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. These RTKs consist of a glycosylated ligand-binding extracellular domain, a transmembrane domain, and a cytoplasmic catalytic intracellular domain that can phosphorylate tyrosine residues in proteins. Another subfamily of RTK consists of the insulin receptor (Rl), the insulin-like growth factor I receptor (RFCI-I) and the insulin receptor-related receptor (RRI). The Rl and the RFCI-I interact with insulin, the FCI-I and the FCI-II to form a heterotetramer of two completely extracellular glycosylated subunits and two subunits that cross the cell membrane and that contain the tyrosine kinase domain. A third subfamily of the RTKs is cited as the platelet-derived growth factor receptor (RFCDP) group, which includes RFCDP, CSFIR, c-kit and c-fms. These receptors consist of extracellular glycosylated domains composed of a variable number of immunoglobulinoid loops and of an intracellular domain in which the tyrosine kinase domain is interrupted by unrelated amino acid sequences. Another group is the subfamily of the fetal liver kinase receptor ("flk"), which, due to its similarity to the RFCDP family, is sometimes included in the previous group. This group is thought to be composed of the receptor with inserted kinase domain / fetal liver kinase 1 (KDR / FLK-1, by its English name), flk-1 R, flk-4 and tyrosine kinase similar to fms (flt-1). Another member of the family of growth factor receptors is the subgroup of vascular endothelial growth factor receptor (VEGF). VEGF is a dimeric glycoprotein similar to FCDP but has different biological functions and focuses on cell specificity in vivo. In particular, it is now believed that the essential function of VEGF is in vasculogenesis and angiogenesis. One more member of the family of growth factor receptors with tyrosine kinase is the subgroup of the fibroblast growth factor receptor (FCF). This group consists of four receivers, RFCF1 to 4 and in seven ligands, FCF1 to 7. Although they have not yet been well defined, it seems that the receptors consist of a glycosylated extracellular domain containing a variable number of immunoglobulinoid loops and an intracellular domain in which the sequence of the Tyrosine kinase is interrupted by regions of unrelated amino acid sequences. Another member of the family of growth factor receptors with tyrosine kinase is MET, often referred to as c-Met. C-Met is also known as a hepatocyte growth factor receptor or scattered factor receptor. It is believed that c-Met plays a role in the growth of the primary tumor and in metastasis. A more complete list of the known RTK subfamilies is described in Plowman et al., DN & P, 7 (6): 334-339 (1994), which is incorporated by reference, including all drawings, as if presented completely in the present report. In addition to RTKs, there is also a family of fully intracellular PTKs called "non-receptor tyrosine kinases" or "cell tyrosine kinases." This last designation, abbreviated "CTK" by its name in English, will be used in this report. CTKs do not contain extracellular or transmembrane domains. Currently, more than 24 CTKs have been identified in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack). So far, the Src subfamily appears to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed explanation of the CTKs, see Bolen, Oncogene, 8: 2025-2031 (1993), which is incorporated by reference, including all the drawings, as if presented in full herein. The serine / threonine kinases, the STKs, as well as the CTKs, are predominantly intracellular, although there are a few receptor kinases of the STK type. STKs are the most common of cytosolic kinases; namely, kinases that perform their function in that part of the cytoplasm apart from the cytoplasmic organelles and the cytoskeleton. The cytosol is the region within the cell where the majority of the metabolic and biosynthetic activity of the cell is produced; p. In the cytosol, for example, proteins are synthesized in ribosomes. The RTK, CTK and STK have been involved in a host with pathological conditions that significantly include cancer. Other disease states that have been associated with PTK include, but are not limited to, psoriasis, liver cirrhosis, diabetes, angiogenesis, restenosis, eye diseases, rheumatoid arthritis and other inflammatory disorders, immune disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis, and various kidney disorders. Regarding cancer, two of the main hypotheses proposed to explain the excessive cell proliferation that drives tumor development refer to functions that are known to be regulated by PK. That is, it has been suggested that malignant cell growth is the result of an anomaly in the mechanisms that control cell division and / or differentiation. It has been demonstrated that the protein products of a series of protooncogenes are involved in the transduction pathways of the signals that regulate cell growth and differentiation. These protein products of proto-oncogenes include extracellular growth factors, transmembrane PTK receptors of growth factors (RTK), cytoplasmic PTK (CTK) and cytosolic STK, explained above. In view of the apparent relationship between cellular activities related to PK and the wide variety of human disorders, it is not surprising that a great effort has been made to try to identify ways to modulate PK activity. Some of these have involved biomimetic methods that use large modeled molecules over those involved in real cellular procedures [p. g., mutant ligands (U.S. Patent Application No. 4 966 849); Soluble receptors and antibodies (International Patent Application No. WO 94/10202, Kendall and Thomas, Proc. Nati Acad. Sci. 90: 10705-10709 (1994), Kim et al., Nature, 362: 841-844 ( 1993)); RNA ligands (Jelinek et al., Biochemistry, 33: 10450-56); Takano et al., Mol. Biol Cell 4: 358A (1993); Kinsella et al., Exp Cell Res., 199: 56-62 (1992); Wright et al., J. Cell Phys. 152: 448-57) and tyrosine kinase inhibitors (International patents WO 94/03427, WO 92/21660, WO 91/15495; WO 94/14808; U.S. patent No. 5 330 992; Mariani, ei al., Proc. Am. Assoc. Cancer Res., 35: 2268 (1994)]. In addition to the above, attempts have been made to identify small molecules that act as PK inhibitors. For example, bis-monocyclic, bicyclic and heterocyclic aryl compounds have been described as inhibitors of tyrosine kinases (PCT International Patent WO 92/20642), vinylene-azaindole derivatives (PCT International Patent WO 94/14808) and 1- cyclopropyl-4-pyridylquinolones (U.S. Patent No. 5 330 992). Styryl compounds (U.S. Patent No. 5 217 999), styryl-substituted pyridyl compounds (US patent no. 5,292,606), quinazoline derivatives (European patent application EP No. 0 566 266 A1), selenaindoles and selenides (PCT international patent WO 94/03427), tricyclic polyhydroxy compounds (PCT international patent WO 92/21660) and benzylphosphonic acid compounds (PCT international patent WO 91/15495).

COMPENDIUM OF THE INVENTION A family of new triazolotriazine compounds has been discovered which show a modulating capacity of c-Met and which have an effect of improvement against the disorders related to the abnormal activity of c-Met. C-Met is an attractive target from the clinical point of view, because: 1) c-Met has been implicated in the growth and metastasis of most types of cancer, 2) growth on the site secondary seems to be the limiting stage of velocity in metastasis and 3) during diagnosis, it is likely that the disease has already spread. C-Met is a receptor tyrosine kinase that is encoded by the Met proto-oncogene and that transduces the biological effects of the hepatocyte growth factor (FCH), which is also cited as a dispersed factor (FD). Jiang et al., Crit. Rev. Oncol. Hematol. 29: 209-248 (1999). C-Met and FCH are expressed in numerous tissues, although their expression is usually limited predominantly to cells of epithelial and mesenchymal origin, respectively. C-Met and FCH are necessary for the normal development of mammals and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation and the organization of three-dimensional tubular structures (e.g. , renal tubular cells, gland formation, etc.). It has been proposed that c-Met-dependent growth, invasion and spread of the tumor are mediated by these cellular actions. In addition to its effects on epithelial cells, it has been described that FCH / FD is an angiogenic factor and that c-Met signaling in endothelial cells can induce many of the cellular responses necessary for angiogenesis (proliferation, motility and invasion ).

It has been shown that the c-Met receptor is expressed in a series of human cancers. It has also been shown that c-Met and its ligand, FCH, are coexpressed in large numbers in various human cancers (particularly sarcomas). However, because the receptor and its ligand are normally expressed by different cell types, c-Met signaling is more commonly regulated by tumor-stromal interactions (tumor-host). In addition, the amplification of the c-Met gene, its mutation and its rearrangement have been observed in a subset of human cancers. Families with mutations in the reproductive cells that activate the c-Met kinase are prone to multiple tumors of the kidney as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and / or FCH / FD with the disease progression status of different types of cancer (including bronchopulmonary cancer, colon cancer, breast cancer, breast cancer). prostate, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer and bone cancer). In addition, overexpression of c-Met or FCH has been shown to correlate with a poor prognosis and outcome of the disease in several of the major human cancers including bronchopulmonary cancer, liver cancer, stomach cancer and cancer. breast cancer The strong correlation of c-Met with the biology of metastasis and invasion and the pathogenesis of the disease comprises a new mechanism for the treatment of metastatic cancers.

C-Met has been directly implicated in malignant neoplasms without satisfactory treatment such as pancreatic cancer, glioma and hepatocellular carcinoma. A c-Met kinase inhibitor could meet an unsatisfied medical need for the treatment of these malignancies. These observations suggest that inhibitors of c-Met kinase would be an effective treatment for primary tumors that are driven by c-Met but, more importantly, would prevent disseminated micrometastases from evolving into life-threatening metastases. Therefore, the utility of the c-Met inhibitor extends into the field of preventive and adjuvant treatment. In addition, some malignancies (eg, carcinoma of the renal papillae, some gastric and bronchopulmonary cancers) may be treated, which are believed to be driven by the mutation / genetic alteration of the c-Met and which depend on the c-Met. Met for your growth and survival. It is expected that these malignant neoplasms are sensitive to treatment. Several human cancers are the indication of the first target of c-Met antagonists. These malignancies include the major cancers such as breast cancer, bronchopulmonary cancer, colorectal cancer, prostate cancer; as well as pancreatic cancer, glioma, liver cancer, stomach cancer, cancers of the head and neck, melanoma, kidney cancer, leukemia, myeloma and sarcomas.

The compounds presented herein are exemplary only and will not be construed, in any way, as limiting the scope of this invention. In one embodiment, the invention relates to the compounds of the formula (I) or a pharmaceutically acceptable salt thereof. Formula (I) is represented as follows: (I) wherein n is 1, 2 or 3; R1 is selected from the group consisting of hydrogen, halogen, -OH, -OR6, NR6R7, -CN, -COR6, -COOR6, -CONR6R7, perfluoroalkyl, Ci-Ce alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl and heteroaryl , wherein the C 1 -C 7 alkyl, cycloalkyl, heterocycle, alkenylene, alkynyl, aryl or heteroaryl of R 1 may be optionally and independently substituted with one or more of halogen, -OH, -OR 6, -COR 7, -CONR 6 R 7, -COOR 8 , -NR6R7, -CN, -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7, -NR6R7, perfluoroalkyl, C? -C6 alkyl, cycloalkyl, heterocycle, alkenyl CrC6, C C6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 and -NR6S (O2) R7; R2 is selected from the group consisting of hydrogen, -OH, halogen, Ci-Cß alkyl, OR8, NR8R9, -CN, -COR8, -COOR9, -CONR8R9, and perfluoroalkyl, each R3 and R4 is independently selected from the group consisting of in hydrogen, halogen, -OH, -OR6, -NR6R7, -CN, -COR6, -COOR6, -CONR8R7, -NR6R7, perfluoroalkyl, C- | -C6 alkyl, aryl, cycloaryl, heterocycle and heteroaryl; R5 is an aromatic ring or a heteroaromatic ring, in which R5 is optionally substituted at one or more positions with halogen, -OH, -OR6, -COR7, -CONR6R7, -COOR6, -NR6R7, -CN, -NO2, -S (O) mR6, (m = 0.1 2), -S (O2) NR6R7, -NR6R7, perfluoroalkyl or CrC6 alkyl; each R6 and R7 is independently hydrogen, C-? -C6 alkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl; and R7 and R8 are each independently C 1 -C 2 alkyl or hydrogen; or a pharmaceutically acceptable salt thereof. In a particular aspect of this embodiment, R1 is aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted at one or more positions with halogen, -OH, -OR6, -COR7, -CONR6R7, -COOR6, -NR6R7, -CN, -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7S, -NR6R7, perfluoroalkyl, CrC6 alkyl, cycloalkyl, heterocycle , C6 alkenyl, C? -C6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 or -NR6S (O2) R7, wherein the aryl or the heteroaryl is a five or six membered ring. In another particular aspect of this modality, and in combination with any other non-inconsistent particular aspect, R2 is H or C? -C alkyl, preferably H. In another particular aspect of this embodiment, and in combination with any other non-inconsistent particular aspect, Rd is an aryl ring or 6-membered heteroaryl, wherein the 6-membered heteroaryl ring may be substituted within the ring with one or more members that are independently selected from the group consisting of S, O, and N. In another particular aspect of this embodiment , and in combination with any other non-inconsistent particular aspect, R5 is a 6-membered heteroaryl ring which is selected from pyranyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In another particular aspect of this embodiment, and in combination with any other non-inconsistent particular aspect, R5 is phenyl, which may be optionally substituted with hydroxy or halo. In another particular aspect of this embodiment, and in combination with any other non-inconsistent particular aspect, n is 1 or 2. In another embodiment, the invention provides the compounds of the formula la in which R1 is selected from the group it consists of hydrogen, halogen, -OH, -OR8, NR6R7, -CN, -COR6, -COOR6, -CONR6R7, perfluoroalkyl, Ci-Cß alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl and heteroaryl, wherein the alkyl Ci-Cβ, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl or heteroaryl of R 1 can be optionally and independently substituted with one or more of halogen, -OH, -OR 6, -COR 7, -CONR 6 R 7, -COOR 6, -NR 6 R 7, -CN , -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7, -NR6R7, perfluoroalkyl, C6 alkyl, cycloalkyl, heterocycle, C6 alkenyl, CrC6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 and -NR6S (O2) R7; R2 is selected from the group consisting of hydrogen, -OH, halogen, CrC6 alkyl, OR8, NR8R9, -CN, -COR9, -COOR9, -CONR8R9, and perfluoroalkyl, R5 is an aromatic ring or a heteroaromatic ring, wherein R5 may be optionally substituted at one or more positions by halogen, -OH, -OR6, -COR7, -CONR6R7, -COOR6, -NR6R7, -CN, -NO2, -S (O) mR6, (m = O, 1 or 2), -S (O2) NR6R7, -NR6R7, perfluoroalkyl or alkyl d-c6; each R6 and R7 is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl; and R8 and R8 are each independently dCS alkyl or hydrogen; or a pharmaceutically acceptable salt thereof. In a particular aspect of this embodiment, R1 is aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted at one or more positions with halogen, -OH, -OR6, -COR7, -CONR6R7, -COOR6, -NR6R7 -CN, -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7S, -NR6R7, perfluoroalkyl, C? -C6 alkyl, cycloalkyl, heterocycle, C? -C6 alkenyl , C? -C6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 or -NR6S (O2) R7, wherein the aryl or heteroaryl is a five or six membered ring. In another particular aspect of this embodiment, and in combination with any other non-inconsistent particular aspect, R2 is H or C-C-C alkyl, preferably H. In another particular aspect of this embodiment, and in combination with any other particular aspect, inconsistent, R5 is a 6-membered aryl or heteroaryl ring, wherein the 6-membered heteroaryl ring may be substituted within the ring with one or more members that are independently selected from the group consisting of S, O and N In another particular aspect of this embodiment, and in combination with any other non-inconsistent particular aspect, R5 is a 6-membered heteroaryl ring which is selected from pyranyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In another embodiment, the invention provides a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. Any of the compounds of the present invention may be present in a pharmaceutical composition with a pharmaceutically acceptable excipient. Another aspect of the present invention is a method of treating a disorder related to c-Met by administering a therapeutically effective amount of a compound of the present invention to an organism in need thereof. In particular, a disorder related to c-Met can be cancer, such as breast cancer, bronchopulmonary cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, stomach cancer , head cancer, neck cancer, melanoma, kidney cancer, leukemia, myeloma and sarcoma. Specific examples of the compounds of the formula I are described in table 2, attached to this report. It is also an aspect of this invention that a compound described in the present invention, or its salt, could be combined with other chemotherapeutic drugs for the treatment of the diseases and disorders explained above. For example, a compound or salt of this invention could be combined with alkylating agents such as fluorouracil (5-FU) alone or in combination in addition with leucovorin; or other alkylating agents such as, but not limited to, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, alkyl sulfonates, e.g. eg, busulfan (used in the treatment of chronic granulocytic leukemia), improsulphan and piposulfane; the aziridines, p. eg, benzodepa, carboquone, meturedepa and uredepa; the ethyleneimines and the methylmelamines, p. eg, altretamine, triethylene-ammine, triethylene-phosphoramide, triethylene-thiophosphoramide and trimethylolmelamine; and nitrogen mustards, p. eg, chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglonemia and non-Hodgkin's lymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, bronchopulmonary cancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustine and uramustine (used in the treatment of primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease and cancer of ovaries); and the triazines, p. eg, dacarbazine (used in the treatment of soft tissue sarcoma). Likewise, it would be expected that a compound or a salt of this invention would have a beneficial effect in combination with other antimetabolite chemotherapeutic agents such as, but not limited to, folic acid analogues, e.g. eg, methotrexate (used in the treatment of severe lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and purine analogues such as mercaptopurine and thioguanine which are used in the treatment of acute granulocytic leukemias, acute lymphocytes and chronic granulocytes. It would also be expected that a compound or a salt of this invention would be effective in combination with chemotherapeutic agents based on natural products such as, without being limited thereto, vinca alkaloids, e.g. eg, vinblastine (used in the treatment of breast cancer and testicular cancer), vincristine and vindesine; the epipodophyllotoxins, p. eg, etoposide and teniposide, which are useful in the treatment of testicular cancer and Kaposi's sarcoma; Antibiotic chemotherapeutic agents, p. eg, daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach cancer, cervical cancer, colon cancer, breast cancer, bladder cancer and pancreatic cancer), dactinomycin, temozolomide, plicamycin , bleomlcina (used in the treatment of skin cancer, cancer of the esophagus and cancer of the genitourinary system); and enzymatic chemotherapeutic agents such as L-asparaginase. In addition to the foregoing, one would expect a compound or salt of this invention to have a beneficial effect used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; the derivatives of methylhydrazine, p. e.g., procarbazine; Adrenocortical inhibitors, p. g., mitotane, aminoglutetlmide; and hormones and hormone antagonists such as adrenocorticosteroids (eg, prednisone), progestins (eg, hydroxyprogesterone caproate); estrogens (eg, diethylstilbesterol); antiestrogens such as tamoxifen; androgens, p. eg, testosterone propionate; and aromatase inhibitors (such as anastrozole). Finally, one might expect that the combination of a compound of this invention would be particularly effective in combination with mitoxantrone or paclitaxel for the treatment of cancers of solid tumors or leukemias such as, but not limited to, myelogenous leukemia. (not lymphocytic) acute. The above method can be performed in combination with a chemotherapeutic agent that is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, anti-allergen agents such as the inhibitors of MMP-2, MMP-9 and COX-2, and antiandrogens. Examples of useful COX-li inhibitors include Vioxx ™, CELEBREX ™ (alecoxib), valdecoxib, paracoxib, rofecoxib and Cox 189. Examples of useful inhibitors of matrix metalloproteinase are described in WO 96/33172 (published October 24, 1996), the international patent WO 96/27583 (published March 7, 1996), the European patent application No. 97304971.1 (filed July 8, 1997), the application of the European Patent No. 99308617.2 (filed October 29, 1999), International Patent WO 98/07697 (published February 26, 1998), International Patent WO 98/03516 (published January 29, 1998), the international patent WO 98/34918 (published August 13, 1998), the international patent WO 98/34915 (published August 13, 1998), the international patent 98/33768 (published August 6, 1998), the international patent WO 98/30566 (published July 16, 1998), the publication European Patent No. 606 046 (published July 13, 1994), European Patent Publication No. 931 788 (published July 28, 1999), International Patent WO 90/05719 (published July 31, 1999). May 1990), the international patent WO 99/52910 (published October 21, 1999), the international patent WO 99/52889 (published October 21, 1999), the international patent WO 99/29667 (published on June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), the application Patent No. 9912961.1 (filed June 3, 1999), the provisional application of the United States of America. No. 60/148464 (filed August 12, 1999), US Pat. No. 5,863,949 (issued January 26, 1999), US Pat. No. 5,861,510 (issued January 19, 1999) and European Patent Publication No. 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety by reference . The preferred MMP-2 and MMP-9 inhibitors are those that do not have or have little inhibitory activity against MMP-1. Most preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix metalloproteinases (ie, MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP). -7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed in the following list: 3 - [[4- (4-fluoro-phenoxy)] -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic; 3-oxo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid; 4- [4- (4-Cioro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R) 3- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3 - [[(4- (4-fluoro-phenoxy) -benzenesulfonyl) - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid; 3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid; 3-Oxo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxo-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and (R) 3- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamide; and salts and solvates of said pharmaceutically acceptable compounds. Other anti-angiogenic agents, including other COX-II inhibitors and other MMP inhibitors, may also be used in the present invention. The compounds of the formula (I) can also be used with inhibitors of signal transduction, such as agents that can inhibit the responses of the EGFR (epidermal growth factor receptor), such as antibodies against the CSFR, antibodies against the CSF. and molecules that are inhibitors of the EGFR; inhibitors of VEGF (vascular endothelial growth factor); and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, Herceptin ™ (Genentech, Inc. of San Francisco South, California, USA). The EGFR inhibitors are described in, for example, the international patent WO 95/19970 (published July 27, 1995), the international patent WO 98/14451 (published April 9, 1998), the international patent 98 / 02434 (published January 22, 1998) and U.S. Pat. No. 5 747498 (issued May 5, 1998) and such substances can be used in the present invention as described herein. EGFR inhibitors include, but are not limited to, monoclonal antibodies C225, Mab anti-EGFR 22 (ImClone Systems Incorporated of New York, New York), and ABX-EGF (Abgenix Inc. of Fremont, California), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey), and OLX-103 (Merck &Co. of Whitehouse Station, New Jersey), VRCTC -310 (Ventech Research) and FCE fusion toxin (Seragen Inc. of Hopkinton, Mass.). These and other agents that inhibit EGFR can be used in the present invention. Inhibitors of VEGF, for example, SU-5416, SU-11248, SU-6668 (Sugen Inc. of San Francisco del Sur, California, USA) can also be combined with compounds of formula (I). Inhibitors of VEGF are described, for example, in international patent WO 99/24440 (published May 20, 1999), the international PCT application PCT / IB99 / 00797 (filed May 3, 1999), the patent International Patent WO 95/21613 (published August 17, 1995), International Patent WO 99/61422 (published December 2, 1999), U.S. Pat. No. 5,834,504 (issued November 10, 1998), international patent WO 01/60814, international patent 98/50356 (published November 12, 1998), US Pat. No. 5,883,131 (issued March 16, 1999), US Pat. No. 5,886,020 (issued March 23, 1999), US Pat. No. 5,792,783 (issued August 11, 1998), the international patent WO 99/10349 (published March 4, 1999), the international patent WO 97/32856 (published September 12, 1997), the international patent WO 97/22596 (published June 26, 1997), the international patent WO 98/54093 (published December 3, 1998), the international patent WO 98/02438 (published January 22, 1998) , the international patent WO 99/16755 (published April 8, 1999) and the international patent WO 98/02437 (published January 22, 1999). 1998), all of which are incorporated herein by reference in their entirety. Other examples of specific inhibitors of VEGF useful in the present invention are IM862 (Cytran Inc. of Kirkland, Washington, USA); the monoclonal antibody against the FCEV of Genentech, Inc. of San Francisco del Sur, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be used in the present invention as described herein. Inhibitors of the ErbB2 receptor, such as GW-282974 (Glaxo Welcome foot) and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron) can also be combined with compounds of the formula (I), for example those mentioned in the international patent WO 98/02434 (published on January 22, 1998), the international patent WO 99/35146 (published on July 15, 1999), the International Patent WO 99/351322 (published July 15, 1999), International Patent WO 98/02437 (published January 22, 1998), International Patent WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Pat. No. 5587458 (issued December 24, 1996) and US Pat. No. 5877305 (issued March 2, 1999), which are incorporated herein in their entirety by reference. Inhibitors of the ErbB2 receptor useful in the present invention are also disclosed in U.S. Provisional Application No. 60 / 117,341, filed January 27, 1999, and in U.S. Provisional Application No. 60 / 117,346, filed on January 27, 1999, which are incorporated herein by reference in their entirety. The compounds and substances that inhibit the erbB2 receptor described in the aforementioned PCT applications, US patents, and US provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compounds of the invention. formulas (I) and (III) - (XII), according to the present invention. The compounds of formula (I) can also be used with other agents useful in the treatment of cancer including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 antibodies (antigen 4 of the cytotoxic lymphocytes) and other agents capable of blocking CTLA4; and antiproliferative agents such as other farnesyl transferase protein inhibitors, for example, farnesyl transferase protein inhibitors described in references cited in the "Background" section of U.S. Patent No. 6,258,824 B1. The CTLA4-specific antibodies that can be used in the present invention include those described in the provisional application of the US. No. 60 / 113,647 (filed on December 23, 1998), which is incorporated by reference in its entirety; however, other antibodies against CTLA4 can be used in the present invention. The above method can also be performed in combination with radiotherapy, in which the amount of a compound of the formula (I) in combination with the radiotherapy is effective for the treatment of the aforementioned diseases. The level of radiotherapy administered can be reduced to a sub-effective dose when administered in combination with the compounds of the preferred embodiments of the present invention. Techniques for administering radiotherapy are known in the art and these techniques can be used in the combination treatment described herein. The administration of the compounds of the invention in this combination treatment can be determined as described herein. Another aspect of the invention relates to the use of the compounds of the formula (I) in the preparation of a medicament, which is useful in the treatment of a disease mediated by an abnormal activity of the Met kinase.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to salts that retain efficacy biological and the properties of the free bases and which are obtained by reacting them with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid and the like. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or to physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. As used herein, a "physiologically acceptable carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not negate the biological activity and properties of the compound administered. An "excipient" refers to a substance added to a pharmaceutical composition to further facilitate the administration of a compound. Examples of excipients include, but not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, thinners, granulating agents, lubricants, binders, disintegrating agents and the like. "Alkyl" refers to a saturated aliphatic hydrocarbon that includes straight chain, branched chain or cyclic groups. Preferably, the alkyl group has from 1 to 20 carbon atoms (provided that it is a numerical range, eg "1 to 20", which is mentioned herein, means that the group, in this case the alkyl group , may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is an alkyl of average size having from 1 to 10 carbon atoms. More preferably, it is a lower alkyl having from 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR, -COOR ', OCOR', -CONRR ', - RNCOR', -NRR ', -CN, -NO2, -CZ3 , -SR ', -SOR', -SO2R \ -SO2OR ', -SO2NRR', thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl , lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. R and R 'are independently H, alkyl or aryl, wherein the alkyl or the aryl can be further substituted with halogen, (CH2) nN (R ") 2, (CH2) nCO2R", (CH2) nOR ", ( CH2) nOC (O) R ", alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, a heteroalicyclic, aryl, alkoxy, -OCZ3, aryloxy, C (O) NH2 or heteroaryl ring. R "is H, alkyl or aryl n is 0 to 3." Alkenyl "refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain, branched chain or cyclic groups they have at least one carbon-carbon double bond Preferably, the alkenyl group has from 2 to 20 carbon atoms (provided it is a numerical range, eg "2 to 20", which is mentioned herein). , means that the group, in this case the alkenyl group, can contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms.) More preferably, it is a medium-sized alkenyl having 2 to 10 carbon atoms, more preferably, it is a lower alkenyl having 2 to 6 carbon atoms The alkenyl group may be substituted or unsubstituted When substituted, each substituent group is preferably one or more Individually selected from halogen, -hydroxy, -CO R ', -COOR', OCOR ', -CONRR', - RNCOR ', -NRR', -CN, -NO2, -CZ3, -SR \ -SOR ', -SO2R', -SO2OR \ -SO2NRR ', thiocarbonyl , -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. Where R and R 'are defined herein. "Alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon triple bond. Preferably, the alkynyl group has from 2 to 20 carbon atoms (provided that it is a numerical range, eg "2 to 20", which is mentioned herein, means that the group, in this case the alkynyl group , may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is a medium-sized alkynyl having from 2 to 10 carbon atoms. More preferably, it is a lower alkynyl having from 2 to 6 carbon atoms. The alkynyl group may be substituted or unsubstituted. When it is replaced, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR1, -COOR1, OCOR ', -CONRR', - RNCOR *, -NRR ', -CN, -NO2, -CZ3, -SR' , -SOR ', -SO2R', -SO2OR ', -O2NRR', thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl , lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. Where R and R 'are defined herein. A "cycloalkyl" group or an "alicyclic" group refers to a group of fused or monocyclic ring all carbon atoms (namely, rings that share an adjacent pair of carbon atoms) in which more than one of the rings does not have a completely conjugated pi electron system. Examples of cycloalkyl groups are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. A cycloalkyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', -CONRR', - RNCOR ', -NRR', -CN, -NO2, - CZ3, -SR ', -SOR', -SO2R ', -SO2OR', -SO2NRR-thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, alkyl lower, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. Where R and R 'are defined herein. An "aryl" group refers to monocyclic or polycyclic groups of rings all fused of carbons (namely, rings that share adjacent pairs of carbon atoms) having a fully conjugated pi electron system. Examples of the aryl groups are, but are not limited to, phenyl, naphthaphenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, each substituted group is preferably one or more selected from halogen, hydroxy, alkoxy, aryloxy, -COR ', -COOR', OCOR ', -CONRR', - RNCOR ', -NRR', -CN, -NO2 , -CZ3, -OCZ3, -SR ', -SOR', -SO2R ', -SO2OR', -SO2NRR ', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl , silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. Where R and R 'are defined herein. As used herein, a "heteroaryl" group refers to a monocyclic or fused ring group (i.e., rings that share an adjacent pair of atoms) having one or more ring (s) in the ring (s). atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a fully conjugated pi electron system. Examples of heteroaryl groups, but not limited to, are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole. The heteroaryl group may be substituted or unsubstituted. When substituted, each substituted group is preferably one or more selected from halogen, -hydroxy, -COR1, -COOR ', OCOR', -CONRR ', - RNCOR', -NRR'CN, -NO2, -CZ3, - SR ', -SOR *, -SO2R', -SO2OR ', -SO2NRR', thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl, where Z is halogen. Where R and R 'are defined herein. A group of "heteroalicyclic rings" or a group "heteroalicyclic" refers to a monocyclic or fused ring group having in the ring (s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings may not have a fully conjugated pi electron system. The heteroalicyclic ring can be substituted or unsubstituted. The heteroalicyclic ring may contain one or more oxo groups. When it is replaced, each substituent group (s) is preferably one or more selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', -CONRR', - RNCOR *, -NRR *, -CN, -NO2 , -CZ3, -SR *, -SOR ', -SO2R', -SO2OR ', -SO2NRR', thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl and aryl. Where R and R 'are defined herein. Z refers to a halogen group selected from the group consisting of fluorine, chlorine, bromine and iodine. A "hydroxy" group refers to an -OH group. An "alkoxy" group refers to both an -O-alkyl group and an -O-cycloalkyl group, as defined herein. An "alkoxycarbonyl" refers to -C (O) -OR. An "aminocarbonyl" refers to a -C (O) -NRR '. An "aryloxycarbonyl" refers to a -C (O) -O-aryl. An "aryloxy" group refers to both an -O-aryl group and an -O-heteroaryl group, as defined herein. An "arylalkyl" group refers to -alkyl-aryl, wherein aryl and alkyl are defined herein. An "arylsulfonyl" group refers to -S? 2-aryl. An "alkylsulfonyl" group refers to -S-2-alkyl. A "heteroaryloxy" group refers to a heteroaryl-O- group with the heteroaryl as defined herein. A "heteroalicycloxy" group refers to a heteroalicyclic- or heteroalicyclic group as defined herein. A "carbonyl" group refers to a -C (= O) -R. An "aldehyde" group refers to a carbonyl group where R is hydrogen. A "thiocarbonyl" group refers to a group -C (= S) -R. A "trihalomethanecarbonyl" group refers to a group Z3C-C (O) - A "C-carboxyl" group refers to -C (O) O-R groups. An "O-carbonyl" group refers to a group R-C (O) O-. A "carboxylic acid" group refers to a C-carbonyl group in which R is hydrogen. A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine. A "trihalomethyl" group refers to a -CZ3 group. A "trihalomethanesulfonyl" group refers to a group Z3CS (O) 2-. A "trihalomethanesulfonamido" group refers to a group Z3CS (O) 2NR-. A "sulfhyl" group refers to a group -S (O) -R. A "sulfonyl" group refers to a -S (O) 2R group. An "S-sulfonamido" group refers to a -S (O) 2NRR 'group. An "N-sulfonamido" group refers to a group -NR-S (O) 2R. An "O-carbamyl" group refers to a group -OC (O) NRR '.

An "N-carbamyl" group refers to an ROC (O) NR- group. An "O-thiocarbamyl" group refers to a group -OC (S) NRR '. A "N-thiocarbamyl" group refers to an ROC (S) NR'- group. An "amino" group refers to an -NH2 or a -NRR group. A "C-amido" group refers to a group -C (O) NRR '. An "N-amido" group refers to a group R'C (O) NR-. A "nitro" group refers to a -NO2 group. A "cyano" group refers to a -CN group. A "silyl" group refers to a group -Si (R) 3. A "phosphonyl" group refers to a P (= O) (OR) 2 group. An "aminoalkyl" group refers to an -alkyl-NRR group. An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group. A "dialkylaminoalkyl" group refers to an -alkyl-N- (alkyl) 2 group. A "perfluoroalkyl" group refers to an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms. The definitions of RrRßß, A, B, X, Y, G, L, R, R 'and R "are defined herein The compounds having the same molecular formula but differing in nature or binding sequence of its atoms or the arrangement of its atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called " diastereomers "and those that are mirror images that do not overlap are called" enantiomers. "When a compound has an asymmetric center, for example, it is attached to four different groups, it is possible that they are a pair of enantiomers. characterized by the absolute configuration of its asymmetric center and is described by the sequential rules R and S of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light, and it is called dextrorotatory or levorotatory (that is, as isomers (+) or (-) respectively). A chiral compound can exist as a single enantiomer or as a mixture of enantiomers. A mixture that contains equal proportions of the enantiomers is called a "racemic mixture." The chemical formulas cited herein can show the phenomena of tautomerism and structural somería. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate the activity of c-Met and is not limited to any other tautomeric or structural isomeric form. This invention encompasses any tautomeric or structural isomer form and mixtures thereof which possess the ability to modulate the activity of c-Met and is not limited to any other tautomeric or structural isomer form. The compounds of this invention may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof. For example, if the substituents R3 and R4 in a compound of the formula (1) are different, then that carbon is an asymmetric center. Thus, the compound of the formula (I) can exist as a stereoisomer (R) or (S). Unless otherwise indicated, the description or the name of a particular compound in the specification and the claims is intended to include both the individual enantiomers and the mixtures, racemic or otherwise, thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the explanation in Chapter 4 of Advanced organic chemistry, 4th edition, J. March, Jonh Wiley and Sons, New York, 1992). Thus, this invention also encompasses any stereoisomeric form, its corresponding enantiomers [isomers D and L or (+) and (-)] and their diastereomers, and their mixtures, which possess the ability to modulate the activity of c-Met and which it is not limited to any other stereoisomeric form. The compounds of the formula (I) or (la) can show the phenomena of tautomerism and structural isomerism. This invention encompasses any tautomeric or structural isomer form and mixtures thereof which possess the ability to modulate the activity of c-Met and is not limited to any other tautomeric or structural isomer form. It is contemplated that the compounds of formulas (I) or (la) would be metabolized by enzymes in the body of organisms such as a human being to generate a metabolite that can modulate c-Met activity. Such metabolites are within the scope of the present invention. The term "method" refers to the ways, means, techniques and procedures to carry out a certain task included, but not limited to, the ways, means, techniques and procedures both known, or easily developed from ways, means, techniques and procedures known, by experts in the chemical, pharmaceutical, biological, biochemical and medical techniques. As used herein, the term "modulation" or "modular" refers to the alteration of the catalytic activity of c-Met. In particular, "modular" refers to the activation of the catalytic activity of c-Met, preferably the activation or inhibition of the catalytic activity of c-Met, depending on the concentration of the compound or of the salt to which it is exposed c-Met or, more preferably, inhibition of the catalytic activity of c-Met. The term "contacting" as used herein refers to linking a compound of this invention and c-Met in such a way that the compound can affect the catalytic activity of c-Met, either directly, namely, when interacting with the same c-Met, or indirectly, namely, by interacting with another molecule on which the catalytic activity of c-Met depends. This "contacting" can be carried out in vitro, namely in a test tube, a Petri dish or the like. In a test tube, contact may involve only one compound and c-Met or may involve whole cells. The cells can also be maintained or cultured in cell culture plates and brought into contact with a compound in that medium. In this context, the ability of a particular compound to affect a c-Met-related disorder, namely, the IC 50 of the compound, defined below, can be determined before attempting to use the compounds in vivo with more complex living organisms. For cells outside the organism, there are numerous methods, and are well known to those skilled in the art, for contacting c-Met with the compounds that include, but are not limited to, direct cell microinjection and numerous techniques of transmembrane transporters. «//? "vitro" refers to procedures performed in an artificial environment such as, but not limited to, p. eg, in a test tube or culture medium. The skilled person will understand that, for example, the isolated c-Met can be contacted with a modulator in an in vitro medium. Alternatively, an isolated cell may be contacted with a modulator in an in vitro medium. As used herein, "in vivo" refers to procedures performed within a living organism such as, but not limited to, a mouse, rat, rabbit, ungulate, bovine, equine, porcine, canine, feline, primate or human. As used herein, "c-Met related disorder" refers to a condition characterized by inappropriate activity, namely, a hypoactivity or, more commonly,, a hyperactivity, of the catalytic activity of c-Met. A "c-Met related disorder" also refers to a state in which there may be a mutation in the gene that produces c-Met which, in turn, produces a c-Met that has increased or decreased activity catalytic of c-Met. Inappropriate catalytic activity can arise as a result of: 1) the expression of c-Met in cells that do not normally express c-Met, 2) an increase in c-Met expression that leads to proliferation, differentiation and / or unwanted cell growth or 3) a decrease in c-Met expression leading to undesired reductions in cell proliferation, differentiation and / or growth. The hyperactivity of a c-Met refers to the amplification of the gene encoding a c-Met or to the production of a level of c-Met activity that can be correlated with a disorder of cellular proliferation, differentiation and / or growth ( that is, as the amount of c-Met increases, the severity of one or more of the symptoms of the cellular disorder increases). Hypoactivity is, of course, the opposite, in which the severity of one or more symptoms of a cell disorder increases as the level of c-Met activity decreases. As used herein, the terms "prevent", "prevent" and "prevent" refer to a method to prevent an organism from acquiring a c-Met-related disorder in the first place. As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a cellular disorder mediated by c-Met and / or its accompanying symptoms. In relation to cancer in particular, these terms simply mean that the life expectancy of an individual affected with a cancer will increase or that one or more of the symptoms of the disease will be reduced. The term "organism" refers to any living entity composed of at least one cell. A living organism can be as simple as, say, a single eukaryotic cell or as complex as a mammal. In a preferred aspect, the organism is a mammal. In a particularly preferred aspect, the mammal is a human being. The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered that will alleviate to some extent one or more of the symptoms of the disorder being treated. Referring to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of 1) reducing the size of the tumor, 2) inhibiting (ie, retarding to some extent, preferably stopping) the tumor metastasis, ) inhibiting to a certain extent (ie, retarding to some extent, preferably stopping) the tumor growth and / or 4) alleviating to some extent (or, preferably, eliminating) one or more of the symptoms associated with the cancer. The term "monitor" refers to observing or detecting the effect of contacting a compound with a cell expressing a c-Met. The observed or detected effect may be a change in the cell phenotype, in the catalytic activity of c-Met or a change in the interaction of c-Met with a natural binding partner. Techniques for observing or detecting such effects are well known in the art. For example, the catalytic activity of c-Met can be observed by determining the rate or amount of phosphorylation of a target molecule. "Cell phenotype" refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples of a cellular phenotype are, but are not limited to, cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis and nutrient uptake and its use. Such phenotypic characteristics are measurable by techniques well known in the art. A "natural binding partner" refers to a polypeptide that binds to a c-Met in a cell. Natural binding partners may be important for propagating a signal in a signal transduction procedure mediated by c-Met. A change in the interaction of the natural binding partner with the c-Met may itself manifest as an increase or decrease in the concentration of the c-Met / associated natural binding complex and, consequently, in an observable change in the ability of c-Met to mediate signal transduction. As used herein, "administering" or "administration" refers to the release of a compound or a salt of the present invention or a pharmaceutical composition containing a compound or a salt of this invention to an organism. for the purpose of preventing or treating a disorder related to c-Met. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. A "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a compound. Examples of the excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. "Pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of the original compound. Said salts include: 1) Salt by addition of acid which is obtained by reacting the free base of the original compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, acid salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L) -malic acid; or 2) salts formed when an acidic proton present in the original compound is replaced with a metal ion, e.g. eg, an alkali metal ion, an alkaline earth ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. The compounds of the formula (I) can also act as prodrugs. A "prodrug" refers to an agent that becomes the original drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the original drug. They may, for example, be bioavailable by oral administration while the original drug is not. The prodrug may also have an improved solubility in the pharmaceutical compositions against the original drug. An example of a prodrug would be, but not limited to, a compound of the present invention that is administered as an ester (the "prodrug"), carbamate or urea.

Indications To implement the present invention, no precise understanding of the mechanism is required by which the compounds of the invention, in particular, the compounds generated in vivo from the compounds of the invention, inhibit c-Met. , although, by the present, it is not under any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of c-Met. The compounds described herein may, therefore, have utility as in vitro assays for such proteins as well as exhibit therapeutic effects in vivo by interaction with such proteins. In another aspect, this invention relates to a method for treating or preventing a disorder related to c-Met by administering a therapeutically effective amount of a compound of this invention, or a salt thereof, to an organism. It is also an aspect of this invention that a pharmaceutical composition containing a compound of this invention, or a salt thereof, is administered to an organism for the purpose of preventing or treating a disorder related to c-Met. Therefore, this invention relates to compounds that modulate signal transduction of PKs by affecting the enzymatic activity of c-Met, and therefore interfering with the signal transduced by c-Met. More particularly, the present invention relates to compounds that modulate signal transduction pathways mediated by c-Met as a therapeutic method to treat the many malignancies described herein. Another aspect of this invention is a method for identifying a chemical compound that modulates the catalytic activity of c-Met. The method involves contacting the cells expressing the c-Met with a compound of this invention (or its salt) and monitoring the cells to detect any effect that the compound has on them. Alternatively, the method may involve contacting the same c-Met protein (ie, not in a cell) with a chemical compound of the preferred embodiments of the present invention and monitoring the protein to detect any effect that the compound has. about her. The effect may be observable, either at a glance or through the use of instrumentation. The effect may be, for example, a change or absence in a cellular phenotype. The change or absence of change in a monitored cell phenotype, for example, can be, but is not limited to, a change or absence of change in the catalytic activity of c-Met in the cells or a change or an absence of change in the interaction of c-Met with a natural binding partner.

PHARMACEUTICAL COMPOSITIONS AND USE A compound of the present invention or a physiologically acceptable salt thereof can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the aforementioned substances are mixed with the carriers or excipients (s). ) adequate. Techniques for the formulation and administration of drugs can be found in Remington's pharmacological sciences, Mack Publishing Co., Easton, PA, latest edition.

Routes of administration Suitable routes of administration may include, but are not limited to, oral, intraoral, rectal, transmucosal or intestinal administration or intramuscular, epicutaneous, parenteral, subcutaneous, transdermal injection, Intramedullary, intrathecal, direct intraventricular, intravenous, intravitral, intraperitoneal, intranasal, intramuscular, intradural, intrarespiratory, nasal inhalation or intraocular injection. The preferred routes of administration are oral and parenteral. Alternatively, the compound can be administered in a local rather than systemic manner, for example, by injecting the compound directly into a solid tumor, often in a sustained or slow release formulation. In addition, the drug can be administered in a drug delivery system only on the target, for example, in a liposome coated with a tumor-specific antibody. The liposomes will be targeted and will be picked up selectively by the tumor.

Composition / Formulation The compositions of the present invention can be manufactured by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, lyophilizing or spray-drying processes. The pharmaceutical compositions to be used in the methods of the present invention may be prepared by any method of pharmacotechnology, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In particular, pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the preparation of the active compounds in preparations that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration. The dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal sprays or oral, aerosol and similar. For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as buffers with or without a low concentration of surfactant or cosolvent, or a physiological saline buffer.

For transmucosal administration, penetrating fluids suitable for the barrier to be penetrated are used in the formulation. Such penetrating fluids are generally known in the art. For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Said vehicles allow the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, viscous suspensions, suspensions and the like, for a patient to take by mouth. Pharmaceutical preparations for oral use can be manufactured using a solid excipient, optionally grinding the resulting mixture and processing the granule mixture, after adding other suitable adjuvants if desired, to obtain tablets or dragee cores. Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol, cellulose preparations such as, for example, corn starch, wheat starch, rice starch and potato starch and other substances such as gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as interlinked polyvinyl pyrrolidone, agar or alginic acid. You can also use a salt like sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain: gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and organic solvents or mixtures of suitable solvents. Colorants or pigments may be added to the tablets or dragee coatings for identification or to characterize different dose associations of active compounds. Pharmaceutical compositions that can be used buccally include soft-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Soft-fit capsules may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium- or long-chain mono-, di- or triglycerides. Stabilizers can be added in these formulations, too. For administration by inhalation, the compounds to be used according to the present invention are conveniently administered in the form of a spray aerosol using a pressurized pack or a nebulizer and a suitable propellant, e.g. eg, not limited to, dichlorodifluoromethane, trichloroforomethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve for dispensing a measured quantity. Capsules and gelatin cartridges, for example, for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can also be formulated for parenteral administration, e.g. eg, by rapid intravenous injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of a water-soluble form such as, but not limited to, a salt, of the active compound. Still further, suspensions of the active compounds can be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or substances such as liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers and / or suitable agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas using, for example, conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds can also be formulated as slow-release drug preparations. Such long acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention can be formulated for this route of administration with suitable polymeric or hydrophobic substances (for example, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a soluble derivative in small amount such as , but without being limited to it, a soluble salt in small quantity. A non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-soluble organic polymer and an aqueous phase such as the VPD cosolvent system. VPD is a 3% w / v benzyl alcohol solution, apolar polysorbate 80 80% w / v surfactant and 65% w / v polyethylene glycol 300, completing up to the final volume with absolute ethanol. The VPD cosolvent system (VPD: D5W) consists of VPD diluted 1: 1 with a 5% dextrose solution in water. This co-solvent system dissolves hydrophobic compounds well and produces low toxicity by itself after systemic administration. Naturally, the proportions of such a cosolvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the joint solvent components can be varied: for example, other apolar surfactants of low toxicity can be used in place of the polysorbate 80, the size of the polyethylene glycol fraction can be varied, other biocompatible polymers can replace the polyethylene glycol, p. eg, polyvinylpyrrolidone, and other sugars or polysaccharides can replace dextrose. Alternatively, other delivery systems for the hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of dispensing vehicles or excipients of hydrophobic drugs. In addition, certain organic solvents such as dimethyl sulfoxide can also be used, although often at the expense of greater toxicity. Additionally, the compounds can be released using a prolonged release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various prolonged release materials have been established and are well known to those skilled in the art. Prolonged-release capsules may, depending on their chemical nature, release the compounds for a few weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions herein may also comprise suitable solid or gel phase vehicles or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Many of the modulator compounds of the PKs of the invention can be provided as physiologically acceptable salts in which the claimed compound can form the negatively or positively charged species. Examples of salts in which the compound forms the positively charged moiety include, but not limited to, quaternary ammonium (defined elsewhere herein), salts such as hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, succinate, malate, acetate and methylsulfonate (CH3SO3), in which the atom Nitrogen of the quaternary ammonium group is a nitrogen of the selected compound of this invention, which has been reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, but are not limited to, the sodium, potassium, calcium and magnesium salts formed by reacting a carboxylic acid group in the compound with a base. adequate [p. eg, sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) 2), etc.].Dosage Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients appear in an amount sufficient to achieve the intended purpose, namely, the modulation of the activity of the PK's or the treatment or prevention of a disorder related to PK. More specifically, a "therapeutically effective amount" means an amount of a compound effective to prevent, alleviate or ameliorate the symptoms of the disease or to prolong the survival of the subject being treated. The determination of a therapeutically effective amount is sufficiently within the ability of those skilled in the art, especially in light of the detailed description provided herein. For any compound used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from the analyzes in the cell cultures. Then, the dose can be formulated for use in animal models so that a concentration range in circulation including the IC50 that was determined in the cell culture (i.e., the concentration of the test compound reaching an inhibition) is reached. half-maximal activity of c-Met). Then, such information can be used to more accurately determine the doses useful in humans. The toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals, e.g. eg, in determining the IC5o and LD50 (discussed elsewhere herein) of a given compound. The data obtained from these cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The posology may vary depending on the pharmaceutical form used and the route of administration used. Each doctor can choose the exact dosage form, the route of administration and the dosage depending on the patient's condition. (See, eg, Fingí, et al., 1975, in The Pharmacological Basis of Therapeutics, Ch.1, p.1). The dosage amount and range can be individually adjusted to provide levels in the plasma of the active species that are sufficient to maintain the modulatory effects of the kinases. These levels in the plasma are cited as minimum effective concentrations (CEM). The CEM will vary for each compound but can be estimated from the in vitro data, p. eg, the concentration necessary to achieve a 50% to 90% inhibition of a kinase can be determined with the assays described herein. The posology needed to achieve CEM will depend on the individual characteristics and the route of administration. HPLC analysis or bioassays can be used to determine concentrations in plasma. The dosing intervals can also be determined using the CEM value. The compounds should be administered using a dosing regimen that maintains plasma levels above the EMC for 10% to 90% of the time, preferably between 30% and 90% % and, most preferably, between 50% and 90%. In cases of local administration or selective absorption, the effective local concentration of the drug should not be related to the concentration in the plasma and other methods known in the art can be used to determine the correct dosage amount and range. The amount of a composition administered will, of course, depend on the subject being treated, the severity of the disease, the mode of administration, the judgment of the prescribing physician, etc.

Conditioning The compositions can, if desired, be presented in a container or in a dispensing device, as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package can, for example, comprise a sheet of metal or plastic, such as a blister pack (blister). The package or dispensing device may be accompanied by instructions for administration. The container or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency that regulates the manufacture, use or sale of the drugs, and such notice is a reflection of the approval by the agency. the form of the compositions or of the human or veterinary administration. Such notice, for example, may be from the labeling approved by the US Food and Drug Administration. for prescription medications or a prospectus of the approved product. The compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container and labeled for the treatment of a designated disease. The appropriate diseases indicated in the data sheet may include the treatment of a tumor, the inhibition of angiogenesis, the treatment of fibrosis, diabetes and the like.

EXAMPLES Scheme 1. General scheme of the synthesis Hydrazide of (4-hydroxy-phenyl) acetic acid 21.0 g (654 mmol) of pure anhydrous hydrazine were added to a solution of 27.18 g (163.5 mmol) of methyl p-hydroxyphenylacetate in MeOH (100 ml) and the mixture was heated from 50 ° C to 50 ° C. 55 ° C and stirred at this temperature for 90 min. (Water bath). It was cooled, stirred for a further 1 hour, the precipitate was collected by filtration, compressed in the frit, washed with MeOH (3 x 10 ml) and dried under high vacuum. A second fraction was obtained by cooling the supernatants at -15 ° C overnight and filtering the formed precipitate. Combined yield: 25.13g of a crystalline white solid (92.5%). 1 H-NMR (DMSO-d 6, 400 MHz): 9,182 (br s, 1 H), 9,108 (br s, 1 H), 7,035 (app d, J = 8.6 Hz, 2 H), 6,666 (app d , J = 8.6 Hz, 2H), 4.176 (br d, J = 3.1 Hz, 2H), 3.207 (s, 2H); 13CH-NMR (DMSO-d6, 100 MHz): 170.66, 156.45, 130.47 (2C), 127.00, 115.63 (2C), 40.48. 4- (5-Amino- [1, 3,4] oxadiazol-2-yl-metll) -phenol 6.069 g (57.2 mmol) of solid BrCN was added in one portion to an ice-cooled viscous suspension of 8.642 g (52.0 mmol) of (4-hydroxy-phenyl) -acetic acid hydrazide and 6.510 g (65%). mmol) of KHCO3 in MeOH (100 mL). The mixture was stirred at 0 ° C to 5 ° C for 1 hour, the ice bath was allowed to melt and stirred at room temperature overnight (18 hours). The reaction mixture was diluted with water (100 ml), stirred for 1 hour, the precipitate was collected by filtration, washed with water and dried under high vacuum. A second fraction was precipitated after concentrating and cooling the supernatants. Combined yield: 9.018 g (90.5%) of a white crystalline solid. 1 H-NMR (DMSO-d 6, 400 MHz): 9.334 (s, 1H), 7.040 (app d, J = 9.0 Hz, 2H), 6.839 (br s, 2H), 6.706 (app d, J = 8.6 Hz, 2H), 3.879 (s, 2H) 4- (4,5-Diamino-4H- [1, 2,4] triazol-3-yl-methyl) -phenol A mixture of 4.902 g (25.64 mmol) of 4- (5-amino- [1, 3,4] oxadiazol-2-yl-methyl) -phenol, 40 ml of water and 13 ml of anhydrous hydrazine were maintained at Reflux in an oil bath (190 ° C) for 18 hours. The mixture was cooled, allowed to crystallize at room temperature for 2 hours, then placed in a freezer (-20 ° C) overnight (16 hours). The precipitated product was collected by filtration, washed with ice-cold MeOH (-15 ° C) and dried under high vacuum. The crude product was retro-crystallized from water (80 ml, refluxed at + 4 ° C overnight). It was filtered, washed with water cooled on ice and dried under high vacuum. Yield = 1.658 g (31.5%) of a white crystalline solid. MS + cAPCI: 206 (M + 1); MS - cAPCI: 204.202 (M-1); 1 H-NMR (DMSO-de, 400 MHz): 9.234 (br s, 1 H), 7.034 (app d, J = 8.6 Hz, 2H), 6.664 (app d, J = 8.6 Hz, 2H) , 5,453 (brs, 2H), 5,338 (s, 2H), 3,772 (s, 2H) (4-Fluoro-phenyl) acetic acid hydrazide ml of pure anhydrous hydrazine was added to a viscous suspension of methyl (4-fluorophenyl) acetate (Acros Organics USA, Morris Plains, NJ, 25.66 g, 152.5 mmol) in MeOH (I20 ml) and the mixture it was heated at 60 ° C with a reflux condenser under nitrogen for 2 hours. It was cooled to room temperature and evaporated to dryness (from room temperature to 60 ° C, from 100 Torr to 7 Torr). The solid residue was retro-crystallized from 1-propanol, 100 ml (refluxing at room temperature, overnight). The crystallized product was collected by filtration, washed with 1-propanol and dried under high vacuum. [1st fraction] Upon evaporation of the supernatants until drying with high vacuum, the solid residue obtained was dried under high vacuum overnight. Then, the rest was retrocrystallized from benzene, (refluxing at room temperature, overnight). The precipitated product was collected by filtration, washed with a mixture of benzene-hexane (1: 1), and then with hexane. It was dried with high vacuum. [2nd fraction] Combined yield: 24,855 g (97%) of crystalline white flakes. 1 H NMR (DMSO-d 8, 400 MHz): 9,194 (br s, 1 H), 7.272 (m, 2H), 7.107 (m, 2H), 4.202 (br d, J = 4.3 Hz, 2H) , 3,329 (s, 2H); 19 F-NMR (DMSO-d 6, 376.5 MHz): -116.96 (m, 1 F). - (4-Fluoro-benzyl) - [1,4] oxadiazol-2-yl-amine 13.37 g (130 mmol, 1.1 eq.) Of solid BrCN were added in one portion to an ice-cooled viscous suspension of (4-fluoro-phenyl) -acetic acid hydrazide (19.85 g, 118 mmol ) and 14.77 g (147.5 mmol, 1.25 eq.) of KHCO3 in MeOH (150 ml) in a 1 L flask (followed by 10 ml of MeOH to wash the funnel). The mixture was stirred in an ice bath at 0 ° C to 5 ° C for 2 hours in a bottle with the cap loose, then the bath was gradually allowed to melt and then the mixture was stirred at 5 ° C to 20 ° C. C for one night (17 hours). The reaction mixture was diluted with water (200 ml), stirred for 1 hour in an open bottle and then cooled in an ice bath. The precipitate was collected by filtration, washed with water and dried under high vacuum. [1st fraction] The supernatants were concentrated in a hot water bath in a rotavapor vessel (40 ° C) to remove all the MeOH and some water. The viscous suspension obtained was cooled to room temperature, the precipitate was collected by filtration, washed with water and dried under high vacuum. [2nd fraction] Combined yield: 20.836 g (91.5%) of a crystalline white solid. 1 H-NMR (DMSO-d 6, 400 MHz): 7.289 (m, 2H), 7.148 (m, 2H), 6.873 (br s, 2H), 4.014 (s, 2H); 19 F-NMR (DMSO-d 6, 376.5 MHz): -116.01 (m, 1 F). - (4-Fluoro-benzyl) - [1, 2,4] triazole-3,4-diamine A mixture of 10.182 g (52.7 mmol) of 5- (4-fluoro-benzyl) - [1, 3,4] oxadiazol-2-yl-amine, 80 ml of water and 20 ml of anhydrous hydrazine was maintained at reflux in nitrogen in a bath with oil (190 to 200 ° C) for 23 hours. The mixture was cooled and allowed to crystallize at room temperature under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 ml) and dried under high vacuum. The crude product was retro-crystallized from 60 ml of water (reflux under nitrogen, which at + 4 ° C in a refrigerator overnight). The product was filtered, washed with water cooled on ice and dried under high vacuum. Yield = 6.210 g (56.5%) of large white crystals. 1 H-NMR (DMSO-de, 400 MHz): 7.267 (app d, J = 8.6 Hz, J = 5.5 Hz, 2H), 7.097 (app t, J = 9.0 Hz, 2H), 5,509 (br s, 2H), 5,339 (s, 2H), 3,884 (s, 2H); 19 F-NMR (DMSO-de, 376.5 MHz): -117.14 (m, 1 F).

Example 1 4-r6- (4-Fluoro-phenol) -p .2.41-triazole-4,3-bip, 2,41-triazin-3-yl-methyl] -phenol General procedure A: a mixture of (4-fluoro-phenyl) -oxo-acetaldehyde (72 mg, 0.4 mmol) and 4- (4,5-diamino-4H- [1,4,4] triazole-3- il-methyl) -phenol (82 mg, 0.4 mmol) in acetic acid was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (CH2Cl2: EtOAc = 2: 8, 3: 7) to obtain two isomers 4- [7- (4-fluoro-phenyl) - [ 1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl] -phenol and the desired product 4- [6- (4-fluoro-phenyl) - [1 , 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl] -phenol (example 1). 4- [7- (4-Fluoro-phenyl) - [1,2,4] triazolo [4,3-b] [1,2,4] triazin-3-yl-methyl] -phenol : yellow solid (67 mg, 52%). 1 H-NMR (400 MHz, DMSO-d 6) d 9.39 (s, 1 H), 9.27 (s, 1 H), 8.37 (m, 2 H), 7.46 (m, 2 H), 7 , 11 (d, J = 8.2 Hz, 2H), 6.66 (d, J = 8.6 Hz, 2H), 4.38 (s, 2H). MS m / z 322 [M + 1]. Example 1: light yellow solid (23 mg, 18%). 1 H-NMR (400 MHz, DMSO-de) d 9.30 (s, 1H), 9.27 (s, 1 H), 8.22 (m, 2H), 7.47 (m, 2H), 7 , 17 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 4.41 (s, 2H). MS (m / z) 322 [M + 1].

Example 2 4- (6-thiophen-2-yl-f1.2.41 triazoloí4.3-bpi .2.41triazin-3-metiP-phenol The general procedure A was followed by the reaction of oxo-thiophen-2-yl-acetaldehyde and 4- (4,5-diamino-4 H- [1,4] triazol-3-yl-methyl) -phenol to provide 4- (7-thiophen-2-yl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl) -phenol and the desired product 4- (6-thiophen-2-yl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl) -phenol (example 2). 4- (7-thiophene-2-yl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methy1) -phenol: yellow solid (39 %). 1 H-NMR (400 MHz, DMSO-de) d 9.33 (s, 1 H), 9.26 (s, 1 H), 8.31 (d, 1 H), 8.02 (d, 1 H ), 7.33 (m, 1H), 7.10 (d, 2H), 6.66 (d, 2H), 4.34 (s, 2H). MS m / z 310 [M + 1]. Example 2: light yellow solid (7%). 1 H-NMR (400 MHz, DMSO-de) d 9.31 (s, 1 H), 9.26 (s, 1 H), 8.23 (d, 1 H), 7.93 (d, 1) H), 7.30 (m, 1 H), 7.16 (d, 2H), 6.66 (d, 2H), 4.34 (s, 2H). MS m / z 310 [M + 1].

Example 3. 4- (6-Phenyl-p .2.41-triazole-4.3-blH, 2.41-triazine-3-yl-methyl) -phenol The general procedure A was followed by the reaction of oxo-phenyl-acetaldehyde and 4- (4,5-diamino-4H- [1, 2,4] triazol-3-yl-methyl) -phenol to provide 4- ( 7-phenyl- [1,2,4] triazolo [4,3-b] [1,2,4] triazin-3-yl-methyl) -phenol and the desired product 4- (6-phenyl- [ 1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl] -phenoI (example 3). 4- (7-phenyl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methylene] phenol: yellow solid (63%) 1 H-NMR (400 MHz, DMSO-d 6) d 9.40 (s, 1 H), 9.27 (s, 1 H), 8.29 (m, 2 H), 7.62 (m, 3 H) ), 7.11 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.6 Hz, 2H), 4.38 (s, 2H) MS m / z 304 [M +1] Example 3: light yellow solid (14%) 1 H-NMR (400 MHz, DMSO-de) d 9.31 (s, 1H), 9.26 (s, 1 H), 8.15 (m, 2H), 7.62 (m, 3H), 7.17 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H) MS m / z 304 [M + 1].

Example 4. 3- (4-fluoro-benzin-6-phenyl-f1,2.41-triazole-4-bip, 2.41-triazine The general procedure A was followed by the reaction of oxo-phenyl-acetaldehyde and 5- (4-fluoro-benzyl) - [1,2,4] triazole-3,4-d-amines to provide the 3- (4 -fluoro-benzyl) -7-phenyl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazine and the desired product 3- (4-fluoro-benzyl) -6-phenyl - [1, 2,4) triazolo [4,3-b] [1, 2,4] triazine (example 4). 3- (4-Fluoro-benzyl) -7-phenyl- (1,2,4] triazolo [4,3-b] [1, 2,4] triazine: yellow solid (68%). 1 H-NMR ( 400 MHz, DMSO-d6) d 9.41 (s, 1H), 8.32 (m, 2H), 7.63 (m, 3H), 7.37 (m, 2H), 7.13 (m, 2H), 4.52 (s, 2H) MS m / z 306 [M + 1] Example 4: light yellow solid (20%). 1 H-NMR (400 MHz, DMSO-de) d 9.33 ( s, 1 H), 8.15 (m, 2H), 7.62 (m, 3H), 7.42 (m, 2H), 7.14 (m, 2H), 4.56 (s, 2H) MS m / z 306 [M + 1].

Example 5. 3- (4-fluoro-benzin-6-thiophen-2-1-f1.2.41-triazole-4-bip .2.41-triazine The general procedure A was followed by the reaction of oxo-thiophen-2-yl-acetaldehyde and 5- (4-fluoro-benzyl) - [1,4] triazole-3,4-diamine to provide the - (4-fluoro-benzyl) -7-thiophen-2-yl- [1, 2,4] triazolo [4,3-b [1,2,4] triazine and 3- (4-fluoro-benzyl) -6-thiophen-2-yl- [1, 2,4] triazolo [4,3b] [1, 2,4] triazine (example 5). 3- (4-Fluoro-benzyl) -7-thiophen-2-yl- [1,2,4] triazolo [4,3-b] [1,2,4] triazo-na: yellow solid (76%). H-NMR (400 MHz, DMSO-de) d 9.34 (s, 1 H), 8.32 (d, 1 H), 8.02 (d, 1 H), 7.34 (m, 3 H) , 7.12 (m, 2H), 4.47 (s, 2H). MS m / z 310 [M + 1]. Example 5: yellow solid (9%). 1 H-NMR (400 MHz, DMSO-d8) d 9.33 (s, 1H), 8.24 (d, 1H), 7.93 (d, 1 H), 7.41 (m, 2H), 7.30 (m, 1 H), 7.13 (m, 2H), 4.48 (s, 2H). MS m / z 310 [M + 1].

Example 6. 6- (4-bromo-phenyl) -3- (4-fluoro-benzyl) -f1, 2,41-triazo-lor4.3-bip .2.41triazine The general procedure A was followed by the reaction of (4-bromo-phenyl) -oxo-acetaldehyde and 5- (4-fluoro-benzyl) - [1,2,4] triazole-3,4-diamine to provide the 7- (4-bromo-phenyl) -3- (4-fluoro-benzyl) - [1,2,4] triazolo [4,3-b] [1, 2,4] triazine and the 6- (4- bromo-phenyl) -3- (4-fluoro-benzyl) - [1,2,4) triazolo [4,3-b] [1, 2,4] triazine (example 5). 7- (4-Bromo-phenyl) -3- (4-fluoro-benzyl) - [1,2,4] triazolo [4,3-b] [1, 2,4] triazine: yellow solid (30%) . 1 H-NMR (400 MHz, DMSO-d 6) d 9.40 (s, 1 H), 8.25 (d, 2 H), 7.83 (d, 2 H), 7.36 (m, 2 H), 7, 15 (m, 2H), 4.52 (s, 2H). MS m / z 384 [M + 1]. Example 6: light yellow solid (61%). 1 H-NMR (400 MHz, DMSO-de) d 9.32 (s, 1 H), 8.10 (d, 2H), 7.83 (d, 2H), 7.42 (m, 2H), 7.16 (m, 2H), 4.55 (s, 2H). MS m / z 384 [M + 1].

Example 7. 4-Í1, 2.41Triazolor4,3-bip, 2,4] triazin-3-yl-methyl-phenol X The general procedure A was followed by the reaction of ethanediol and 4- (4,5-diamino-4H - [1, 2,4) triazol-3-yl-methyl) -phenol to provide 4- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl -methanol-phenol (example 7). 1 H-NMR (400 MHz, DMSO-de) d 9.25 (s, 1 H), 8.68 (d, 2H), 7.16 (m, 2H), 6.65 (m, 2H), 4.35 (s, 2H). MS m / z 228 [M + 1].

Example 8. 4- (6.7-dimethyl-p, 2,41-triazole-4-bip, 2,41-triazin-3-yl-methyl-Henol) The general procedure A was followed by the reaction of butane-2,3-dione and 4- (4,5-diamino4H- [1,2,4] triazol-3-yl-methyl) -phenol to provide the 4- (6,7-dimethyl- [1,2,4] triazolo [4,3-b] [1,2,4] triazin-3-yl-methy1) -phenol (example 8). 1 H-NMR (400 MHz, DMSO-d 6) d 9.25 (s, 1 H), 7.12 (m, 2 H), 6.65 (m, 2 H), 4.30 (s, 2 H), 2, 58 (s, 3H), 2.50 (s, 3H). MS (m / z) 256 [M + 1].

Example 9. 3- (4-Hydroxy-benzin-6-methyl-ri.2.41-triazole-4-bir.2.21-azain-7-ol The general procedure A was followed by the reaction of methyl 2-oxo-propionate and 4- (4,5-diamino-4H- [1, 2,4] triazol-3-yl-methyl) -phenol to provide the reaction. - (4-hydroxy-benzyl) -6-methyl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-7-ol. 1 H-NMR (400 MHz, DMSO-d 6) d 9.26 (s, 1 H), 7.10 (d, 2 H), 6.65 (d, 2 H), 4.05 (s, 214), 2 , 22 (s, 3H). MS (m / z) 258 [M + 1].

Example 10. 4- (7-chloro-6-methyl-p, 2,4] triazolof4.3-bip, 2.41triazin-3-yl-metiP-phenol A solution of 3- (4-hydroxy-benzyl-6-methyl- [1,2,4] tria-zolo [4,3-b] [1,2,4] triazin-7-ol (170 mg, 0 , 62 mmol) in POCI3 (5 ml) was heated at 80 ° C for 15 minutes and then the POCI3 was evaporated.The residue was purified on a column of silica gel, eluting with 5% methanol in dichloromethane to give the residue. - (7-chloro-6-methyl- [1, 2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl) -phenol (80 mg) MS m / z 275 [M + 1].

Example 11. 4- (7-amino-6-methyl-H .2,4] triazolol-4,3-bip, 2,41-triazin-3-yl-methyl) -phenol The gaseous NH3 was bubbled through a solution of 4- (7-chloro-6-methyl- [1, 2,4] triazolo [4,3b] [1, 2,4] triazin-3-yl-methyl ) -phenol (70 mg, 0.25 mmol) in methanol (5 ml) at 0 ° C. The saturated solution was stirred at 70 ° C until the starting material disappeared. After evaporation of the solvent, the residue was purified on a column of silica gel eluting with 10% methanol in dichloromethane to give 4- (7-amino-6-methylene- [1,2,4] triazolo [4,3-b] [1, 2,4] triazin-3-yl-methyl) -phenol (35 mg). 1 H-NMR (400 MHz, DMSO-d 6) d 9.22 (s, 1H), 7.05 (d, 2H), 6.65 (d, 2H), 4.12 (s, 2H), 2 , 35 (s, 3H). MS m / z 257 [M + 1].

Biological examples The following analyzes are used to find the compounds that demonstrate the optimum degree of the desired activity.

A. Analysis Procedures The following analyzes can be used to determine the level of activity and the effect of the different compounds of the present invention on one or more of the PK's. Similar analyzes can be designed along with the same lines for any PK using techniques that are well known in the art. Several of the assays described herein are performed in an ELISA (immunoenzymatic analysis) format (Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," Manual of Clinical Immunology, 2nd ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington, DC, pp. 359-371). The general procedure is as explained below: a compound is introduced into cells expressing, both naturally and recombinantly, the kinase to be tested for a certain period after which, if the kinase to be tested is a receptor, it is added a ligand that is known to activate the receptor. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody that recognizes the substrate of the enzymatic reaction of phosphorylation The components of the cell lysate that are not substrates are removed with washes and the amount of phosphorylation in the substrate is detected with an antibody that specifically recognizes phosphotyrosine compared to the control cells that were not contacted with a compound to be tested. The currently preferred protocols for carrying out the ELISA experiments for the specific PKs are provided below. However, the adaptation of these protocols to determine the activity of the compounds against other RTKs, as well as for CTKs and STKs, is also within the scope of the knowledge of those skilled in the art. Other assays described herein measure the amount of DNA that is made in response to the activation of a kinase to be tested, which is a general measure of a proliferative response. The general procedure for this analysis is as explained below: a compound is introduced into the cells expressing the kinase, either naturally or recombinantly, to be tested for a period after which, if the kinase to be tested is a receptor, a ligand is added which is known to activate the receptor. After incubation, at least overnight, a DNA labeling reagent is added, such as 5-bromodeoxyuridine (BrdU) or 3H-thymidine. The amount of the labeled DNA is detected both with an anti-BrdU antibody and by measuring the radioactivity, and compared with the control cells that were not contacted with a compound to be tested.

MET TRANSFOSFORILATION ANALYSIS This analysis is used to measure the levels of phosphotyrosine in a poll (glutamic acid: tyrosine (4: 1) substrate) as a means to identify the agonists / antagonists of substrate transphosphorylation by Met.

Materials and reagents: 1. 96-well ELISA plates from Corning, No. 25805-96 from the Corning catalog. 2. Poly (glu, tyr) 4: 1, Sigma, catalog no .: P 0275. 3. PBS, No. 450-1300EB from the Gibco catalog 4. HEPES at 50 nM. 5. Blocking buffer: dissolve 25 g of bovine serum albumin, No. A-7888 from the Sigma catalog, in 500 ml of PBS, filter through a 4 μm filter. 6. Purified GST fusion protein containing the kinase domain of Met, Sugen, Inc. 7. Buffer TBST 8. DMSO 10% aqueous (H2O MilliQ). 9. Aqueous adenosine-5'-triphosphate (dH2?) At 10 mM, No. A-5394 from the Sigma catalog. 10. 2X Kinase Dilution Buffer: for 100 ml, mix 10 ml of 1 M HEPES at pH 7.5 with 0.4 ml of 5% ASB in PBS, 0.2 ml of sodium orthovanadate at 0, 1 M and 1 ml of 5 M sodium chloride in 88.4 ml of dH2O. 11. 4X ATP reaction mixture: for 10 ml, mix 0.4 ml of 1 M manganese chloride and 0.02 ml of 0.1 M ATP in 9.56 ml of dH2O. 12. Mix of the 4X negative controls: for 10 ml, mix 0.4 ml of 1 M manganese chloride in 9.6 ml of dH2 ?. 13. NUNC 96-well V-bottom polypropylene plates, No. S-72092 from the Applied Scientific catalog. 14. EDTA at 500 mM. 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL of 5% ASB in PBS, 0.5 mL of 5% Camation Instant Milk® and 0.1 mL of 0.1 M sodium orthovanadate in 88.4 ml of TBST. 16. Polyclonal rabbit antiphosphotyrosine antibody, Sugen, Inc. 17. Anti-rabbit goat antibody conjugated to horseradish peroxidase, Biosource Inc. 18. ABTS solution: for 1 I, mix 19,219 g of citric acid, 35,49 g of Na2HPO and 500 mg of ABTS with sufficient dH2? to produce 1 I. 19. ABTS / H202: mix 15 ml of the ABST solution with 2 μl H2O2 five minutes before using it. 20. 0.2 M HCl Procedure: 1. Cover ELISA plates with 2 μg of poly (Glu-Tyr) in 100 μl of PBS and store overnight at 40 ° C. 2. Block the plate with 150 μl of 5% ASB in PBS for 60 minutes. 3. Wash the plate twice with PBS, once with HEPES buffer, pH 7.4, at 50 mM. 4. Add 50 μl of the diluted kinase to all wells. (The purified kinase is diluted with the kinase dilution buffer). The final concentration should be 10 ng / well. 5. Add 25 μl of the compound to be tested (in 4% DMSO) or DMSO alone (4% in dH2O) to the plate controls. 6 Incubate the kinase / compound mixture for 15 minutes. 7. Add 25 μl of 40 mM MnCl2 to the negative control wells. 8. Add 25 μl of the ATP / MnCl2 mixture to all other wells (except for negative controls). Incubate for 5 minutes. 9. Add 25 μl EDTA to 500 mM to stop the reaction. 10. Wash the plate 3 times with TBST. 11. Add 100 μl of diluted rabbit polyclonal anti-Ptyr 1: 10,000 in the antibody dilution buffer for each well. Incubate, with shaking, at room temperature for 1 hour. 12. Wash the plate 3 times with TBST. 13. Dilute the anti-rabbit antibody conjugated to the HRP of Biosource 1: 6,000 in an antibody dilution buffer. Add 100 μl per well and incubate at room temperature, with shaking, for 1 hour. 14. Wash the plate once with PBS. 15. Add 100 μl of the ABTS / H2O2 solution to each well. 16. If necessary, stop the development reaction with the addition of 100 μl of 0.2 M HCl per well. 17. Read the plate on a Dynatech MR7000 ELISA reader with the analysis filter at 410 nM and the reference filter at 630 nM.

Results of the MET Transphosphorylation Analysis: Table 1 shows the IC values or obtained from numerous compounds of the preferred embodiments of the invention.

Table 1 The person skilled in the art will also readily appreciate that the present invention is also well adapted to carry out the objects and obtain the purposes and advantages mentioned, as well as those inherent in the present specification. The molecular complexes and methods, procedures, treatments, molecules, specific compounds described herein are currently representative of the preferred embodiments, are exemplary and are not intended to limit the scope of the invention. Changes in this regard and other uses that will occur to those skilled in the art, which are included within the spirit of the invention, are defined by the scope of the claims. It will be readily apparent to one skilled in the art that various modifications and variations of the invention described herein can be made without departing from the scope and spirit of the invention. All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The invention described illustratively herein may be suitably practiced in the absence of any element or elements, limitation or limitations not specifically described herein. Thus, for example, in each case within the present specification, any of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced by any of the other two terms. The terms and expressions that have been used are used as terms of description and not of limitation and it is not intended, by the use of such terms and expressions, to exclude any equivalents of the characteristics shown and described or portions thereof, but rather to recognizes that several modifications are possible within the scope of the claimed invention. Thus, it should be understood that, although the present invention has been specifically described by the preferred embodiments and optional features, those skilled in the art may resort to the modification and variation of the concepts described herein, and that it is considered that such modifications and variations are within the scope of this invention.

In addition, when the features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also, for that reason, described in terms of any specific member or subgroup of group members. Markush. For example, if X is described as being selected from the group consisting of bromine, chlorine and iodine, the claims for X when it is bromine and the claims for X when it is bromine and chlorine are fully described.

Table 2

Claims (16)

1. - A compound of the formula (I):

(I) wherein n is 1, 2 or 3; R1 is selected from the group consisting of hydrogen, halogen, -OH, -OR6, NR6R7, -CN, -COR6, -COOR6, -CONR6R7, perfluorosalkyl, d-Cß alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl and heteroaryl , wherein the d-Cß, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl or heteroaryl alkyl of R 1 may be optionally and independently substituted with one or more of halogen, -OH, -OR 6, -COR 7, -CONR 6 R 7, -COOR 8 , -NR6R7, -CN, -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7, -NR6R7, perfluoroalkyl, d-C6 alkyl, cycloalkyl, heterocycle, alkenyl d -C6, C6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 or -NR6S (O2) R7; R2 is selected from the group consisting of hydrogen, -OH, halogen, d-C6 alkyl, OR8, NR8R9, -CN, -COR8, -COOR9, -CONR8R9, and perfluoroalkyl, each R3 and R4 is independently selected from the group consisting of in hydrogen, halogen, -OH, -OR6, -NR6R7, -CN, -COR6, -COOR6, -CONR6R7, -NR6R7, perfluoroalkyl, d-Cß alkyl, aryl, cycloaryl, heterocycle and heteroaryl; R5 is an aromatic ring or a heteroaromatic ring, wherein R5 is optionally substituted at one or more positions with halogen, -OH, -OR6, -COR7, -CONR6R7, -COOR6, -NR6R7, -CN, -NO2, - S (O) mR 6, (m = 0, 1 or 2), -S (O 2) NR 6 R 7, -NR 6 R 7, perfluoroalkyl or C 6 alkyl; each R6 and R7 is independently hydrogen, C-alkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl; and each R8 and R9 is independently C1-C6 alkyl or hydrogen; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted at one or more positions with halogen, -OH, -OR6, -COR7, -CONR6R7, - COOR6, -NR6R7, -CN, -NO2, -S (O) mR6, (m = 0, 1 or 2), -S (O2) NR6R7S, -NR6R7, perfluoroalkyl, d-C6 alkyl, cycloalkyl, heterocycle, alkenyl C? -C6, d-C6 alkynyl, aryl, heteroaryl, -NR6ONR6R7, -NR6OR7 or -NR6S (O2) R7.

3. The compound of claim 1, wherein the aryl or the heteroaryl is a five or six membered ring.

4. - The compound of claim 1, wherein R2 is H or C1-C4 alkyl.

5. The compound of claim 4, wherein R2 is H. The compound of claim 1, wherein R5 is a 6-membered aryl or heteroaryl ring, wherein the heteroaryl ring of 6 members contains one or more heteroatoms selected from the group consisting of S, O or N. 7. The compound of claim 1, wherein the 6-membered heteroaryl ring contains a nitrogen. 8. The compound of claim 6, wherein R5 is a 6-membered heteroaryl ring that is pyranyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. 9. The compound of claim 5, wherein R5 is phenyl and is optionally substituted with hydroxy or halo. 10. The compound of claim 1, wherein n is 1 or 2. 11. The compound of claim 1, wherein n is 1, R3 is H and R is H. 12.- A selected compound of the group that consists of or a pharmaceutically acceptable salt thereof. 13. A pharmaceutically acceptable composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A method for treating a disorder related to c-Met by administering a therapeutically effective amount of the composition of claim 13 to an organism in need thereof. 15. The method of claim 14, wherein said disorder related to c-Met is cancer. 1

6. The method of claim 15, wherein said cancer is breast cancer, bronchopulmonary cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, stomach cancer, head cancer, cancer. neck, melanoma, kidney cancer, leukemia, myeloma or sarcoma.