MX2007007419A - Sulfonamido-macrocycles as tie2 inhibitors - Google Patents

Abstract

The invention relates to sulfonamido-macrocycles according to the general Formula I and the salts thereof, to pharmaceutical compositions comprising the sulfonamido-macrocycles and to a method of preparing the sulfonamido-macrocycles as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulatedvascular growth, wherein the compounds effectively interfere with angiopoietin and therefore influence Tie2 signalling. (I), wherein R1, R2and R3have the meaning as given in the specification and the claims.

Description

SULFONAMIDO-MACROCICLOS AND ITS SALTS, A PHARMACEUTICAL COMPOSITION THAT COMPRISES THESE COMPOUNDS, A METHOD OF PREPARATION AND THE USE OF THESE COMPOUNDS Field of the Invention The invention relates to sulfonamide-macrocycles and their salts, to pharmaceutical compositions comprising the sulfonamido-macrocycles and to methods for preparing the sulfonamido-macrocycles, as well as to the use thereof.

Background of the Invention In order to defeat diseases related to dysregulated vascular growth, such as cancer, different strategies have been developed. One possible strategy involves the blocking of angiogenesis in tumor tissue, because tumor angiogenesis is a prerequisite for the growth of solid tumors. In addition to vasculogenesis, angiogenesis represents one of the two basic processes during the genesis of the vasculature. Vasculogenesis designates the neoplasm of the vasculature during embryonic development, while angiogenesis describes the neoplasm of the vasculature by budding or division of the existing vasculature. Two receptors have been discovered that are expressed in endothelial cells, the VEGF (vascular endothelial growth factor) and Tie receptors, which are essential for the normal development of vascular tissue, such as blood vessels (Dumont et al., (1994). The dominant negative and null mutations directed in the endothelial receptor Ti-rosin kinase Tie2 (also called tek) reveal a critical participation in the vasculogenesis of the embryo Genes Dev, 8: 1897-909; Sato ef al .: "Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation "Nature, 1995, July 6; 376 (6535): 70-4.). The signaling mechanism of Tie2 has been characterized by different researchers, and it was discovered that different angiopoietins participate in it. In this way, it could be explained that angiopoietin-1, once bound to the extracellular domain of the Tie2 receptor, stimulates autophosphorylation and activates the intracellular domain of the kinase. However, the activation of Tie2 by the angio- poyetina-1 does not stimulate mitogenesis, but rather migration. Angiopoietin-2 can block the activation of Tie2 mediated by angiopoietin-1, and the resulting endothelial migration. This indicates that angiopoietin-2 is a natural inhibitor of Tie2 activation (isoenpierre ef al .: "Angio-poietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis." Science. 1997, July 4; 277 (5322): 55-60; Witzenbicler ef al .: "Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2." J Biol Chem. 1998, Jul 17; 273 (29): 18514-21). For a review, see Figure 1, modified by Peters ef al. (Peters ef al .: "Functional sig-nificance of Tie2 signaling the adult vasculature." Recent Prog Horm Res. 2004; 59: 51-71. The dimerization of the receptor results in cross-phosphorylation at specific tyrosine residues. Cross-phosphorylation of the receptor has a double effect: it potentiates the activity of the receptor kinase and provides binding sites for signaling molecules that possess phosphotyrosine binding domains (SH2 and PTB domains) (Pawson T .: "Regulation and targets of receptor tyrosine kinases. "EurJ Cancer 2002, Sep, 38 Supplement 5: S3-10 Review. The signaling ratio between the PI3-K pathway and the Dok-R pathway is necessary for an optimal posterior chemotactic response in the Tie2 pathway. Other recent studies have shown that the activation of the PI3-K / Akt pathway mediated by Tie2 is necessary for the activation of endothelial nitric oxide synthetase (eNOS), the activation of the focal adhesion kinase and the secretion of proteases, factors that can contribute significantly in the function of Tie2 during angiogenesis (Kim I. ef al .: "Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase / Akt signal transduction pathway." Circ Res. 2000, 7- January 21st; 86 (1): 24-9; Babaei ef al .: "Angiogenic actions of angiopoietin-1 requires endothelium-derived nitric oxide". Am J Pathol. 2003, June; 162 (6): 1927-36). For normal development, a balanced interaction between the receptors and the so-called ligands is necessary. Especially angiopoietins, which effect signaling through Tie2 receptors, have an important participation in angiogenesis (Babaei et al., 2003).

The wide expression of Tie2 in the vasculature in transgenic mice has been confirmed, using informants directed by the Tie2 promoter (Sclaeger et al .: "Uniform vascular-endothelial- cell-specific gene expression n both embryonic and adult transgenic mice. "Proc Nati Acad Sci USA 1997, April 1; 94 (7): 3058-63; Motoike et al .:" Universal GFP reporrter for the study of vascular development. "Genesis, 2000, October; 28 (2): 75-81.) Immunohistochemical analysis demonstrated the expression of Tie2 in adult rat tissues in the angiogenesis process During fo-liculogenesis in the ovary, Tie2 was expressed in neo-vessels of the developing corpus luteum.Angiopoietin-1 and angiopoietin-2 were also expressed in the corpus luteum: angiopoietin-2 was located at the front end of the proliferating vessels, and the Angiopoietin-1 was located diffusely behind the front edge (Maisonpierre et al., 1997) It was suggested that the inhibition of Tie2 activation mediated by angiopoietin-2 served to "destabilize" the vessel, to allow it to respond to other angiogenic growth factors, such as VEGF. the activation of Tie2 mediated by angiopoietin-2 would trigger the stabilization of the neovasculature. The interruption of the Tie2 function shows the relevance of T, 2 for neoangiogenesis in transgenic mice, which results in early embryonic lethality as a consequence of vascular abnormalities (Dumont et al., 1994, Sato et al., 1995). In embryos Tie2 - / - does not develop the normal hierarchy of vessels, which suggests the presence of a failure in branching and vascular differentiation. The Tie2 - / - embryos have a lower number of endothelial cells, and also have fewer contacts between the endothelial cells and the pericytes / underlying smooth muscle cells. This implies a participation in the maturation and stabilization of the newly formed vasculature. Studies in transgenic mice or ablated T &e2 genes suggest a critical role of Tie2 in the maturation of vascular development in embryos and the adult vasculature. The conditioned expression of Tie2 in the endoteiio of mice homozygous for a null allele of Tie2 partially restored the embryonic lethality of the null phenotype for Tie2 (Jones N er al .: "Tie re-ceptors: new modulators of angiogenic and lymphangiogenic responses." Nat Rev Mol Cali Biol. 2001, April; 2 (4): 257-67 Review). Mice lacking the expression of functional angiopoietin-1, and mice overexpressing angiopoietin-2 have a phenotype similar to that of Tie2 - / - mice (Suri er al .: "Requisite role of angiopoietin-1, a ligand for The Tie2 receiver, during embryonic angiogenesis. "Cell 1996, December 27; 87 (7): 171-80; Maisonpierre PC et al .:" Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997, July 4; 277 (5322): 55-60). Mice with angiopoietin-2 - / - have major defects in growth and pattern 5 of the lymphatic vasculature, and can not reshape or reduce the hyaloid vasculature of the neonatal lens (Gale et al .: "Angiopoietin 2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. "Dev Cell, 2002, September; 3 (3): 411-23). Angiopoietin-1 restored lymphatic defects, but not defects in vascular remodeling. Thus, angiopoietin-2 can function as a Tie2 antagonist in the Sanguine vasculature, but as a Tie2 agonist in the development of the lymphatic vasculature. Tie2 also participates in pathological angiogenesis. It has been shown that mutations in Tie2 cause hereditary venous malformations and improve the activity of Tie2 dependent and ligand-independent kinase activity (Vikkula er al .: "Dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase Tie2" Cell. December 27; 87 (7): 1181-90). The expression of Tie2 in samples of human breast cancer tumors was investigated and Tie2 expression was discovered in the vascular endothelium, both in normal breast tissue and in breast tumors. The proportion of positive microvessels for Tie2 in the vessels was higher in the tumors, compared with normal breast tissue (Peters KG er al .: "Expression of Tie2 / Tek in breast tumor vasculature provides a new marker for evaluation of tumor angiogenesis Br J Cancer 1998 77 (1): 51-6). Overexpression of angiopoietin-1 in tumor models resulted in lower tumor growth. The effect is possibly related to the stabilization of the tumoral vasculature mediated by angiopoietin-1, which makes the vessels resistant to angiogenic stimuli (Hayes et al .: "Expression and function of angiopoietin-1 in breast cancer. "Br J Cancer, 2000, November, 83 (9): 1154-60, Shim et al .:" Inhibition of angiopoietin-1 expression in tumor cells by an antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice. "Int. J Cancer, 2001, October 1, 94 (1): 6-15, Shim et al .: "Angiopoietin 1 promotes tumor angiogenesis and tumor plasticity of human cervical cancer in mice." Exp Cell Res. 2002, October 1; 279 (2): 299-309; Hawighorst et al .: "Activation of the T2e2 receptor by angiopoietin-1 enhances tu-mour vessel maturation and impairs squamous cell carcinoma growth". Am J Pathol. 2002, April; 160 (4): 1381-92; Stoeltzing er al .: "Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumours". Cancer Res. 2003, June 15; 63 (12): 3370-7). Corneal angiogenesis induced by conditioned medium of tumor cells was inhibited by recombinant sTie, despite the presence of VEGF. The growth of mammary tumors was significantly inhibited in a cutaneous chamber tumor model by recombinant sTie2 (Lin ef al .: "Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth." J Clin Invest. , October 15; 100 (8): 2072-8; Lin ef al .: "Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2." Proc Nati Acad Sci USA, 1998, July 21; 95 (15): 8829-34). Other similar constructions of sTie have presented comparable effects in different tumor models (Siemeister ef al .: "Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xeno-graft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie -2 pathway. "Cancer Res. 1999, July 1; 59 (13): 3185-91; Stratmann et al .:" Differential inhibition of tumor angiogenesis by Tie2 and vascular endothelial growth factor receptor-2 dominant-negative receptor mutants " Int J Cancer 2001, February 1; 91 (3): 273-82; Tanaka et al .: Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. "Hepatology 2002, April; 35 (4): 861- 7) When the interaction between angiopoietin-2 and its receptor is blocked by the application of a neutralizing anti-angiopoietin-2 monoclonal antibody, it is possible to effectively block the growth of experimental tumors, which highlights again The important participation of Tie2 in angiogenesis and tumor growth (Oliner er al .: "Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2". Cancer Cell. 2004, November; 6 (5): 507-16). In this way, inhibition of the Tie2 pathway will inhibit pathological angiogenesis. To affect the interaction between the receptor and the ligand, it could be shown that angiogenesis can be blocked with blockers, such as Avastin, which interfere with the transduction of VEGF signals to endothelial cells.

Avastin is an effective antibody for clinical use that functions as an inhibitor of tumor growth through the blocking of angiogenic signaling mediated by VEGFR. Therefore, interference with VEGF signaling is a proven clinical principle. VEGF-C is a molecule that induces angiogenesis through VEGFR 3. Blocking this signaling pathway 5 allows to inhibit diseases associated with lymphatic angiogenesis, such as lymphedema and related diseases (Saharinen ef al .: "Lymphatic vasculature: deve- lopment, molecular regulation and role in tumor metastasis and inflammation. "Trends Immunol., 2004, July: 25 (7): 387-95. Pyrimidines and their derivatives have often been described as therapeutic agents for various diseases. A number of recently published patent applications describe their use as inhibitors of various protein kinases, for example, WO 2003/032994 A. WO 2003/063794 A and WO 2002/096888 A. More specifically, numerous pyrimidine derivatives have been described as inhibitors of protein kinases involved in angiogenesis, such as VEGF or Tie2, eg, 2,4-diaminopyrimidines substituted with benzimidazole (WO 2003/074515 A) or (bi) aniline-pyrimidines (WO 2003/066601 A). Very recently, pyrimidine derivatives have been described in which pyrimidine constitutes a part of a system of macrocyclic rings as inhibitors of CDK and / or VEGF (WO 2004/026881 A), or of CDK2 and / or CDK5, respectively ( WO 2004/078682 A). A particular problem with the use of these substances known as inhibitors or blockers is that their simultaneous use is commonly accompanied by undesired cytotoxic side effects on the development and normal proliferation of tissues. This causes substances that are less selective and, at the same time, problems of tolerance to the dosage.

Detailed Description of the Invention The objective of the present invention is to provide compounds that are useful for the treatment of diseases related to dysregulated vascular growth or diseases accompanied by dysregulated vascular growth. In addition, problems described in the prior art can be prevented, in particular, compounds that exhibit few toxic side effects on normal proliferating tissue but which, at small concentrations, are effective in inhibiting the migration of endothelial cells. This will also reduce unwanted side effects. . The above problems are solved by providing compounds derived from a class of sulfonamido-macrocycles, and salts thereof, methods for preparing sulfonamido-macrocycles, a pharmaceutical composition containing said sulfonamido-macrocycles, the use of said compounds as a medicament, and a method for treating diseases with said compounds, all in accordance with this description, and as defined in the claims of the present application. The application relates to a compound of general Formula I R1 is hydrogen and -d-C10-alkyl; R2 is selected from the group consisting preferably of hydrogen, halogen, cyano, -NR4COR5, -NR4S (0) 2R5, -NR CONR5R6, -NR4COOR5, -COR4, -S (0) 2R4, -S (0) 2NR4R5 and -CONR4R5; R3 is selected from the group consisting preferably of -C-C6-alkyl, -C2-C6-alkenyl, -C2-C6-alkynyl, -C3-C8-cycloalkyl, -C6-C1 aryl and -C5-C10-heteroaryl, wherein said re-residues are unsubstituted or are mono- or polysubstituted independently with hydroxy, halogen, -CrCValkoxy, -CVCValkylthio, amino, -CrC6-alkyl, -Ci-C6-hydroxyalkyl, -C2-C6-alkenyl, -C2-C6- alkynyl, -CrC 6 -alkoxy-Ci-C 6 -alkyl, -NH-CrC 6 -alkyl, -N-Ce -alkyl) -S (0) 2 (C 1 -C-Ce-alkyl), -CrCe-alkanoyl, -CONR R5, -COR4, -C6-C1 aryl, -C5-Ci0-heteroaryl and / or -NR R5, where - C6-Cii-aryl and -C5-C-0-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-Ce-alkyl, -CrCValkoxy, -CF3 or -OCF3 where one or more C atoms of the C-C3-C8-cycloalkyl C-main chain are optionally mono or polysubstituted independently by nitrogen atoms, oxygen atoms, sulfur atoms and / or residues C = 0; or: phenyl- (CH2) p-COR * optionally substituted or phenyl- (CH2) p-CONR4R5 optionally substituted, where p is an integer between 1 and 4, preferably between 1 and 3, more preferably is 1 or 2. R4 , R5 and R6 are the same or different and are independently selected from the group consisting preferably of hydrogen and residues selected from the group preferably formed by -Ci-Ci0-alkyl, -C, -C6-alkoxy, -C2-C6- alkenyl, -C2-C6-alkynyl, -C3-C8-cycloalkyl, -Ce-Cn-aryl and -C5-C10-heteroaryl, wherein said residues are unsubstituted or are mono- or polysubstituted independently with hydroxy, halogen, -d-Ce-alkoxy, -C6-alkylthio, amino, cyano, -Ci-Ce-alkyl, -C3-C10-cycloalkyl, -C6-hydroxyalkyl, -C2-C6-alkenyl, -C2-C6-alkyne It, -d-Ce-alkoxy-C ^ Ce-alkyl, -NH-C, -C6-alkyl, -N (C1-C6-alkyl) 2, -S ^ Xd-Ce-alkyl), -S ( 0) 2 (Ci-C6-alkyl), -d-C6-alkanoyl, -CONR7R8, -COR7, carboxy, -C6-Cn-aryl, -C5-C10-heteroaryl or -NR7R8; where C6-di-aryl and -C5-C10-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -C6-alkyl, -C6-alkoxy, -CF3 or -OCF3 and where one or more C atoms of the C-chain of C3-C8-cycloalkyl are optionally mono or polysubstituted independently by nitrogen atoms, oxygen atoms, sulfur atoms and / or residues C = 0; R7 and R8 are identical or different and are independently selected from the group consisting preferably of -d-C6-alkyl or phenyl, optionally substituted by halogen, hydroxy, -Ct-Ce-alkyl, -C6-alkoxy, phenyl, -CF3 and -OCF3; and solvates, hydrates, N-oxides, isomers, diastereomers, enantiomers and salts thereof. As used in the present documentation, the terms mentioned below and in the claims preferably have the following meanings: As used herein, the term "alkyl" preferably designates branched and unbranched alkyls, comprising, .ej., methyl, ethyl, n-propyl, / so-propyl, n- butyl, / 'so-butyl, tert-butyl, sec-butyl, pentyl, / so-pentyl, hexyl, eptyl, octyl, nonyl and decyl, and the isomers thereof. As used herein, the term "alkoxy" preferably designates branched and unbranched alkoxys, comprising, eg, methoxy, ethoxy, propyloxy, iso-propyloxy, butyloxy, / -sobutyloxy, ter- butylox, sec-butyloxy, pentyloxy, so-pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy, and the isomers thereof. As used in the present documentation, the term "cycloalkyl" preferably designates cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl portions which are interrupted one or more times by nitrogen atoms, oxygen atoms and / or sulfur atoms include, for example, oxiranyl, oxetanyl, aziridinyl, azetidynyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trityanil and quinu-clidinyl. Cycloalkyl portions in which the C-skeleton contains one or more double bonds include, for example, cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, where the linkage can be with the double bond or the linkage simple.

As used in the present documentation, the term "halogen" preferably designates fluorine, chlorine, bromine or iodine. As used herein, the term "alkenyl" preferably designates branched and unbranched alkenyls, for example, vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but -1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en- 1-yl and 2-methyl-prop-1-en-1-yl. As used herein, the term "alkynyl" preferably designates branched and unbranched alkynyl, for example, ethynyl, prop-1-yl, but-1 -lo, but-2-yl-1-yl and but-3-yl-1-yl. As used in the present documentation, in each case the term "aryl" is defined as a group of 3-12 carbon atoms, preferably 6-12 carbon atoms, such as, for example, cyclopropenyl, cyclopentadienyl, phenyl , tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc., where phenyl is preferred.

As used herein, the term "arylene" designates cyclic or polycyclic aromatic groups, for example, phenylene, naphthylene and biphenylene. More particularly, the term "phenylene" refers to ortho, meta or para-phenylene. Preferably, it refers to meta-phenylene. As used herein, the term "heteroaryl" refers to an aromatic ring system comprising 3-16 ring atoms, preferably 5 or 6 or 9 or 10 atoms, and containing at least one heteroatom which can being identical or different, wherein said heteroatom may be oxygen, nitrogen and sulfur, and may be monocyclic, bicyclic or tricyclic, and in addition, in each case may be benzocondensed. Preferably, the heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc., and benzoderivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, in-dolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, and the like; or azocinyl, n-tolylene-zinyl, purinyl, etc., and benzo derivatives thereof; or cinolinyl, phthalazinyl, quinazolinyl, quinoxali-nyl, napthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc. As used herein, the term "heteroarylene" preferably refers to cyclic or polycyclic aromatic groups, for example, five-membered heteroaromatic groups, such as thiophenylene, furanylene, pyrrolylene, oxazolylene, thiazolylene, imidazolium, pyrazolylene, triazolylene, thia-4H-pyrazolylene and benzo derivatives thereof, such as, for example, indole, or groups six-membered heteroaromatics, such as pyridinylene, pyrimidinylene, triazinylene and benzo derivatives thereof, for example, quinolinylene, isoquinolinylene. As used in this documentation, the term "Ci-C10", as used in this text, eg, in the context of the definition of "Cí-Cío-alquilo", refers to a group alkyl having a finite amount of carbon atoms of between 1 and 10, ie 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It should be understood that said term "C ^ do" includes any subset included in the defined range, for example, C ^ C ^, C2-C9i C3-C8 C4-C7i C5-C6, Ci-C2, C ^ -C3 : C, -C4, C, -C5, C, -C6. C, -C7. d-Ce. CrC9: preferably C, -C2, CrC3. C, -C4, C C5, C C6; more preferably C1-C3 Similarly, as used herein, the term "C Ce", as used herein, for example, in the context of the definitions of "Ci-Ce-alkyl" , uC Ce-alkoxy "," CrCe-alkylthiol "," CrCe-hydroxyalkyl "," CrCs-alkoxy-Ci-Ce-alkyl "," -NH-d-Ce-alkyl "," -N (Ci-C6- alkyl) 2"," -S (0) 2 (CrC6-alkylo) "and" -Ci-C6-alkanyl ", refers to an alkyl group having a finite amount of carbon atoms of from 1 to and 6, that is to say 1, 2, 3, 4, 5 or 6 carbon atoms In addition, it should be understood that said term "CRC6" includes any subset included in the defined range, for example C C6i C2-C5 C3-C4i C C2, CRC3, Ci-C, C Cs C Ce, preferably C, -C2, C, -C3 CC, CTC5, C C6, more preferably C, -C3, similarly, as used herein documentation, the term "CrC6", as used in this text, for example, in the context of the definitions of "C ^ Ce-alkenyl" and "Cr C6-alkynyl", it refers to an alkenyl group or an alkenyl group having a finite amount of carbon atoms of between 2 and 6, ie 2, 3, 4, 5 or 6 carbon atoms. Furthermore, it should be understood that said term "C2-C6" includes any subset included in the defined range, for example C2-C6 C3-C5. C3-C C2-C3 C2-C C2-C¾ preferably C2-C3 In addition, as used herein, the term "C3-C8", as used in this text, p. eg, in the context of the definition of "C3-C8-cycloalkyl", refers to a cycloalkyl group having a finite amount of carbon atoms of between 3 and 8, ie 3, 4, 5, 6 , 7 or 8 carbon atoms, preferably 5 or 6 carbon atoms. Furthermore, it should be understood that said term "C3-C8" includes any subset included in the defined range, for example C3-CB, C4-C7. C5-C6. C3-C4; C3-C5. C3-C6, C3-C7 preferably C5-C6. Furthermore, as used in this documentation, the term "Ce-Cu", as used in this text, for example, in the context of the definition of "C6-C-aryl", refers to a aryl group having a finite amount of carbon atoms of between 6 and 11, ie 6, 7, 8, 9, 10 or 11 carbon atoms, preferably 5, 6 or 10 carbon atoms. Furthermore, it should be understood that said term "Cg-C" includes any subset included in the defined range, for example C6-Cni C7-C10, C8-C9i C9-C10; preferably C5-C6 0 C9-C10. Similarly, as it is used in the present documentation, the term "C5-C10", as used in this text, for example, in the context of the definition of "C5-C10-heteroaryl", refers to a heteroa-ryl group having a finite amount of carbon atoms of between 5 and 10, ie 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 5, 6 or 10 carbon atoms, of which at least one atom carbon is replaced by a heteroatom, where said heteroatom is as previously defined. Furthermore, it should be understood that said term "C5-C10" includes any sub-set included in the range it defines, for example C5-C10, C6-Cg, C7-C8; preferably C5-C6 or Cg-C1 (). The compound according to Formula I (sulfonamido-macrocycles) can exist in the form of N-oxides, which are defined as being compounds of general Formula I in which at least one of the nitrogens is oxidized. The compound according to Formula I (sulfonamido-macrocycles) can exist as solvate, in particular as a hydrate, where the compound according to Formula I can contain polar solvents, in particular water, as a structural element of the crystalline lattice of the com ponents. The amount of polar solvents, in particular water, can exist in an este-quiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrates, hemi, (semi) are possible, mono, sesqui, di, tri, tetra, penta-solvates or hydrates, respectively, etc. As used in this documentation, the term "isomers" refers to chemical compounds with the same amount and same types of atoms as other chemical species. There are two main classes of isomers, constitution isomers and stereoisomers. As used in this documentation, the term "constitution isomers" refers to chemical compounds with the same amount and the same types of atoms, but linked in different sequences. There are functional isomers, structural isomers, tautomers or valence isomers. In stereoisomers, the atoms are joined in the same sequence, so that the condensed formulas of two isomeric molecules are identical. However, the isomers differ in the way that the atoms are arranged in space. There are two main sub-classes of stereoisomers: the conformational isomers, which are converted to one another by rotations around single bonds, and configuration isomers, which can not be converted to one another. In turn, the configuration isomers are composed of enantiomers and diastereomers. Enantiomers are stereoisomers that are related to each other as mirror images. The enantiomers can contain any number of stereogenic centers, provided that each center is the exact mirror image of the corresponding center in the other molecule. If one or more of these centers has a different configuration, the two molecules cease to be mirror images. Stereoisomers that are not enantiomers are called diastereomers. The diastereomers that still have a different constitution are another subclass of diastereomers, among which the simple cis-trans isomers are the best known. In order to differentiate the different types of isomers from each other, Section E of the IUPAC rules may be used as a reference. { Puré Appl Chem 45, 11-30, 1976). As used herein, the term "in vivo hydrolysable ester" refers to an ester of a compound of formula (I) that contains a terminal carboxy or hydroxyl group, which can be hydrolyzed in vivo, e.g. eg, an ester acceptable for pharmaceutical use that is hydrolyzed in the human or animal body to produce the original acid or alcohol. Carboxy acid esters acceptable for pharmaceutical use include, eg, alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C 2 alkoxymethyl esters, eg, methoxymethyl, C 1-6 alkanoymethyl esters, .ej., esters of pivalyloxymethyl, phthalidyl, esters of C3.8 cycloalkoxy-car-bonzyloxy-ClJ3 alkyl, eg, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g., 5-methyl-1,3-dioxolen-2-onylmethyl; and C.sub.1.e alkoxycarbonyloxyethyl esters, e.g., 1-methoxycarbonyloxyethyl, and can be formed in any carboxy group of the compounds of this invention. An in vivo hydrolysable ester of a compound of formula (I) containing a hydroxyl group includes organic esters, such as phosphate esters and [alpha] -acyloxyalkyl esters, and related compounds, from which in vivo hydrolysis is obtained original hydroxyl group. Examples of [alpha] -acyloxyalkyl esters include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. One lesson of hydrolysable ester forming groups in vivo for hydroxyl include alkanoyl, benzoyl, phenylacetyl and benzyl and substituted phenylacetyl, alkoxycarbonyl (to obtain alkyl carbonate esters), dialkylcarbamyl and N- (dialkylaminoethyl) -N-alkylcarbamyl (for obtain carbamates), dialkylaminoacetyl and carboxyacetyl. The compound according to Formula I (sulfonamido-macrocycles) can exist in free form or in salt form. An appropriate salt acceptable for pharmaceutical use of the sulfonamido macrocycles of the invention is, for example, an acid addition salt of a sulfonamido-macrocyclic compound of the invention which is sufficiently basic, for example, an acid addition salt, for example , with an inorganic or organic acid, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition, an appropriate salt acceptable for pharmaceutical use of a sulfonamido-macrocycle of the invention is a sufficiently acidic alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, eg, a calcium salt or magnesium, an ammonium salt or a salt with an organic base that provides an acceptable cation for physiological use, for example, a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropanediol, Sovak base, 1-amino-2,3,4-butantriol.

The compounds of Formula I of the present invention are particularly preferred, wherein R3 is -Ci-C6-alkyl, unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -Ci-C6-alkoxy, -d-C6-alkylthio, amino, -NH-C C6-alkyl, -N (C1-C6-alkyl) 2, -S (0) 2 (d-C6-alkyl), -d-C6-alkanoyl, -CONR4R5, -COR4, -C6 -C1 aryl, -C5-C10-heteroaryl and / or -NR4R5, where -Ce-Cn-aryl and -C5-C10-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -CrC6-alkyl, -CrCValkoxy , -CF3 or -OCF3. Other compounds are preferred in which R3 is -C2-C6-alkenyl, as defined above, unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -d-C6-alkoxy, amino, -Ci-C6-alkyl, -d-C6-hydroxyalkyl, -d-Ce-alkoxy-Ci-Ce-alkyl, -NH-d-Ce-alkyl, -N (d-C6-alkyl) 2, -S (0) 2 (d-C6) -alkyl), -d-C6-alkanoyl, -CONR4R5, -COR4, -Ce-Cn-aryl, -C5-Ci0-heteroaryl and / or -NR4R5, where -Ce-Cn-aryl and -C5-C10-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-C6-alkyl, -Ci-Ce-alkoxy, - Other compounds are preferred in which R3 is -C2-C6-alkynyl, as defined above, unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -Ci-C6-alkoxy, amino, -CVC6-alkyl , -CrC6-hydroxyalkyl, -d-C6-alkoxy-Ci-C6-alkyl, -NH-d-Ce-alkyl, -N-Cyd-alkyl);;, -S (0) 2 (C1-C6-alkyl) ), -d-C6-alkanoyl, -CONR4R5, -COR4, -C6-di-aryl, -C5-C10-heteroaryl and / or -NR R5, where -C6-di-aryl and -C5- Ci0-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-C6-alkyl, -Ci-C6-alkoxy, - Other compounds are preferred in which R3 is -C5-C7-cycloalkyl, as defined above, unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -d-C6-alkyl, -S (0) 2 (C1- C6-alkyl), -C, -C6-alkanoyl, -CONR R5 and / or -COR4, where one or more C atoms of the C-chain of the C5-C7-cycloalkyl are optionally independently substituted by each other or two nitrogen atoms, where in this case those compounds in which R3 is piperazine or piperidine are particularly preferred, where piperazine or piperidine are unsubstituted or are mono- or polysubstituted independently with -d-Ce-alkyl, -S (0 ) 2 (Ci-C6-alkyl), -d-C6-alkanoyl, -CONR4R5 and / or -COR4. Other compounds are preferred in which R3 is: either: -C6-C -aryl, as defined above, preferably phenyl, unsubstituted or mono- or polysubstituted independently from each other with hydroxy, halogen, -d-C6-alkoxy, -d-Ce-alkylthio, amino, -CrC6-alkyl, -d-C6-hydroxyalkyl, -d-Ce-alkoxy-d-Ce-alkyl, -NH-d-C6-alkyl, -N (d-) C6-alkyl) 2, -S (0) 2 (C, -C6-alkyl), -C6-alkanoyl, -COR4, -C6-Cn-aryl, -C5-C10-heteroaryl and / or -NR4R5, where -C6-C1 aryl and -C5-d0-heteroanyl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-C6-alkyl, -d-C6-alkoxy, -CF3 or -OCF3; or: optionally substituted phenyl- (CH2) p-COR4 or optionally substituted phenyl- (CH2) p-CONR4R5, where p is an integer from 1 to 4, preferably 1 to 3, more preferably 1 or 2.

More advantageously, compounds are preferred where: R3 is either unsubstituted or mono- or polysubstituted phenyl independently of each other with hydroxy, halogen, -d-C6-alkoxy, -C, -C6-alkylthio, amino, -d -C6-alkyl, -d-C6-hydroxyalkyl, d-Ce-alkoxy-d-Ce-alkyl, -NH-CrC6-alkyl, -N (C1-C6-alkyl) 2, -S (0) 2 (C1-C6-alkyl), -Ci-C6-alkanoyl, -COR4, -Ce-Cu-aryl, -C5-C10-heteroaryl and / or -NR4R5, wherein -C6-C1 aryl and -Cs-C10- heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-Ce-alkyl, -Ci-C6-alkoxy, -CF3 or -OCF3; or: phenyl- (CH2) p-COR4 optionally substituted or phenyl- (CH2) p-CONR4R5 optionally substituted, where p is an integer from 1 to 3, more preferably 1 or 2. Even more advantageously, compounds are preferred where R3 is either phenyl which is unsubstituted or mono- or polysubstituted independently of one another by halogen, - Ci-C6-alkoxy, -Ci-C6-alkyl, -Ci-C6-hydroxyalkyl, C-C6-alkoxy-d-C6 -alkyl, -NH-d-C6-alkyl, -N (d-C6-alkyl) 2, -C6-alkanoyl, -COR4, and / or -NR4R5; or: phenyl- (CH2) p-COR4 optionally substituted or phenyl- (CH2) p-CONR4R5 optionally substituted, where p is an integer of 1 or 2. Particularly advantageously, compounds are preferred where: R3 is phenyl mono - or polysubstituted independently from each other with d-C6-alkoxy, -Ci-Ce-alkyl. Even more advantageously, compounds where R3 is phenyl are preferred. The compounds of the present invention can be used to treat diseases related to dysregulated vascular growth or diseases accompanied by dysregulated vascular growth. In particular, the compounds effectively interfere with angiopoietin, so they influence the signaling of Tie2. Surprisingly, the compounds block the signaling of Tie2, where the activity of Tie2 kinase is blocked with little or no cellular toxicity for cells other than endothelial cells at low concentrations, which constitutes an important advantage over the substances of the prior art . Therefore, this effect may allow the prolonged treatment of patients with compounds that have a good tolerance and high anti-angiogenic efficacy, where persistent angiogenesis has a pathological participation. Accordingly, the compounds of the present invention can be applied for the treatment of diseases accompanied by neoangiogenesis. This applies mainly to all solid tumors, for example, breast, colon, renal, pulmonary and / or brain tumors, and can be extended to a wide range of diseases in which pathological angiogenesis is persistent. This applies to diseases with inflammatory processes, diseases associated with edemas of various forms and diseases generally associated with stromal proliferation and pathological stromal reactions. The treatment of gynecological diseases is especially appropriate, in which an inhibition of the angiogenic, inflammatory and stromal pathological processes can be carried out. At the same time, toxic side effects on normal proliferating tissue are reduced. Therefore, the treatment constitutes an additional weapon to those already existing to treat diseases associated with neoangiogenesis. The compounds of the present invention can be used in particular in the therapy and prevention of tumor growth and metastasis, especially in solid tumors of all types of indications and stages, with or without previous treatment if the tumor growth is accompanied by a persistent angiogenesis. However, it is not restricted to tumor therapy, but is also of great value for the treatment of other diseases associated with dysregulated vascular growth. This includes retinopathy and other ocular diseases dependent on angiogenesis (eg, rejection of corneal transplants, age-related macular degeneration), rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, such as psoriasis, type hypersensitivity. delayed, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, cerebrovascular accidents and intestinal inflammatory diseases, such as Crohn's disease. Includes diseases of coronary arteries and peripheral arteries. It can be applied to disease states, such as ascites, edema, such as edema associated with brain tumors, trauma caused by high altitudes, cerebral edema induced by hypoxia, pulmonary edema and macular edema or post-burn edema and trauma. In addition, it is useful for chronic lung diseases, such as respiratory distress syndrome in adults. It is also useful for diseases related to bone resorption and benign proliferation, such as myoma, benign prosthetic hyperplasia and wound healing, for the reduction of scar formation. It has therapeutic value for the treatment of diseases in which the deposition of fibrin or extracellular matrix is a problem and the proliferation of the stroma is accelerated (eg, fibrosis, cirrhosis, carpal tunnel syndrome, etc.). In addition, it can be used to reduce the formation of lesions during the regeneration of damaged nerves, allowing the reconnection of axons. Other uses include endometriosis, pre-eclampsia, postmenopausal hemorrhage, and ovarian hyperstimulation. A second aspect of the invention is a pharmaceutical composition containing a compound of formula I, or a salt thereof acceptable for pharmaceutical use, isomers or mixtures of isomers thereof, in combination with one or more suitable excipients. This composition is particularly suitable for the treatment of diseases related to dysregulated vascular growth, or diseases accompanied by dysregulated vascular growth, as previously explained. In order that the compounds of the present invention can be used as pharmaceuticals, the compounds, or mixtures thereof, can be provided in a pharmaceutical composition, which, as well as the compounds of the present invention, can be for enteral administration, oral or parenteral, may contain suitable organic or inorganic basic materials acceptable for pharmaceutical use, eg, purified water, gelatin, gum arabic, lactate, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol, etc. The pharmaceutical composition can be provided in a solid form, eg, as tablets, dragees, suppositories or capsules, or in liquid form, for example, as a solution, a suspension or an emulsion. In addition, the pharmaceutical composition may contain auxiliary substances, for example, preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting the osmotic pressure or buffer solutions. For parenteral administrations (including intravenous, subcutaneous, intramuscular, vascular or infusion) sterile injectable solutions or suspensions are preferred, especially aqueous solutions of the compounds in castor oil containing polyhydroxyethoxyol. In addition, the pharmaceutical compositions of the present invention may contain surfactants. Eg, galenic acid salts, phospholipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof. For oral application, dragees or capsules containing vehicles and binders containing talc and / or hydrocarbons are preferred, for example lactose, corn starch and potato. Other possible forms of application in liquid form comprise, for example, juices which, if necessary, may contain sweeteners. The dosage will necessarily vary depending on the route of administration, the age, the weight of the patient, the type and severity of the disease to be treated and similar factors. The daily dosage is in the range of 0.5-1500 mg. A dosage may be administered as a unit dosage or as a part thereof, and may be distributed during the day. Therefore, the optimal dosage will be determined by the specialist in charge of each particular patient. Another aspect of the present invention is a method that can be used to prepare the compounds according to the present invention. The abbreviations used in this paragraph and in the Examples section are indicated in the following table. The shapes of the NMR peaks are indicated as they appear in the spectra, the possible higher order effects have not been considered.

The following general schemes and procedures illustrate general synthetic routes to the compounds of general formula I of the invention, and should not be understood in a limiting sense. The specific examples are described in the subsequent paragraph. Therefore, the compounds of the invention can be prepared from halogenated macrocycles (A) by metal-catalyzed coupling reactions, such as Suzuki, Heck or Sonogashira couplings, particularly a coupling reaction catalyzed by a transition metal, eg Cu, Pd, or by well-known amination methods for those skilled in the art. technique. Next, a first general scheme of reaction is described: Scheme 1: Coupling, for example, Suzuki or Ullmann coupling of macrocycles A, where in the macrocycles A preferably comprises phenylene, Z is -NR3 and m = 3, where in Formula I X it is a bond and Y is p. ex. -phenylene-D-NH-CORs, -phenylene-D-NH-CONF ^ R6, -phenylene-D-NH-S (0) 2R5, -phenylene-D-0- (CH2) p-COR5, -oxi- C6-C1-Rrilo or -oxi-C5-C10-heteroaryl with the foregoing meaning. Next, a second particular reaction scheme is described: Scheme 2: Amination of A with cycloaliphatic amines, eg N-Boc-piperazine can be used. The amination of macrocycle A gives compounds of Formula I in which R3 is pre- preferably C3-C10-unsubstituted or substituted cycloalkyl containing at least one heteroatom.p.ej. a nitrogen atom, which replaces the halide in the macrocycle A. The synthesis of the halogenated macrocycle A is described in WO 2004/026881 A, and is exemplified in the present invention as Preparation Example A, particularly with respect to the brominated macrocycle A , and as Preparation Example B, with respect to the iodinated macrocycle A.

Preparation Example A: Production of 15-bromo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphan-4,4-dioxide Method A A solution of 200 mg (0.48 mmol) of 3-amino-A / - [3- (5-bromo-2-chloro-pyrimidin-4-ylamino) -propyl] -benzenesulfonamide in acetonitrile is added. / water / 2-butanol (9, 0 ml / 1.0 ml / 0.3 ml) by means of a syringe pump over a period of 2.5 hours to a refluxing mixture of acetonitrile / water / 4M solution of hydrochloric acid in dioxane (45 ml). ml / 5 ml / 0.6 ml). After a further 3 hours at reflux, the oil bath is removed and the reaction solution is stirred overnight at room temperature. The precipitate formed is separated by filtration, washed with water and then dried in vacuo. 1 12 mg (0.31 mmol) of the product are obtained. The filtrate is concentrated by evaporation in a rotary evaporator. The precipitate formed is washed with water and filtered off. After drying, another 45 mg (0.12 mmol) of the product are obtained. The total yield of the product is then 157 mg (0.41 mmol, corresponding to 85% of theory). Method B A solution of 450 mg (1.00 mmol) of A / - [3- (5-bromo-2-chloro-pyrimidin-4-ylamino) -propyl] -3-nitro-benzenesulfonamide is mixed in 9.5 ml of ethanol with 960 mg of tin (II) chloride and stir for 30 minutes at 70 ° C. After cooling, the reaction mixture is added carefully to ice water and basify with 1 N NaOH solution. Extract with ethyl acetate (3x). The combined organic phases are dried (Na 2 SO), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (ethyl acetate / hexane 4: 1). 72 mg of the crude product are obtained. It is mixed with 1 N HCl and extracted with ethyl acetate. A colorless solid precipitates from the aqueous phase. The solid is filtered off and dried. 20 mg (0.05 mmol, corresponding to 5% of theory) of the product are obtained. ? -NMR (DIVISO): 10.45 (s, 1 H), 9.07 (s, 1 H), 8.35 (br, 1 H), 8.18 (s, 1 H), 7.78 (t, 1 H), 7.45 (m, 2H), 7.32 (m, 1 H), 3.44 (m, 2H), 3.28 (m, 2H), 1.82 (m, 2H). MS: 384 (ES). Production of the intermediate product Production of 3-Amino- / V- [3- (5-bromo-2-chloro-pyrimidin-4-ylamino) -propyl] -benzenesulfonamide A solution of 1.35 g (2.99 mmol) of N- [3- (5-bromo-2-chloro-pyrimidin-4-ylamino) -propyl] -3-nitro-benzenesulfonamide in 100 ml is mixed. of tetrahydrofuran under argon at room temperature with 15 ml of a 15% solution of Ti (III) CI3 in approximately 10% hydrochloric acid. After 17 hours, the reaction solution is again mixed with 1 ml of the Ti (III) CI3 solution and stirred for another 3 hours. The batch is made alkaline with NaOH 1 solution and then filtered. The filtered cake is washed again 2x with 100 ml of ethyl acetate / eOH (30 ml / 20 ml) in each case. The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2x). The combined organic phases are washed with NaCl solution, dried (Na 2 SO 4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (dichloromethane / MeOH 95: 5, Flashmaster II). 624 mg (1.48 mmol, corresponding to 49% of theory) of the product are obtained.

? -NMR (DMSO): 8.21 (s, 1 H), 7.63 (t, 1 H), 7.38 (t, 1 H), 7.13 (t, 1 H), 6.97 (m, 1 H), 6.83 (m, 1H), 6.71 (m, 1 H), 5.53 (s, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 1.65 (m, 2H). Preparation Example B: Production of 15-bromo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide A solution of 2.34 g (5.00 mmol) of 3-amino-rV- [3- (5-iodo-2-chloro-pyrimidin-4-ylamino) -propyl] -benzenesulfonamide in acetonitrile is added. water / 2-butanol (94 ml / 10.4 ml / 3.1 ml) by means of a syringe pump over a period of 3 hours to a reflux mixture of a solution of acetonitrile / water / 4M hydrochloric acid in dioxane (470 ml / 52 ml / 6.2 ml). After a further 3 hours at reflux, the heat source of the respective oil bath is turned off and the reaction solution is stirred overnight at room temperature. The precipitate formed is separated by filtration, washed with acetonitrile and then dried in vacuo to give 1.71 g (79% yield) of the desired product. 1 H-NMR (DMSO, 300 MHz): 10.81 (s, 1 H), 9.02 (s, 1 H), 8.30-8.38 (m, 1H), 8.27 (s, 1 H), 7.82 (t, 1 H), 7.43-7.56 (m, 2H), 7.29-7.40 (m, 1 H), 3.38- 3.52 (m, 2H), 3.21-3.36 (m, 2H), 1.72-1.90 (m, 2H). ESI-MS: [M + H '] = 432. Production of the intermediate product Production of 3-Amino-A / - [3- (5-iodo-2-chloro-pyrimidin-4-ylamino) -propyl] -benzenesulfonamide A solution of 9.95 g (20.0 mmol) of A / - [3- (5-iodo-2-chloro-pyrimidin-4-ylamino) -propyl] -3-nitro-benzenesulfonamide in 660 is mixed. of tetrahydrofuran under argon at room temperature with 100 ml of a 15% solution of Ti (11) CI3 in approximately 10% hydrochloric acid. After 2 hours, the reaction solution is again mixed with 7 ml of the Ti (III) CI3 solution and then stirred for another hour. The mixture is made alkaline (pH 14) by the addition of 1 N NaOH solution and then filtered over Celite. The filtrate is extracted with ethyl acetate (3 × 400 ml), the combined organic layers are then washed with brine (200 ml), and concentrated in vacuo. The filtered cake is washed again 4x with 500 ml of ethyl acetate / MeOH (3: 2), followed by evaporation of the resulting washing fractions. The resulting residues are combined and purified by column chromatography on silica (dichloromethane / ethyl acetate) to give 5.42 g (58% yield) of the desired compound. 1 H-NMR (DMSO, 300 MHz): 8.31 (s, 1 H), 7.39 (t, 1 H), 7.27 (t, 1 H), 7, 16 (t, 1 H), 6.95 - 7.01 (m, 1 H), 6.82 - 6.88 (m, 1 H), 6.68 - 6.76 (m, 1 H), 5.53 (s, 2H) , 3.27-3.39 (m, 2H), 2.68-2.82 (m, 2H), 1.64 (me, 2H). ESI-MS: [M + H +] = 468 (35CI signal; isotope 37CI also well detected). Examples 1 to 43 were prepared using the following general procedure for Suzuki couplings: General procedure 1 (GP1): Suzuki coupling (typical scale: 0.25 mmol) A solution of the respective macrocyclic halide in DMF (8 ml per mmol. halide) was treated with the respective organoboron compound (1.25 eq.), K2C03 (2.5 eq., either as a solid or as an aqueous solution 2), and POPd (2.5-5 mol-%) a room temperature. The resulting mixture in stirring was placed in a preheated oil bath at 100 ° C. The evolution of the reaction was monitored by TLC, and in case of incomplete reaction of the macrocyclic halide after 2h additional portions of POPd and the organoboron compound were added followed by further stirring at 100 ° C. After cooling to room temperature, water was added and the resulting suspension was stirred for 30 min. The crude product was isolated by vacuum filtration, dried in vacuo and purified by column chromatography, and then optionally by trituration with methanol and / or preparative HPLC (eg YMC Pro C18RS 5μ, 150 x 20 mm, , 2% NH3 in water / ace-tonitrile) to give the products analytically pure. Alternatively, after the total conversion, the reaction mixture was diluted with ethyl acetate, the reaction was stopped with water. The layers were separated, the organic layer was extracted twice with ethyl acetate and the combined organic layers were dried and concentrated in vacuo followed by the aforementioned purification steps. In all examples except where explicitly stated otherwise, boric acids were used as organoboron compounds for the general procedure of Suzuki described. The preparation of commercially available organoboron compounds used as substrates for Suzuki couplings is described in the following sections. Intermediary 1 Preparation of 1-phenyl-3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ll) -phenyl] -propan-1-one (Scheme A) Scheme A Preparation of 3- (4-bromophenyl) -N-methoxy-N-methyl-propionamide (Step 1, 1) 4.0 g of 3- (4-bromophenyl) propionic acid (17.5 mmol) were dissolved in 45 ml of THF (0.4 M) and then treated with 5.75 ml of v-methylmorpholine (52, 4 mmol, 3.0 eq.) And 3.7 g of 2-chloro-4,6-dimethoxy [1, 3,5] triazine (CDMT, 20.95 mmol, 1.2 eq.). The resulting mixture was stirred for 1 h at room temperature after which 1.87 g HNMe (OMe) »HCl (19.2 mmol, 1.1 eq.) Was added and stirring was continued for 16 h. The reaction was quenched with water and extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous Na 2 CO 3 solution, with 1N HCl, then dried and concentrated in vacuo to give 4.38 g of 3- (4-bromophenyl) - / v-methoxy-W-methyl-propionamide (92%) after flash column chromatography. 1 H-NMR (SO, 300 MHz): 7.64 (d, 2 H); 7, 19 (d, 2 H); 3.58 (s, 3 H); 3.04 (s, 3 H); 2.74 (t, 2 H); 2.64 (t, 2 H). 3- (4-bromophenyl) -1-phenyl-propan-1-one (Step 1.2) 700 mg of 3- (4-bromophenyl) -A / -methoxy-A / -methyl-proponamide was dissolved ( 2.57 mmol) in 13 ml of dry THF (0.2 M), cooled to 0 ° C and treated dropwise with 3.1 ml of phenylmagnesium bromide solution (1.0 M in THF, 3, 1 mmol, 1, 2 eq.). The reaction was stirred for 2 h at 0 ° C, quenched with 1 N HCl, extracted with ethyl acetate, the combined organic extracts were dried and concentrated in vacuo. Flash column chromatography gave 509 mg (68%) of 3- (4-bromo-phenyl) -1-phenyl-propan-1 -one as a white solid. 1 H-NMR (CDCl 3, 300 MHz): 7.96 (d, 2 H); 7.58 (m, 1 H); 7.40-7.50 (m, 4 H); 7, 16 (d, 2 H); 3.60 (t, 2 H); 3.08 (t, 2 H) 1-phenyl-3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -phenyl] -propan-1 -one (Step 1.3) Weigh and introduce 100 mg of 3- (4-bromophenyl) -1-phenyl-propan-1 -one (0.35 mmol), 133 mg of bi (pinacolato) diboro (0.525 mmol, 1.5 eq.) , 103 mg of KOAc (1.05 mmol, 3.0 eq.) And 29 mg of PdCI2 complex (dppf) »CH2Cl2 (0.035 mmol, 10 mol%) in a flame-dried Schlenk flask and fixed under an atmosphere of argon. 1.8 ml of DMSO was added and the resulting suspension was stirred at 80 ° C for 5 h. The reaction was diluted with ethyl acetate, quenched with water, filtered through Celite and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried and concentrated in vacuo. Chromatography in Instneous column gave 89 mg (76%) of 1-phenyl-3- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenyl] -propan-1- ona as a colorless solid. 1 H-NMR (CDCl 3, 300 MHz): 7.97 (d, 2 H); 7.76 (d, 2 H); 7.56 (t, 1 H); 7.43 (t, 2 H); 7.27 (d, 2 H); 3.32 (t, 2 H); 3.10 (t, 2 H); 1, 37 (s, 12 H). The following intermediates 2 to 7 were prepared in a manner analogous to steps 1, 1 to 1, 3 using appropriately functionalized Grignard reagents: Examples 44 to 48 were prepared by forming the amides of Intermediates 8 and 9 with the respective amines following general procedure GP3. Intermediates 8 and 9 are derived from the respective carboxylic acid esters using general procedure GP2.

General Procedure 2 (GP 2): Saponification of Alkyl Esters To a suspension or solution of the respective ester in 2-propanol (10 ml per mmol) was added 0.5 M aqueous sodium hydroxide (20 eq), and the resulting mixture was stirred for 6 h at 60 ° C. Additional sodium hydroxide was added as necessary, and stirring was continued until the reaction was finished as determined by TLC. Dilute acetic acid (1.0 M) was added to maintain the pH at 4, and the precipitated acid was isolated by filtration, washed with water and dried under vacuum, and then used without further purification. General procedure 3 (GP3): Amide couplings with EDC / HOBt To a solution of the respective carboxylic acid in DMAc (20 ml per mmol) were added consecutively HOBt (0.11 eq), EDC (1.0 eq) and TEA (2.0 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 45 min, after which the respective amine was added as a 0.1 M solution in DMAc. After stirring overnight, the mixture was concentrated in vacuo, diluted with water and stirred at room temperature for 30 min. The precipitate was isolated by filtration and then dried. Purification of the crude product was performed by preparative HPLC (eg on a Gemini C18 5μ 250x21 column, 2mm with a water / acetonitrile gradient), or column chromatography, optionally followed by trituration with methanol. Intermediary 8 Preparation of 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-15-yl) benzenepropanoic acid Intermediate 8 was prepared according to GP 2 from 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1, 3) - methyl benzenecyclononafan-15-yl) benzene propanoate (Example 41) in quantitative yield. 1 H-NMR (CDCl 3, 400 MHz): 12.14 (s br, 1 H); 9.53 (s, 1 H); 9.42 (s, 1 H); 7.70 - 7.76 (m, 2 H); 7.34 (me, 1 H); 7.21-7.31 (m, 6 H); 6.88 (t br, 1 H); 3.21 - 3.42 (m, 4 H); 2.83 (t, 2 H); 2.53 (t, 2 H); 1, 76-1, 86 (m, 2 H). MS (ESI): [-H] '= 454. Intermediate 9 Preparation of 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 ( 1,3) -benzenecyclineonafan-1s-il) benzenacetic Intermediary 9 was prepared according to a GP2 from 4- (4,4-dioxo-4-thia-2,5,9- triaza-1 (2,4) ^ irimidin-3 (1,3) -benzenocyclononafan-15-yl) benzene-methyl acetate (Example 43) in quantitative yield. 1 H-N R (CDCl 3, 400 MHz): 12.33 (s br, 1 H); 9.56 (s, 1 H); 9.41 (s, 1 H); 7.77 (s, 1 H); 7.74 (t br. 1 H); 7.21-7.38 (m, 7 H); 6.91 (t br, 1 H); 3.58 (s, 2 H); 3.19 - 3.44 (m, 4 H); 1, 75-1, 85 (m, 2 H). MS (ESI): [MH] * = 440. Intermediate 10 Preparation of V-methyl-W- [4- (4,4-dioxo-4-thia-2I5,9-triaza-1 (2,4) -pyrimidine Fer-butyl -3 (1,3) -benzenocyclononafan-15-yl) phenyl] carbamate Intermediate 10 was prepared according to a GP 1 from 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononane- 4,4-dioxide and re-butyl A-methyl -A- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenol] carbamate. 1 H-NMR (DMSO, 400 MHz): 9.58 (s, 1 H); 9.42 (s, 1 H); 7.77 (s, 1 H); 7.73 (t br, 1 H); 7.31 -7.38 (m, 5 H); 7.26 (t br, 2 H); 6.95 (t br, 1 H); 3.32 - 3.44 (m, 2 H); 3.20 - 3.28 (m, 2 H); 3.18 (s, 3 H); 1, 74-1, 87 (m, 2 H); , 38 (s, 9 H). MS (ESI): [M + H] + = 51 1. Preparation of the compounds of the examples The following compounds of the examples were prepared by Suzuki coupling according to the general procedure GP1 from 15-iodo-4- thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-4,4-dioxide and the corresponding free boric acid or in example 27 and 33 to 40 the corresponding pinacolato boric esters.

Example 44 Preparation of 4,4-dioxk! Or 15- (thien-2-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidine-3 (1,3) 'benzenenoi.lononafano A suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide was treated (150 mg, 0.36 mmol) and thiophene-2-boronic acid (65 mg, 0.51 mmol) in toluene / ethanol 1: 1 (15 mL) with Na 2 CO 3 aq. 1 (0.9 ml), followed by LiCl (43 mg, 1.02 mmol) and Pd (PPh3) 4 (32 mg, 0.03 mmol) and then refluxed for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered through Celite. The filtrate was washed with aq. NaHCO 3. and brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography to give 37 mg of the desired compound (26%). 1 H-NMR (DMSO, 400 MHz): 9.68 (s, 1 H); 9.41 (s, 1 H); 7.89 (s, 1 H); 7.74 (t, 1 H); 7.51 -7.57 (m, 1 H); 7.34-7.41 (m, 1 H); 7.25-7.31 (m, 2 H); 7.1-1-7, 18 (m, 2 H); 7.06 (t, 1 H); 3.35 - 3.49 (m, 2 H); 3.20-3.30 (m, 2 H); 1, 75-1, 91 (m, 2 H). MS (ESI): [M + H] + = 387. EXAMPLE 45 Preparation of 4,4-dioxide of 15- (thien-3-yl) -4-tia-2,5,9-triaza- 1 (2,4) -pyrimidin-3 (1,3) benzene cyclononaphhane A suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide (150 mg; 0.36 mmol), thiophene-3-boronic acid (65 mg, 0.51 mmol) in toluene / ethanol 1: 1 (15 mL) with Na 2 CO 3 aq. 1 M (0.9 ml), followed by LiCl (43 mg, 1.02 mmol) and Pd (PPh3) 4 (32 mg, 0.03 mmol) and then refluxed for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered through Celite. The filtrate was washed with aq. NaHCO 3. and brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography to give 65 mg of the desired compound (46%). 1 H-NMR (DMSO, 400 MHz): 9.63 (s, 1 H); 9.45 (s, 1 H); 7.93 (s, 1 H); 7.78 (t, 1 H); 7.64 -7.71 (m, 1 H); 7.52-7.60 (m, 1 H); 7.34-7.41 (m, 1 H); 7.21-7.31 (m, 3 H); 6.94 (t, 1 H); 3.36 -3.51 (m, 2 H); 3.23-3.34 (m, 2 H); 1, 75-1, 92 (m, 2 H). MS (ESI): [M + Hf = 387. EXAMPLE 46 Preparation of W-benzyl-4- (4,4-d-oxo-4-tia-2,5,9-triaza-1 (2 , 4) -pIrimidin-3 (1, 3) - The compound of Example 46 was prepared according to a GP 3 from 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3) (1, 3) -benzenocyclononafan-15-yl) benzenacetic (Intermediate 9) and benzylamine. Performance 15%. 1 H-NMR (DMSO, 300 MHz): 9.56 (s, 1 H); 9.41 (s br, 1 H); 8.57 (t br, 1 H); 7.70 - 7.78 (m, 2 H); 7.16-7.40 (m, 12 H); 6.91 (t br, 1 H); 4.24 (d, 2 H); 3.49 (s, 2 H); 3.18 - 3.45 (m, 4 H); 1, 72 -1, 88 (m, 2 H).

Example 47 Preparation of 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-15-yl) - W-phenylbenzenepropanamide The compound of Example 47 was prepared according to a GP 3 from 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin -3 (1, 3) -benzenocyclononafan-15-yl) benzenepropanoic (Intermediate 8) and aniline. Performance 50%. 1 H-NMR (DMSO, 300 MHz): 9.91 (s, 1 H); 9.53 (s, 1 H); 9.41 (s, 1 H); 7.68 - 7.80 (m, 2 H); 7.57 (d, 2 H); 7.20-7.40 (m, 10 H); 6.98 (t, 1 H); 6.89 (t br, 1 H); 3.18 - 3.45 (m, 4 H); 2.92 (t, 2 H); 2.63 (t, 2 H); 1, 72-1, 87 (m, 2 H). MS (ESI): [M + H] * = 529. EXAMPLE 48 Preparation of rV-benzyl-4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) - pyrimidin-3 (1,3) -benzenocyclononafan-1s-jl) benzenepropanamide The compound of Example 48 was prepared according to a GP 3 from 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyr Imin-3 (1, 3) -benzenecyclononafan-15-yl) benzenepropanoic (Intermediate 8) and benzylamine. Performance 46%. 1 H-N R (DMSO, 300 MHz): 9.55 (s, 1 H); 9.41 (s, 1 H); 8.33 (t, 1 H); 7.68 - 7.78 (m, 2 H); 7.12-7.41 (m, 12 H); 6.89 (t br, 1 H); 4.27 (d, 2 H); 3.16 - 3.44 (m, 4 H); 2.86 (t, 2 H); -2.47 (t, "2 H", mostly covered by the DMSO peak); 1, 72-1, 87 (m, 2 H). MS (ESI): [M + Hf = 544. EXAMPLE 49 Preparation of 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1, 3) -benzenocyclononafan-5-yl) - / V-phenylbenzenacetamide The compound of Example 49 was prepared according to a GP3 from 4- (4,4-dioxo-4-tia-2,5,9-triaza-1 (2,4) -pyrimide). d-n-3 (1,3) -benzenecyclononafan-15-yl) benzenacetic (Intermediate 9) and aniline. Performance 32%. H-NMR (DMSO, 400 MHz): 10.18 (s, 1 H); 9.56 (s, 1 H); 9.41 (s, 1 H); 7.75 (s, 1 H); 7.72 (t, 1 H); 7.58 (d, 2 H); 7.40 (d, 2 H); 7.22-7.37 (m, 7 H); 7.01 (t, 1 H); 6.91 (t br, 1 H); 3.62 (s, 2 H); 3.32 - 3.41 (m, 2 H); 3.19 - 3.25 (m, 2 H); 1, 75-1, 86 (m, 2 H). MS (ESI): [M + Hf = 515. EXAMPLE 50 Preparation of 4,4-dioxide 15-ethynyl-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) benzenecyclononanefano Weigh and introduce 100 mg of 4,4-dioxide of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane (0, 23 mmol), 8 mg of PdCI2 (PPh3) 2 (0.0115 mmol, 5 mol%) and Cul 4 mg (0.023 mmol, 10 mol%) in a Schlenk vessel and placed under an argon atmosphere. Dry DMF (2 mL) was added, followed by 0.64 mL of triethylamine (4.6 mmol, 20 eq.) And 0.3 mL of TMS-acetylene (1.15 mmol, 5 eq). The resulting solution was stirred for 90 min, diluted with ethyl acetate and cooled with water. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried and concentrated in vacuo. The residue was taken up in 3 ml of THF and treated under argon with 0.3 ml of a solution of TBAF (1.0 M in THF, 0.3 mmol). The resulting solution was stirred for 1 h at room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. Flash column chromatography gave 26 mg (34%) of the desired alkyne as a whitish solid. 1 H-NMR (DMSO, 300 MHz): 9.80 (s, 1 H); 9.35 (s, 1 H); 8.02 (s, 1 H); 7.75 (t, 1 H); 7.20-7.38 (m, 4 H); 4.41 (s, 1 H); 3.35 - 3.43 (m, 2 H); 3.20-3.30 (m, 2 H); 1, 75-1, 88 (m, 2 H). MS (ESI): [MH] "= 328. Examples 51 and 52 Preparation of 4,4-dioxide of 15 - ((Z) -styryl) -4-thia-2,5,9-triaza-1 (2, 4) -pyrimidine-3 (1,3) -benzenecyclononafano (Example 51) and 4,4-dioxide of 1-CI-phenol-vinyi-tia ^. SS-triaza-ICa ^ J-plrimidin-Síl .a) -benzenecyclononanefano (Example 52) Example 51 Example 52 A suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide was stirred (165 mg, 0.38 mmol), palladium (II) acetate), (8.6 mg, 0.038 mmol), triphenylphosphine (20 mg, 0.08 mmol), potassium acetate (150 mg, 1.5 mmol), tetra-n-propylammonium bromide (101 mg, 0.38 mmol) and styrene (44 μ ?, 0.38 mmol) in DMF under argon at 70 ° C for 7 h. Then, the reaction mixture was poured into ice cold aqueous sodium chloride solution. It was stirred for 8 h at 23 ° C. Then, the suspension was filtered and the crude precipitate was purified by column chromatography on silica gel. The obtained mixture of compounds of examples 51 and 52 was separated by preparative HPLC (column: Xterra RP18, eluent: acetonitrile, water, 0.1% NH3) to give 22 mg (14%) of the compound of Example 51 and 4 mg (2.6%) of the compound of Example 52. Example 51: 1 H-NMR (DMSO): d = 9.55 (s, 1 H); 9.44 (s, 1 H); 7.79 (t, 1 H); 7.64 (s, 1 H); 7.15-7.40 (m, 9 H); 6.00 (d, 1 H); 6.31 (d, 1 H); 3.60 (m, 2 H); 3.40 (m, 2 H); 1.82 (m, 2 H).

Example 52: 1 H-NMR (DMSO): d = 9.63 (s, 1 H); 9.42 (s, 1 H); 7.73 (t, 1 H); 7.70 (s, 1 H); 7.25-7.42 (m, 9 H); 5.82 (s, 1 H); 5.33 (s, 1 H); 3.61 (m, 2 H); 3.40 (m, 2 H); 1.74 (m, 2 H).

Example 53 Preparation of 15- (2-phenylethyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidine-4,4-dioxide (1.3 -benzenecyclononanefano A suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide (200 mg, 0, 46 mmol), phenylacetylene (61 μl, 5.56 mmol), copper (I) iodide (25 mg) and Pd (PPh3) 4 (54 mg, 0.046 mmol) in Et3N (20 mL) at 60 ° C. for 2.5 hours. Then, the reaction mixture was poured into water. It was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude material obtained was purified by recrystallization from a mixture of dichloromethane / methanol (8: 2). 175 mg (93%) of product were isolated. 1 H-NR (DMSO): d = 9.82 (s, 1 H); 9.38 (s, 1 H); 8, 11 (s, 1 H); 7.77 (t, 1 H); 7.22-7.62 (m, 9H); 3.44 (m, 2H); 3.40 (m, 2H); 1.84 (m, 2H). S (ESI): [M + H] + = 406 Example 54 Preparation of 4,4-dioxide of 15- (2-phenylethyl) -4-thia-2,5,9-triaza-1 (2,4) - pyrimidim-3 (1,3) -benzenecyclononane A solution of 4,4-dioxide of 1- (2-phenylethynyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane (100 g) was stirred. mg, 0.25 mmol) and 10% palladium on charcoal (20 mg) in a mixture of tetrahydrofuran (5 ml) and ethanol (1 ml) under a hydrogen atmosphere (ambient pressure) for 6 hours at 23 ° C. It was then filtered through Celite and evaporated to vacuum. The crude material was recrystallized from a dichloromethane / methanol (8: 2) mixture. 66 mg (65%) of product were isolated. 1 H-NMR (DMSO): d = 9.40 (s, 1 H); 9.31 (s, 1 H); 7.73 (t, 1 H); 7.59 (s, 1 H); 7.10-7.36 (m, 9H); 3.39 (m, 2H); 3.26 (m, 2H); 2.72 (t, 2H); 2.55 (t, 2H); 1.80 (m, 2H) ppm. MS (ESI): [M + Hf = 410 Example 55 Preparation of 4 - [(4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 ( 1, 3) -benzenocyclononafan-5-yl)] - / V-methylbenzenamine To a solution of Intermediate 10 (88 mg, 0.17 mmol) in acetonitrile (12 mL) was added 4 N HCl in dioxane (0.6 mL, 2.4 mmol) and the resulting mixture was stirred overnight at room temperature. ambient. Then, another portion of 4 N HCl in dioxane (0.2 ml, 0.8 mmol) was added and stirring was continued at room temperature for 3 h. The precipitate was isolated by filtration, washed with acetonitrile and dissolved in water by addition of aq K2CO3, the pH was kept at 10, the mixture was stirred for 1 h at room temperature and the precipitated product was isolated by filtration and dried to give the pure product (40 mg, 57%). 1 H-NMR (DMSO, 400 MHz): 9.47 (s, 1 H); 9.43 (s, 1 H); 7.73 (t br, 1 H); 7.68 (s, 1 H); 7.32 (t, 1 H); 7.24 (me, 2 H); 7.07 (d, 2 H); 6.72 (t br, 1 H); 6.58 (d, 2 H); 5.73 (q, 1 H); 3.32 - 3.43 (m, 2 H); 3.17 - 3.28 (m, 2 H); 2.66 (d, 3 H); 1, 73-1, 88 (m, 2 H). MS (ESI): [M + H] * = 411. EXAMPLE 56 Preparation of 1,1-dimethylethyl-4 - [(4,4-d -oxo-4-thia-2,5,9-triaza-1 ( 2,4) -pyrimidine-3 (1,3) - benzenecyclononafan-1 s-il)] piperazine-1-carboxylate To a suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-4,4-dioxide (86 mg, 0.20 mmol) in DMSO (2 mL) was added tert-butyl piperazine carboxylate (186 mg, 1.00 mmol), copper (II) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0, 20 mmol) and potassium carbonate (55 mg, 0.40 mmol). The resulting mixture was stirred under a nitrogen atmosphere for 6 h at 100 ° C. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was triturated with water (5 ml), followed by purification by HPLC (Purospher Star C18 5 μ 25x150 mm, water (gradient of (+0.2% NH3 ) / acetonitrile) Yield 13%, 1 H-NMR (DMSO, 400 MHz): 9.40 (s br, 1 H), 9.34 (s, 1 H), 7.72 (t, 1 H); 7.68 (s, 1 H), 7.32 (t, 1 H), 7.17 - 7.24 (m, 2 H), 7.03 (s br, 1 H), 3, 18 - 3 , 58 (m, 8 H), 2.69 (s br, 4 H), 1, 74-1, 87 (m, 2 H), 1.38 (s, 9 H), MS (ESI): [ M + H] + = 489. EXAMPLE 57 Preparation of 4,4-dioxide of 15- (morpholin-4-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononanefano To a suspension of 15-iodo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-4,4-dioxide (86 mg , 0.20 mmol) in DMSO (2 mL) was added morpholine (350 μ ?, 4.00 mmol), copper (II) iodide (19 mg, 0.10 mmol), L-proline (23 mg, , 20 mmol) and potassium carbonate (55 mg, 0.40 mmol). The resulting mixture was stirred under a nitrogen atmosphere for 6 h at 100 ° C. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was triturated with water (5 ml), followed by purification by HPLC (Purospher Star C18 5 μ 25x150 mm, water (gradient of (+0.2% NH3 ) / acetonitrile) Yield 29% .1H-NMR (DMSO, 300 MHz): 9.38 (s br, 1 H), 9.35 (s, 1 H), 7.64-7.76 (m, 2 H), 7.26-7.34 (m, 1 H), 7.15-7.23 (m, 2 H), 6.94 (t br, 1 H), 3.68 (me, 4) H), 3.20 - 3.47 (m, 4 H), 2.73 (me, 4 H), 1.72 - 1.89 (m, 2 H), MS (ESI): [M + H ] + = 390. The following compounds of the examples can be obtained using the methods described above or by standard procedures known to the specialists: 61 Biological experiment 1: ELISA method To demonstrate the inhibition activity of Tie2 kinase and high potency of Tie2 kinase, the following ELISA method was established and used. In this method, cultures of CHO cells, stably transfected with Tie2 according to known procedures, are stimulated with angiopoietin-2, using DHFR deficiency as selection marker. Specific autophosphorylation of Tie2 receptors is quantified with a sandwich ELISA, using anti-Tie2 antibodies for capture and anti-phosphotyrosine antibodies bound to HRP for detection. Materials: Greiner 96-well sterile culture dish FluoroNunc MaxiSorp Surface C, Nunc 96-well plate 96-well polypropylene plate to dilute the compound in DIVISO CHO Tie2 / DHFR (transfected cells) PBS-; PBS ++, DMSO Medium MEM alpha with Glutamax-I without ribonucleosides or Deoxyribonucleosides (Gibco No. 32561-029) with 10% FCS after dialysis and PenStrep 1% Lysis buffer: 1"Complete" tablet of protease inhibitor 1 measurement of vanadate (1 ml> 40 mg / ml, working solution 2 mM) taken to 50 ml with Duschl-Puffer solution, pH 7.6 Antibody 1 anti-TIE-ll 1: 425 in buffer solution, pH 9.6 Stock solution: 1.275 mg / ml > working solution: 3 pg / ml PBST: 2 bottles of PBS (10x) + 10 ml of Tween, filled with water-VE RotiBlock 1: 10 in water-VE Anti-phosphotyrosine conjugated with HRP 1: 10000 in TopBlock 3% TopBlock 3% in PBST Chemiluminescent BM Substrate for ELISA (POD) Solution B 1: Solution A 100 Culture medium for SF9 cells Ang2-Fc in culture medium for SF9 cells Cell experiment: 5 x 10 4 cells / well / 98 μm are placed ? in a 96-well tissue culture plate. Incubate at 37 ° C / 5% C02. After 24 hours, add the compounds according to the desired concentrations. Also add 2 μ? of DMSO to the control and the stimulated values without compounds Y is mixed a few minutes at room temperature. 100 μ? of Ang2-Fc to all the cavities except the control, which receives medium for insects. It is incubated 20 minutes at 37 ° C. It is washed 3 times with PBS ++ 100 μ? of lysis buffer / cavity and stirred for a few minutes at room temperature. The lysates are stored at 20 ° C before being used for the ELISA Execution of the sandwich ELISA A 96-cavity plate is coated FluoroNunc MaxiSorp Surface C Mab1 anti-Tie2: 1: 425 in coating buffer at pH 9.6; 100 μ? / Cavity overnight at 4 ° C Wash 2x with PBST Plates are blocked with 250 μl / 1: 10 RotiBlock cavity in EV-water. Incubate for 2 hours at room temperature or overnight at 4 ° C with shaking. Wash 2 times in PBST. Thawed lysates are added to cavities and incubated overnight with shaking at 4 ° C. Washed 2x with PBST. 100 μ? / Cavity of anti-phosphotyrosine conjugated with HRP 1: 10000 in Top-Block 3% (TopBlock 3% in PBST) and incubated overnight under agitation Washed 6 times with PBST 100 pl / cavity of substrate for BM ELISA added Chemiluminescence (POD) solutions 1 and 2 (1: 100) Luminescence is determined with LumiCount. Biological experiment 2: HTRF assay with Tie-2-kinase To demonstrate the effectiveness of the compound according to the present invention, an HTRF assay with Tie-2-kinase was established. Tie-2 phosphorylates the tyrosine residues of the artificial substrate polyGAT (polyGluAlaTyr biotinila-do). Specific detection of the phosphorylated product is performed with a trimeric detection complex consisting of the phosphorylated substrate, streptavidin-XLent (SA-XLent), which binds to biotin, and anti-phosphotyrosine antibody labeled with europium cryptate PT66, which is binds phosphorylated tyrosine. The excitation of the fluorescence of europium with light at 337 nm results in the emission of extended life light at 620 nm. In the case where a trimeric detection complex has been formed, part of the energy will be transferred to the SA-XIent fluorophore, which will then emit by itself prolonged life light at 665 nm (FRET: fluorescence resonance energy transfer). The non-phosphorylated substrate does not emit light at 665 nm because the trimeric de-tection complex can not be formed. The measurement is made on a Packard Discovery or BMG Rubystar instrument. A counts (emission at 665 nm) will be divided by counts B (emission at 620 nm) and multiplied by a factor of 10000. The resulting values are called the "cavity ratio" of the sample. Material: Enzyme: Tie-2-kinase, own preparation, aliquots (12 x 10 ml) stored at -80 ° C Substrate: Biotin-labeled PoliGAT (1000 pg / ml); CIS Bio; No. 61 GATBLB; Aliquots stored at -20 ° C ATP: Amersham Pharmacia Biotech Inc. No. 27-2056-01; 100 mM; stored at -20 ° C Antibody: PT66-Eu ciprate; CIS Bio; No. 61T66KLB; 30 pg / ml; aliquots stored at -20 ° C SA-XLent; CIS Bio; No. 61 1 SAXLB; 1000 pg / ml; aliquots stored at -80 ° C Microplates: SV black plate 384 cavities, Greiner, No. 784076 Solutions: Assay buffer: 50 mM HEPES (pH 7.0), 25 mM MgCl2, 5 mM MnCl2, 1 mM DTT, 0.5mM Na3V04, 0.01% (v / v) of NP40, 1 x complete EDTA-free Working solution with enzyme: Tie-2 stock solution is diluted 1: 250 in assay buffer solution Enzyme working solution: PolyAGAT is diluted (1000 mg / ml, 36.23 μ? ) 1: 90.6 to 400 nM or 77.3 ng / well, diluted ATP (100 mM) 1: 5000 to 20.0 μ?,. Both dilutions in assay buffer. Final assay concentrations: poly-GAT: 200 nM or 5.25 pg / ml, ATP: 10 μ? (1 x Km each). Detection solution: 50 mM HEPES (pH 7.0), 0.2% BSA, 0.6 M KF, 200 mM EDTA, 2.5 ng / cuvette of PT66-europium cryptate, 90 ng / SA cavity -XLent Cis Bio. Test steps All steps at 20 ° C 1. Use 0.75 μ? of compound solution in 30% (v / v) of DMSO 2. Add 7 pl of working solution with substrate 3. Add 7 μ? of working solution with enzyme 4. Incubate for 75 minutes (reaction volume: 14.75 μ?) 5. Add 8 μ? of detection solution 6. Incubate for 180 minutes or overnight at 4 ° C (total volume: 22.75 μ?) 7. Measure the HTRF on a Packard Discovery or BMG Rubystar instrument (with a delay of 50 μe, an integrated time of 400 ps) Final concentrations (in a reaction volume of 14.75 μ?): Enzyme: unknown polyGAT (1 x Km): 200 nM (77.3 ng) ATP (1 x Km) : 10 μ DMSO: 1, 5% (v / v) Conditions of the buffer solutions. 50 mM HEPES (pH 7.0), MgCl225 m, MnCl25 m, 1 mM DTT, 0.5 mM NaV04, 0.01% (v / v) of NP40, 1 x complete Controls: C0: uninhibited reaction (only with DMSO) C: inhibited reaction with 20 μ staurosporine? Biological experiment 3: Proliferation test To test the toxicity, a cell proliferation test was established. Tumor cell lines (eg, Du 145) can be examined with the cell proliferation test. The cells were placed in RPMI 1640 culture medium, supplemented with 10% (v / v) fetal bovine serum, plus 1% (v / v) penicillin / streptomycin solution, at a cell density of 2000 cells / 100 μ. ? of medium per cavity (96-well plate). After three hours, the cells were washed with PBS (containing calcium and magnesium). 100 μ? of the above culture medium with bovine fetal serum 0.1% (v / v), and all were cultured at 37 ° C under a 5% C02 atmosphere. The next day, the compounds of the present invention were added in DMSO to obtain the appropriate concentrations and another 100 μ? of culture medium with bovine fetal serum 0.5% (v / v). After 5 days of cell culture at 37 ° C under a 5% C02 atmosphere, the cells were washed with PBS. 20 μ? of glutaraldehyde solution (11% (v / v)) and the cells were gently shaken at room temperature for 15 minutes. After washing the cells 3 times and dry them in the air. 100 μ? of crystalline violet solution (0.1% at pH 3.5) and the cells were shaken for 30 minutes. The cells were washed with tap water and air dried. The dye is dissolved with 100 μ? of acetic acid (10% (v / v)) low strong agitation for 5 minutes. The absorption was measured at a wavelength of 595 nm. Biological experiments show that the compounds presented in this application have high potency Tie2 kinase inhibition and auto-phosphorylation activity measured with the ELISA method. The IC50 values are less than 1 μ ?. At the same time, the toxicity of the compounds is much higher than 1 μ ?, different from that of other compounds in this kind of structure; the toxicity for the tumor cell lines is such that IC50 values less than 1 μ are observed. It has been found that certain compounds of the invention are potent inhibitors of Tie2. For example, the compounds synthesized in Examples 6, 7, 8, 9, 10, 11, 51 and 52 inhibit Tie2 with an IC50 of approximately 2 μ? or lower in the Tie2 kinase assay or in the Tie2 autophosphorylation test in ELISA. Although they exhibit an inhibition activity of Tie2 kinase with high potency, it has been found that certain compounds of the invention are in particular weakly cytotoxic or non-cytotoxic. More specifically, the compounds of the selected examples 6, 7, 8, 9 and 10 exhibited an IC50 > 1 μ? in the state of cytotoxicity using the DU 145 cell line. Biological experiment 4: Tie-2 assay without prior kinase activation A recombinant fusion protein of GST as a kinase and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by affinity chromatography on glutathione-sepharose. Alternatively, a commercially available GST-Tie2 fusion protein (Upstate Biotechnology, Dundee, Scotland) can be used. The biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in the form of an amide), which can be purchased, for example, from Biosynthan GmbH (Berlin-Buch, Germany), was used as the substrate for the kinase reaction.

Tie-2 (3.5 ng / measurement point) was incubated for 60 minutes at 22 ° C in the presence of 10 μ adenosine tri-phosphate. (ATP) and peptide substrate 1 μ? (Biotin-Ahx-EPKDDAYPLYSDFG-NH2), with different concentrations of test compounds (0 μ? and concentrations in the range of 0.001-20?) in 5 μ? of assay buffer [Hepes / NaOH 50 mM, pH 7, MgCl2 10 mM, MnCit. 0.5 mM, 1.0 mM dithiothreitol, 0.01% NP40, mixture of protease inhibitors (Roche's "complete without EDTA", 1 tablet per 2.5 ml), 1% (v / v) of dimethyl sulfoxide]. The reaction stopped adding 5 μ? of an aqueous buffer solution (25 mM Hepes / NaOH, pH 7.5, 0.28% (w / v) bovine serum albumin) containing EDTA (90 mM) and HTRF reagents (homogeneous fluorescence with temporal resolution) ) Streptavidin-XLent (0.2 μ ?, from Cis Biointer-national, Marcoule, France) and PT66-Eu-chelate (0.3 ng / μ?; an anti-phospho-tyrosine antibody labeled with europium chelate) by Perkin Elmer). The resulting mixture was incubated for 1 hour at 22 ° C to allow binding of the biotinylated peptide to streptavidin-XLent and the chelate PT66-Eu. Next, the peptide substrate was evaluated by measuring the resonance transfer energy from the PT66-Eu chelate towards streptavidin-XLent. Accordingly, the fluorescence emissions were measured at 620 nm and 665 nm, after an excitation at 350 nm, in a HTRF reader, for example, a Rubystar device (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin -Elmer) The ratio between the emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated peptide substrate. The data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components of the assay but without enzyme = 100% inhibition) and the IC50 values were calculated with a 4-parameter adjustment using proprietary software. Biological experiment 5: Tie-2 kinase assay with kinase preactivation As a kinase, a recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (H-5) and purified by affinity chromatography on glutathione-sepharose. As a substrate for the kinase reaction, the biotinylated peptide bio-tine-Ahx-EPKDDAYPLYSDFG (amide-shaped C-terminus) was used, which can be purchased, for example, from the company Biosynthan GmbH (Berlin-Buch, Germany). For activation, Tie-2 was incubated at a concentration of 12.5 ng / μ? for 20 minutes at 22 ° C, in the presence of adenosine tri-phosphate (ATP) 250 μ? in assay buffer [50 mM Hepes / NaOH, pH 7, 10 mM MgCl 2, 0.5 mM MnCl 2, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture ("complete without EDTA") Roche, 1 tablet per 2.5 ml)]. For the subsequent kinase reaction, previously activated Tie-2 (0.5 ng / measurement point) was incubated for 20 minutes at 22 ° C, in the presence of 10 μ adenosine tri-phosphate (ATP). and peptide substrate (biotin-Ahx-EPKDDAYPLYSDFG-NH2) 1 μ ?, with different concentrate- of the test compounds (0 μ? and concentrations in the range of 0.001-20?) in 5 μ? of assay buffer [50 mM Hepes / NaOH, pH 7, 10 mM MgCl 2, 0.5 mM MnCl 2, 0.1 mM sodium orthovanadate, 0.1 mM dithiothreitol, 0.01% NP40, mixed protease inhibitor ("complete without EDTA" from Roche, 1 tablet per 2.5 ml), 1% (v / v) dimethyl sulfoxide]. The reaction was stopped by adding 5 μ? of an aqueous buffer solution (25 mM Hepes / NaOH, pH 7.5, 0.28% (w / v) of bovine serum albumin) containing EDTA (90 mM) and HTRF reagents (homogeneous fluorescence with temporal resolution) ) streptavidin-XLent (0.2 μ ?, from Cis Biointernational, Marcoule, France) and PT66-Eu-chelate (0.3 ng / μ?; an anti-phospho-tyrosine antibody labeled with europium chelate by Perkin Elmer) . The resulting mixture was incubated for 1 hour at 22 ° C to allow binding of the biotinylated peptide to streptavidin-XLent and the chelate PT66-Eu. Then, the peptide substrate was evaluated by measuring the resonance transfer energy from the PT66-Eu chelate towards the streptavidin-XLent. Accordingly, fluorescence emissions at 620 nm and 665 nm, after excitation at 350 nm, were measured in a HTRF reader, eg, a Rubystar device (BMG Lab-technologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio between the emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated peptide substrate. The data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components of the assay but without enzyme = 100% inhibition) and the IC50 values were calculated with a 4-parameter adjustment using proprietary software. Accordingly, the compounds of the present invention exhibit preferential activity as inhibitors of antiangiogenesis, and not as cytostatic or cytotoxic agents that directly affect tumor cells and other cells that proliferate in tissue.

Claims (5)

1. Claims 1. A compound that responds to General Formula I: wherein R1 is hydrogen and -CC ^ -alkyl; R2 is selected from the group consisting preferably of hydrogen, halogen, cyano, -NR4COR5, -NR4S (0) 2R5, -NR4CONRsR6, - NR4COOR5, -COR4, -S (0) 2R4, -S (0) 2NR4R5 and -CONR R5; R3 is selected from the group consisting preferably of -C-C6-alkyl, -C2-C6-alkenyl, -C2-C6-alkynyl, -C3-C8-cycloalkyl, -C6-Cn-aryl and -C5-C10-heteroaryl , wherein said residues are unsubstituted or are mono- or poly-substituted independently with hydroxy, halogen, -C-Ce-alkoxy, -C-Ce-alkylthio, amino, -C1-C6-alkyl, -d-Ce-hydroxyalkyl , -C2-C6-alkenyl, -C2-C6-alkynyl, -C, -C6-alkoxy-CrC6-alkyl, -NH-C ^ Ce-alkyl, -N ^ -Ce-alkyl) ^ S (0 ) 2 (C1-C6-alkyl), -C, -C6-alkanoyl, -CONR R5, -COR4, -C6-C1 aryl, -C5-C10-heteroaryl and / or -NR4R5, where -C6-Cn-ar And C5-C0-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -Ci-Ce-alkyl, -Ci-C6-alkoxy, -CF3 or -OCF3 and where one or more C of the C-chain of C3-C8-cycloalkyl are optionally mono or polysubstituted independently by nitrogen atoms, oxygen atoms, sulfur atoms and / or residues C = 0; or phenyl- (CH2) p-C0R4 or phenyl- (CH2) p-CONR4R5 optionally substituted, where p is an integer from 1 to 4, preferably 1 to 3, more preferably 1 or 2; R4, R5, and R6 are identical or different and are independently selected from the group consisting preferably of hydrogen and residues selected from the group consisting preferably of -Ci-do-alkyl, -d-C6-alkoxy, -C2- C6-alkenyl, -C2-C6-alkynyl, -C3-C8-cycloalkyl, -C6-Cn-aryl and -C5-C10-heteroaryl, where said residues are unsubstituted or are mono- or poly-substituted independently with hydroxy, halogen, -d-C6-alkoxy, -d-C6-alkylthio, amino, cyano, -CrC6-alkyl, -C3-C10-cycloalkyl, -d-C6-hydroxyalkyl, C2-C6-alkenyl, -C2-C6-alkynyl, -d-C6-alkoxy-d-C6-alkyl, -NH-CVC6-alkyl, -N (C, -C6-alkyl) 2, -S ( 0) (C, -C6-alkyl), -S (0) 2 (C1-C6-alkyl), -d-C6-alkanoyl, - CONR7R8, -COR7, carboxy, -C6-di-aryl , -C5-C10-heteroaryl or -NR7R8; where C6-C -aryl and -C5-C10-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-C6-alkyl, -d-C6-alkoxy, -CF3 or -OCF3 and where one or more C atoms of the C-chain of C3-C8-cycloalkyl are optionally mono or polysubstituted independently by nitrogen atoms, oxygen atoms, sulfur atoms and / or residues C = 0; R7 and R8 are the same or different and are independently selected from the group consisting preferably of -d-C6-alkyl or phenyl, optionally substituted with halogen, hydroxy, -d-C6-alkyl, -d-C6-alkoxy; , phenyl, -CF3 and -OCF3; and solvates, hydrates, N-oxides, isomers, diastereomers, enantiomers and salts thereof. 2. The compound of claim 1, wherein R3 is -d-C6-alkyl unsubstituted or mono- or polysubstituted independently from each other with hydroxy, halogen, -d-C6-alkoxy, -d-C6-alkylthio, amino, -NH-d-C6-alkyl, -N (C, -C6-alkyl) 2, -S (0) 2 (C, -C6-alkyl), -C, -C6-alkanoyl, -CONR R5, -COR4 , -dd-aryl, -C5-C10-heteroaryl and / or -NR R5, where -
2. C6-C-aryl and -C5-Ci0-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -C-C6-alkyl, -d-C6-alkoxy, -CF3 or -OCF3. The compound of claim 1, wherein R3 is unsubstituted -C2-C6-alkenyl or mono- or polysubstituted independently with hydroxy, halogen, -C-C6-alkoxy, amino, -CVCe-alkyl, -d-C6-hydroxyalkyl, -CrCe-alkoxy-CrCValkyl, -NH-d-C6-alkyl, -N (d-C6-al-chyl) 2, -S (0) 2 (C, -C6-alkyl), -d-C6 -alkyl, -CONR4R5, -COR4, -Ce-C -aryl, -C5-C10-heteroaryl and / or -NRR5, where unsubstituted or mono- or polysubstituted -C6-Cn-aryl and -C5-C10-heteroaryl independently with halogen, hydroxy, -d-C6-alkyl, -C6-alkoxy, -CF3 or -OCF3. The compound of claim 1, wherein R3 is -C2-C6-alkynyl unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -C (-C6-alkoxy, amino, -CVCe-alkyl, -d-C6-hydroxyalkyl, -d-Cs- alkoxy-d-di-alkyl, -NH-CrC6-alkyl, -N (d-C6-alkylo) 2, -S (0) 2 (C, -C6-alkyl), -d-C6- alkanoyl, -CONR4R5, -COR4, -Ce-C -aryl, -C5-C10-heteroaryl and / or -NRR5, where unsubstituted -C6-Cn-aryl and -C5-C10-heteroaryl or mono- or polysubstituted independently with halogen, hydroxy, -Ci-C6-alkyl, -C, -C6-alkoxy, -CF3 or -OCF3 The compound of claim 1, wherein R3 is unsubstituted or mono-C5-C7-cycloalkyl or polysubstituted independently with hydroxy, halogen, -d-C6-alkyl, -S (0) 2 (C1-C6-alkyl), -C, -C6-alkanoyl, -CONR4R5 and / or -COR4, where one or more atoms of C of the C-chain of C5-C7-cycloalkyl are optionally independently substituted by one or two nitrogen atoms The compound of claim 5, wherein R3 is piperazine or piperidine a, wherein said piperazine or piperidine is unsubstituted or is mono- or polysubstituted independently with -d-C6- alkyl, -S (0) 2 (C, -C6-alkyl), -C, -C6-alkanoyl, -CONR4R5 and / or -COR4. The compound of claim 1, wherein R3 is either: -Cg-C-aryl unsubstituted or mono- or polysubstituted independently with hydroxy, halogen, -d-C6-alkoxy, -d-Ce-alkylthio, amino, - d-C6-alkyl, -Ci-C6-hydroxyalkyl, d-C6-alkoxy-d-C6-alkyl, -NH-d-C6-alkyl, -N (Ci-C6-al-chyl) 2, -S ( 0) 2 (C, -C6-alkyl), -C6C6-alkanoyl, -COR4, -C6-Cii-aryl, -C5-C10-heteroaryl and / or -NR4R5, where -Ce-d-aryl and - C5-C10-heteroaryl unsubstituted or mono- or polysubstituted independently with halogen, hydroxy, -d-C6-alkyl, -d-Cg-alkoxy, -CF3 or -OCF3,; or: optionally substituted phenyl- (CH2) p-COR4 or optionally substituted phenyl- (CH2) p-CONR4R5, where p is an integer from 1 to 3, preferably 1 or 2. The compound of claim 7, wherein R3 is either: unsubstituted phenyl or mono- or polysubstituted independently with hydroxy, halogen, -C C6-alkoxy, -Ci-C6-alkylt, amino, -d-Ce-alkyl, -d-C6- hydroxyalkyl, d-C6-alkoxy-d-C6-alkyl, -NH-Ci-C6-alkyl, -N d-Ce-al-chyl) 2, -S (0) 2 (d-C6-alkyl) , -d-C6-alkanoyl, -COR4, -C6-C1 aryl, -C5-C10-heteroaryl and / or -NR4R5, where unsubstituted or mono- or polysubstituted -C6-Cn-aryl and -C5-C10-heteroaryl independently with halogen, hydroxy, -Ci-C6-alkyl, -C6-alkoxy, -CF3 or -OCF3; or: optionally substituted phenyl- (CH2) p-COR4 or optionally substituted phenyl- (CH2) p-CONR4R5, where p is an integer from 1 to 3, preferably 1 or 2. The compound of claim 7 or 8, wherein is either: unsubstituted phenyl or mono- or polysubstituted independently with halogen, -CrC6-alkoxy, -CVC6-alkyl, -C-hydroxyalkyl, C-Ce-alkoxy-CrC alkyl, -NH-C, -C6- alkyl, -N (C C6-alkyl) 2, -C Ce-alkanoyl, -COR4, and / or -NR R5; or: optionally substituted phenyl- (CH2) p-COR4 or optionally substituted phenyl- (CH2) p-CONR4R5. 10. The compound of any of claims 7 to 9, wherein R3 is phenyl mono- or polysubstituted independently with C, -C6-alkoxy, -d-Ce-alkyl. 11. The compound of claim 7, wherein R3 is phenyl. 12. The compound of any of Claims 1 or 11, selected from the group consisting of: 4- [4,4-dioxo-4D6-thia-2,5,9-triaza-1 (2,4) - pyrimidin-3 (1, 3) -benzenecyclononafan-15-yl] -W, / V-dimethylbenzenesulfonamide; 4- [4,4-dioxo-4D6-thia-2,5,9-tnaza-1 (2,4) -pyrimidn-3 (1,3) -benzenocyclononafan-15-yl] -benzenamine; 4- [4,4-dioxo-4D6-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl] - / / / V -dimethylbenzene amide; 15- (pyridin-4-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-4,4-dioxide; 4- [4,4-dioxo-4D6-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl] -benzonitrile; 4- [4,4-dioxo-4D6-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononapham-15-yl] methyl benzoate; 1 - [4- [4,4-dioxo-4n6-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-15-yl] phenyl] -ethanone; 4,4-dioxide 15-phenyl-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4- [4,4-dioxo-4D6-thia-2,5,9-triaza-1 (2,4) -pyrimidn-3 (1,3) -benzenocyclononafan-15-yl] phenol; 4,4-dioxido of 15- (4-methoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pinmidin-3 (1,3) -bencenacyclo-nonafano; 4,4-dioxide 15- (4-methylsulfonyl-phenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaptophan; 4,4-dioxide, 15- (4-ethylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (4-ethoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (3-methoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyridin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (4-S-propoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (4-methoxy-2-methylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (4-propylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- [4- (methoxymethyl) -phenyl] -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphne; 4,4-dioxide 15- (4-ethoxy-3-fluorophenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzene cyclononaphne; 4,4-dioxide 15- (4-propoxyphenyl) -4-lia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphane; 4,4-dioxide 15- (3-fluoro-4-propoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) ^ irimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (2,4-dimethoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (3-fluoro-4-methoxy-phenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4 - [(4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl)] benzenemethanol; 4,4-dioxide 15- (4-methylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (4 - / 'so-propylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) - benzenecyclononafon; 4,4-dioxide 15- (4-methoxypyrid-3-yl) -4-tia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1, 3) benzenecyclononaphane; 4,4-dioxide 15- (3-fluoro-4- / so-propoxyphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononanefano; 4,4-dioxide 15- (3-fluoro-4-methylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- [4- (benzyloxy) -3-fluorophenyl] -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) - benzenecyclononafon; 4,4-dioxide 15- [4- (benzyloxy) -2-fluorophenyl] -4-thia-2,5,9-triaza-1 (2,4) -pyrimidine-3 (1 , 3) -benzenecyclononanefano; 4,4-dioxide 15- (4-vinylphenyl) -4-thia-2,5,9-triaza-1 (2,4) -pyridin-3 (1,3) -benzenecyclononaptophan; 3 4- (4,4-dioxo-4 ia-2,5,9-triaza-1 (2,4) ^ irimidin-3 (1,3) -benzenocyclononafan-15-yl) phenyl] -1-phenylpropan- 1-one; 3- [4- (4i4-d.oxo-4-tia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan- 15-yl) phenyl] -1- (4-fluorophenyl) -propan-1 -one; 3- [4- (4,4-dioxo-4-thia-2,5,9-tnaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) phenyl] -1 - (4-methylphenyl) -propan-1-one; 1- (2,4-dimethylphenyl) -3- [4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) - benzenecyclononafan-15-yl) phenyl] -propan-1 -one; 3- [4- (4,4-dioxo-4-thia-2,5,9-tnaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) phenyl] -1 - (3-fluorophenyl) -propan-1 -one; 1- (4-chlorophenyl) -3- [4- (4,4-d-oxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) - benzenecyclononafan-15-yl) phenyl] -propan-1 -one; 3- [4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) phenyl] -1 - (4-methoxy-phenyl) propan-1 -one;
3. 3- [4- (4,4-d¡oxo-4 ¡a-2,5,9-tr¡aza-1 (2,4) ^ ¡r¡m¡d¡n-3 (1, 3) -benzenocyclononafan-15-yl) phenyl] -1- (2-fluorophenyl) -propan-1-one; 4- (4,4-dioxo-4-tia-2,5,9 riaza-1 (2,4) -p¡r¡m¡din-3 (1,3) -benzenocyclononafan-15- il) methyl benzene propanoate; 4- (4,4-d.oxo-4-thia-2,5,9-riaza-1 (2,4) -pyridin-3 (1,3) -benzenecyclononafan-15-yl) benzene ethyl propanoate; 4- (4,4-dioxo-4 aia-2,5,9-aza-1 (2,4) -pinmidin-3 (1,3) -benzenocyclononafan-15-yl) benzene-methyl acetate; 4,4-dioxide of 15- (thien-2-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyridin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (thien-3-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaptophan; V-benzyl-4- (4,4-dioxo-4-thia-2,5,94 -riaza-1 (2,4) ^ irimidin-3 (1,3) -benzenocyclononafan-15-yl) bencenacetamide; 4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) - / / - phenylbenzenepropanamide; A / -benzyl-4- (4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) benzenepropanamide; 4- (4,4-dioxo-44ia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenocyclononafan-15-yl) -V-phenylbenzenacetamide; 4-dioxy-15-ethynyl-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15 - ((Z) -styryl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (1-phenyl-vinyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (2-phenylethyl) -4-thia-2,5,9-triaza-1 (2,4) -pyridin-3 (1,3) -benzenecyclononaphhane; 4,4-dioxide 15- (2-phenylethyl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononaphhane;
4. 4 - [(4,4-dioxo-4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononafan-1
5. 5-yl)] - / V -methylbenzenamine; 1, 1 -dimethylethyl-4 - [(4,4-dioxo-4-tia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) -benzenecyclononane- 15-yl)] piperazin-1-carboxylate; and 4,4-dioxide of 15- (morpholin-4-yl) -4-thia-2,5,9-triaza-1 (2,4) -pyrimidin-3 (1,3) - benzenecyclononafon; The method for preparing the compound of any of claims 12 comprising the following step: A I where R1 and R2 in the halogenated macrocycle A have the same values as in Formula I, where in Formula I R3 is selected from the group comprising ethyl, vinyl, ethynyl, phenyl or heteroaryl unsubstituted or substituted with the indicated values. 14. A method for preparing the compound of any of claims 1 -12 comprising the following step: where R1 and R2 in the halogenated macrocycle A have the same values as in Formula I, where in Formula I R3 is -C3-C10-unsubstituted or substituted cycloalkyl containing at least one hetero atom, it replaces the halide in macrocycle A 15. A pharmaceutical composition comprising the compounds of Formula I of according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or hydrolysable ester thereof, and a diluent or carrier acceptable for pharmaceutical use. 16. Use of the compound of any of claims 1 to 12 in the manufacture of a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or diseases accompanied by dysregulated vascular growth. 17. The use according to claim 16, wherein said diseases are retinopathy, other ophthalmological conditions dependent on angiogenesis, rheumatoid arthritis and other inflammatory diseases associated with angiogenesis. 18. The use of claim 17, wherein said ophthalmological diseases dependent on angiogenesis are rejection to corneal transplantation, macular degeneration related to age. The use of claim 17, wherein said inflammatory diseases associated with angiogenesis are psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, cerebrovascular accidents and diseases of the intestine. 20. The use according to claim 16, wherein said diseases are coronary and peripheral artery disorders. 21. The use according to claim 16, wherein said diseases are ascites, edema, such as edema associated with brain tumors, trauma caused by high altitudes, cerebral edema induced by hypoxia, pulmonary edema and macular edema or subsequent edema to burns and traumatisms , chronic lung disease, respiratory distress syndrome in adults, bone resorption and benign proliferative diseases such as myoma, benign prosthetic hyperplasia and scarring and wounds to reduce scar formation, reduce scar formation during the regeneration of damaged nerves, endometriosis, pre-eclampsia, post-menopausal hemorrhages and ovarian hyperstimulation. 22. The use according to claim 16, wherein the disease is a solid tumor and / or metastasis thereof. 23. A compound of Formula (I) according to any one of claims 1 to 12, to be used as inhibitor of the Tie2 kinase. 24. A method of treating a dysregulated vascular growth disease or diseases accompanied by an unregulated vascular growth comprising the use of the compound of any one of claims 1 to 12. 25. The method according to claim 24, wherein the diseases are retinopathy, other ophthalmological conditions dependent on angiogenesis rheumatoid arthritis and other inflammatory diseases associated with angiogenesis. 26. The method according to claim 25, wherein the ophthalmological conditions dependent on angiogenesis are the rejection of corneal transplantation and macular degeneration related to age. The method according to claim 25, wherein the inflammatory diseases associated with angiogenesis are psoriasis, delayed-type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, accidents cerebrovascular diseases and intestinal inflammatory diseases. 28. The method according to claim 24, wherein the diseases are coronary and peripheral artery disorders. 29. The method according to claim 24, wherein the diseases are ascites, edema, such as edema associated with brain tumors, trauma caused by high altitudes., cerebral edema induced by hypoxia, pulmonary edema and macular edema following burns and trauma, chronic lung disease, respiratory distress syndrome in adults, bone resorption and for benign proliferative diseases such as myoma, benign prostatic hyperplasia and scarring and wounding reduce the formation of scars, reduce the formation of scars during the regeneration of damaged nerves, endometriosis, pre-eclampsia, post-menopausal hemorrhages and ovarian hyperstimulation. 30. The method according to claim 24, wherein the disease is a solid tumor and / or its metastasis.