ES2355718T3 - PIRROLOPIRIDAZINE COMPOUNDS AND PROCEDURES FOR USING THE SAME FOR THE TREATMENT OF PROLIFERATIVE DISORDERS. - Google Patents

Abstract

A compound of formula (I): ** (See formula) ** including its pharmaceutically acceptable enantiomers, diastereomers, salts and solvates, in which: R1 is selected from the group consisting of H, hydroxyl, alkyl, aralkyl, halogen, OR1 ', OC (O) R1', OC (O) OR1 ', OC (O) NR1'R1' ', OS (O) 2R1' '' and OS (O) 2NR1'R1 ''; wherein R1 'and R1' 'are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, heterocycle and cycloalkyl groups; R1 'and R1' 'can also be taken together from one of a cycloalkyl, an aryl and a heterocyclic group; R1 '' 'is selected from the group consisting of alkyl, aryl, aralkyl, heterocycle and cycloalkyl; R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R1'OC (O), R1'C (O), R1''R1'NC (O), R1 '' 'O (O) 2S, R1'R1''N (O) 2S and R1 '' '(O) nS, where n is the integer selected from 1 or 2; R1 and R2 can be taken together to form a cycloalkyl, aryl or heterocyclic group; X is selected from the group consisting of a valence bond, O, S and NR2 '; and R2 'is selected from the group consisting of H, alkyl, aralkyl, C (O) R1, C (O) OR1, SO2NR1'R1' ', C (O) NR1'R1' 'and SO2R1' ''; with the proviso that when X is S, R2 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl; R3 is selected from the group consisting of H, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido, halogen, amine, substituted amine, OR3 ', CH2OR3', CH2NR3'R3 '', CH2SR3 ', OC (O) R3 ', OC (O) OR3' ', OC (O) NR3'R3' ', OS (O) 2R3' and OS (O) 2NR3'R3 ''; wherein R3 'and R3' 'are each independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; R3 'and R3' 'can also be taken together to form a cycloalkyl, aryl or heterocyclic group; when R3 is a carbalkoxy, acyl or carboxamido group, these groups are optionally substituted with one or two substituent groups, said substituent groups are independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; said substituent groups can also be taken together to form a cycloalkyl, aryl or heterocyclic group; R2 and R3 can also be taken together to form a cycloalkyl, aryl or heterocyclic group; R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R1'OC (O), R1'C (O), R1''R1'NC (O), R1''O (O) 2S , R1'R1''N (O) 2S and R1 '' '(O) nS, where n is the integer selected from 1 or 2; And it is selected from the group consisting of a valence bond, O, S and NR4 '; R4 'is selected from the group consisting of H, alkyl, aralkyl, a heterocycle, C (O) R1, C (O) OR1, S (O2) NR1'R1' ', C (O) NR1'R1' 'and S (O2) R1; with the proviso that when Y is S, R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle and aralkyl; when Y is NR4 ', R4' can be taken together with R3 to form a heterocyclic ring system; R5 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, a heterocycle group, aryl, aralkyl, acyl, substituted alkylene, R1'OC (O), R1'C (O), R1''R1 ' NC (O), R1 '' 'O (O) 2S, R1'R1''N (O) 2S and R1' '' (O) nS; where n is the integer 1 or 2; Z is selected from the group consisting of a valence bond, O, S and NR5 '; R5 'is selected from the group consisting of H, alkyl, aralkyl and a heterocycle; with the proviso that when Z is a valence bond, R5 is selected from the group consisting of H, halogen, a substituted alkylene group and a cyano group; and, with the other condition that when Z is S, R5 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl; and R6 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, a heterocycle, acyl, carbalkoxy and carboxamido; said carbalkoxy, acyl and carboxamido groups are optionally substituted with one or two substituent groups, each of which is independently selected from the group consisting of H, alkyl, aralkyl and a heterocycle, wherein, "alkyl" or "alk" in reference to R1, R1 ', R1' ', R1' '', R2, R2 ', R3, R3', R3 '', R4, R4 ', R5, R5' and R6, refers to chain hydrocarbon radicals linear or branched, optionally substituted with 1 to 4 substituents which may include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogen, heterocycle, hydroxy, cyano, nitro, amino, monoalkylamino, dialkylamino, hydroxylamine, sulfonate, sulfamide, cyano-guanidine, oxo, carbalkoxy, carboxamido, SOn, in which n is 0, 1 or 2, and / or acyl groups.

Description

Pyrrolopyridazine compounds and procedures of their use for the treatment of disorders proliferative

Related Requests

The present application claims the benefit of priority of provisional US applications No. 60 / 368,249, filed on March 28, 2002 and 60 / 402,118, filed on August 8, 2002.

Field of the Invention

The present invention relates to compounds of pyrrolopyridazine, to procedures for preparing these compounds and their use for the treatment of disorders Proliferative and other disorders.

Background of the invention

Protein kinases are a class of enzymes which catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue located in a protein substrate Protein kinases clearly play a function in normal cell growth. Many of the growth factor receptor proteins have intracellular domains that function as protein kinases, and it is a Through this function they have signaling effect. The interaction of growth factors with their receptors is a necessary event in the normal regulation of cell growth, and the phosphorylation state of the substrate proteins is often related to cell growth modulation.

The family of factor receptors Human epidermal growth (HER) consists of four distinct tyrosine kinase receptors called HER1, HER2, HER3 and HER4. These kinases are also known as erbB1, erbB2, etc. HER1 It is commonly known as the growth factor receptor epidermal (EGFr). With the exception of HER3, these receptors they have specific intrinsic protein kinase activity for Tyrosine residues of phosphorus acceptor proteins. Kinases HER are expressed in most epithelial cells, as well as in the cells of tumors of epithelial origin. Often express themselves in cells of mesenchymal tumors such as sarcomas or rhabdomyosarcomas Tyrosine kinase receptors (RTK) such as HER1 and HER2 are involved in cell proliferation and are associated with diseases such as psoriasis and cancer. Be knows that the interruption of signal transduction by Inhibition of these kinases in target cells has an effect antiproliferative and therapeutic.

Enzymatic activity of receptors Tyrosine kinase can be stimulated by overexpression or by ligand mediated dimerization. The formation of homodimers, as well as heterodimers for the receptor family HER An example of homodimerization is the dimerization of HER1 (EGF receptor) by one of the EGF family ligands (which includes the EGF, transforming growth factor alpha, betacellulin, heparin-binding EGF and epiregulin). The heterodimerization between the four HER kinase receptors can be promote by union members of the family of ligands of heregulin (also called neuregulin). Such heterodimerization, which implies HER2 and HER3 or a combination of HER3 / HER4, gives as result a significant stimulation of the activity of tyrosine kinase of the receptor dimers even though one of the Receptors (HER3) is enzymatically inert. It has been shown that the HER2 kinase activity is also activated under the overexpression of the receptor only in a variety of types cell phones. Activation of homodimers and heterodimers receptors results in phosphorylation of tyrosine residues in receptors and in other intracellular proteins. This is what follow the activation of intracellular signaling pathways such such as those involving microtubule-associated protein kinase (MAP kinase) and phosphatidylinositol 3-kinase (PI3 kinase). It has been shown that the activation of these pathways gives place to cell proliferation and inhibition of apoptosis. It has been shown that inhibition of kinase signaling HER inhibits cell proliferation and survival.

Deregulation of EGF receptors plays a role in aberrant cyst growth epithelial in the disease described as kidney disease polycystic [Du, J., Wilson, P. D., Amer. J. Physio., 269 (2 Pt 1), 487 (1995); Nauta, J., et al., Pediatric Research, 37 (6), 755 (nineteen ninety five); Gattone, V. H. et al., Developmental Biology, 169 (2), 504 (nineteen ninety five); Wilson, P. D. et al., Eur. J. Cell Biol., 61 (1), 131, (1993)]. The compounds of the present invention, which inhibit the catalytic function of EGF receptors, are, therefore, Useful for the treatment of this disease.

The mitogen-activated protein kinase (MAPK) pathway is an important pathway in the cell signal transduction cascade of growth factors to the cell nucleus. The pathway involves kinases at two levels: MAP kinase kinases (MAPKK) and their MAP kinase substrates (mitogen activated protein) (MAPK). There are different isoforms in the MAP kinase family. [For a review, see Seger, R .; Krebs, EG FASEB, 9, 726, (1995)]. The compounds of the present invention can inhibit the action of one or both of these kinases: MEK, a MAP kinase kinase and its ERK substrate, a MAP kinase. ERK (extracellular regulated kinases), a p42 MAPK, has been found to be essential for cell differentiation and proliferation. It has been found that overexpression and / or overactivation of MEK or ERK are associated with various types of human cancer [For example, Sivaraman, VS et al., CCJ Clin. Invest., 99, 1478 (1997)]. It has been shown that MEK inhibition that prevents ERK activation and subsequent activation of ERK substrates in cells, resulting in inhibition of cell growth stimulation and reversal of the phenotype of ras transformed cells [Dudley, DT et al., Proc. Nat. Acad. Sci., 92, 7686 (1995)].

The members of the raf kinase family phosphorylate serine residues in MEK. There are three members serine / threonine kinase of the raf family known as a-raf, b-raf and c-raf. Although mutations in raf genes they are rare in human cancers, c-raf is activated by the ras oncogene, which is mutated in a large number of human tumors Therefore, the inhibition of the activity of c-raf kinase can provide a way to prevent the growth of ras-mediated tumors [Campbell, S. L., Oncogene, 17, 1395 (1998)].

The protein tyrosine kinase family Src cytoplasmic consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) who participate in a diversity of signaling pathways [Schwartzberg, P. L., Oncogene, 17, 1463 (1998)]. The prototype member of this tyrosine kinase family is p60 src (Src). Src is involved in proliferation and in Migration responses in many cell types. In studies limited, it has been shown that Src activity is high in breast tumors, colon (approximately 90%), pancreatic (> 90%) and liver (> 90%). A large increase in activity of Src is also associated with metastases (> 90%) and poor prognosis. Src's antisense message prevents cell growth colon tumors in athymic mice [Staley et al., Cell Growtlz & Differentation, 8, 269 (1997)], which suggests that Src inhibitors should slow tumor growth. further of its role in cell proliferation, Src also acts in the Stress response pathways, including hypoxia response. Previous studies have shown that tumor cells from colon produced by genetic engineering to express the Src antisense message form tumors that demonstrate reduced vascularization in nude mouse models [Ellis, and col., J. Biol. Chem., 273,1052 (1998)], suggesting that Src inhibitors could be antiangiogenic, as well as antiproliferative

Apart from his role in cancer, Src also It seems to play a role in osteoporosis. It has been found that genetically engineered mice to have poor src production show osteopetrosis, resorption insufficient bone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin. Invest., 90, 1622 (1992)]. This defect was characterized by the lack of activity of osteoclasts. Since the Osteoclasts normally express high levels of Src, the inhibition of Src kinase activity may be useful in the Osteoporosis treatment [Missbach, M., Bone, 24, 437 (1999)].

In addition to EGFr, there are several other RTKs including FGFr, the fibroblast growth factor receptor (FGF); flk-1, also known as KDR and flt-1, the receptors for growth factor vascular endothelial (VEGF); and PDGFr, the receptor for the factor of platelet derived growth (PDGF). The formation of new blood vessels, a process known as angiogenesis, is essential for tumor growth. The two natural inhibitors of angiogenesis, angiostatin and endostatin, inhibited drastically the growth of a variety of solid tumors. [O'Reilly, M. S., Cell, 79, 315 (1994); O'Reilly, M. S., Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell, 88, 277 (1997)]. While it is known that FGF and VEGF stimulate angiogenesis, the inhibition of the kinase activity of its receptors should block the angiogenic effects of these growth factors. In addition, the tyrosine kinase tie-1 receptors and tie-2 also play a fundamental role in the angiogenesis [Sato, T. N., Nature, 376, 70 (1995)]. The compounds which inhibit the kinase activity of FGFr, flk-1, flt-1, tie-1 or tie-2 they can inhibit the growth of tumors by their effect on the angiogenesis

PDGF is a powerful growth factor and chemoattractant for smooth muscle cells (SMC), and the narrowing of the coronary arteries after angioplasty is due in part to the increased proliferation of SMC in response to elevated PDGF levels. Therefore, Compounds that inhibit PDGFr kinase activity can be useful in the treatment of restenosis. Also, since PDGF and PDGFr are overexpressed in various types of human gliomas, small molecules capable of suppressing PDGFr activity have potential utility as cancer therapy [Nister, M., J. Biol. Chem., 266, 16755 (1991); Strawn, L. M., J. Biol. Chem. 269, 21215 (1994)].

In addition, a large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8 and TNF-? The overproduction of cytokines, such as IL-1 and TNF-? is involved in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, the psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease and insufficiency Congestive heart, among others [Henry et al., Drugs Fut., 24: 1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6: 807-823 (1999)]. Patient tests humans indicate that cytokine protein antagonists they are effective in the treatment of inflammatory diseases chronic, such as the monoclonal antibody against TNF-? (Enbrel) [Rankin et al., Br. J. Rheumatol., 34: 334-342 (1995)], and the protein of soluble receptor fusion of TNF-? -Fc (Etanercept) [Moreland et al. Ann. Intern. Med., 130: 478-486 (1999)].

The biosynthesis of TNF-? It occurs in many cell types in response to a stimulus external, such as a mitogen, an infectious organism or trauma. Important mediators of the production of TNF-? Are protein kinases activated by mitogens (MAP) and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including, but not limited to, proinflammatory cytokines, endotoxins, light ultraviolet and osmotic shock. Activation of p38 requires the dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) in threonine and tyrosine within a motive Thr-Gly-Tyr characteristic of p38 isoenzymes.

There are four known isoforms of p38, that is, p38-?, p38?, p38? and p38?. The α and β isoforms are expressed in the cells inflammatory and are key mediators of the production of TNF-? The inhibition of enzymes p38? and? in cells results in reduction of TNF-α expression levels. Also, the administration of p38? And? Inhibitors in animal models of inflammatory disease has shown that these inhibitors are effective in treating those diseases. Therefore, p38 enzymes play a role important in inflammatory processes mediated by IL-1 and TNF-?. The compounds which apparently inhibit p38 kinase and cytokines, such as IL-1 and TNF-? For use in The treatment of inflammatory diseases are disclosed in the  following published international patent applications: WO 12/12497 (quinazoline derivatives as inhibitors of p38 kinase); WO 00/56738 (pyridine and pyrimidine derivatives therefor purpose); WO 00/12497 (analyzes the relationship between inhibitors from p38 kinase); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors).

In short, the strict regulation of signal transduction normally exerted by the enzyme matrix Kinase is often lost in neoplastic cells. The compounds which modulate these kinases are therefore very desirable for the treatment of disorders associated with cell proliferation aberrant. In addition, the compounds that modulate cytokines associated with the inflammatory response are very desirable for the Treatment of inflammatory disorders.

EP 1 085 021 describes compounds of pyrrolo-pyridazine for the treatment of shock septic, of adult respiratory failure syndrome, of asthma, psoriasis, etc. that have a substituent that contains acid (or ester) in position 4 and an amide containing substituent (or hydrazide) in position 5 of the ring pyrrolo-pyridazine, and in particular the compounds with the following structure:

one

Summary of the Invention

Advantageously, the present invention provides compositions and procedures for the treatment of proliferative disorders, which include cancer and diseases inflammatory The procedures include the administration of a therapeutically effective amount of a kinase inhibitor of formula I, below, or one of its salts, solvates, or stereoisomers and, optionally, at least one therapeutic agent additional. The treatment is preferably administered to a mammal species, more preferably a human being, than need.

More specifically, the present invention provides a compound of formula I:

2

including its enantiomers, pharmaceutically acceptable diastereomers, salts and solvates, in the that:

R_ {1} is selected from the group consisting of H, hydroxyl, alkyl, aralkyl, halogen, OR1 ', OC (O) R_ {1} ', OC (O) OR_ {1}', OC (O) NR_ {1} 'R_ {1}' ', OS (O) 2 R 1 '' 'and OS (O) 2 NR 1 'R 1'; in which R_ {1} 'and R_ {1} '' are each independently selected from the group that It consists of groups H, alkyl, aryl, aralkyl, heterocycle and cycloalkyl; R_ {1} 'and R_ {1}' 'can also be taken together to form one of a cycloalkyl, an aryl and a group heterocyclic; R_ {1} '' 'is selected from the group consisting of alkyl, aryl, aralkyl, heterocycle and cycloalkyl;

R 2 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R 1 'OC (O),
R_ {1} 'C (O), R_ {1}''R_{1}' NC (O), R_ {1} '''O (O) 2 S, R_ {1}' R_ { 1 '' N (O) 2 S and R 1 '''(O) n S; where n is the integer selected from 1 or 2;

R_ {1} and R2 can be taken together to forming a cycloalkyl, aryl or heterocyclic group;

X is selected from the group consisting of a Valencia bond, O, S and NR2 '; and R2 is selected from group consisting of H, alkyl, aralkyl, C (O) R 1, C (O) OR 1, SO_ {2} NR_ {1} 'R_ {1}' ', C (O) NR_ {1}' R_ {1} '' and SO_ {R} {1} '' '; with the proviso that when X is S, R2 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl;

R 3 is selected from the group consisting of H, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido, halogen, amine, substituted amine, OR 3 ', CH 2 OR 3} ', CH_ {NR} {3}' R_ {3} '', CH_ {2} SR_ {3} ', OC (O) R_ {3}',
OC (O) OR_ {3} '', OC (O) NR_ {3} 'R_ {3}'', OS (O) 2 R_ {3}' and OS (O) 2 NR_ {3} 'R 3''; wherein R 3 'and R 3''are each independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; R 3 'and R 3''can also be taken together to form a cycloalkyl, aryl or heterocyclic group; when R 3 is a carbalkoxy, acyl or carboxamido group, these groups are optionally substituted with one or two substituent groups, said substituent groups are independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; said substituent groups can also be taken together to form a cycloalkyl, aryl or heterocyclic group;

R 2 and R 3 can also be taken together to form a cycloalkyl, aryl or heterocyclic group;

R_ {4} is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R_ {1} 'OC (O), R_ {'} C (O), R 1 '' R 1 'NC (O), R 1' O (O) 2 S, R 1 'R 1' N (O) 2 S and R_ {1} '' (O) n S, where n is the integer selected from 1 or 2;

And it is selected from the group consisting of a Valencia bond, O, S and NR4 '; R_ {4} 'is selected from group consisting of H, alkyl, aralkyl, a heterocycle, C (O) R 1, C (O) OR 1, S (O2) NR_ {1} 'R_ {1}' ', C (O) NR 1 'R 1' and S (O 2) R 1; with the proviso that when Y is S, R_ {4} is selected from group consisting of alkyl, cycloalkyl, aryl, heterocycle and aralkyl; when Y is NR_ {4} ', R_ {4}' can be taken together with R 3 to form a heterocyclic ring system;

R_ {5} is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, a heterocycle group, aryl, aralkyl, acyl, substituted alkylene, R1 'OC (O), R_ {1} 'C (O), R_ {1}' 'R_ {1}' NC (O), R 1 '' 'O (O) 2 S, R 1 'R 1' N (O) 2 S and R 1 '' (O) n S; in which n is 1 or 2;

Z is selected from the group consisting of a Valencia bond, O, S and NR5 '; R_ {5} 'is selected from group consisting of H, alkyl, aralkyl and a heterocycle; with the condition that when Z is a valence link, R_ {5} is select from the group consisting of H, halogen, an alkylene group substituted and a cyano group; and, with the other condition that when Z is S, R5 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl; Y

R_ {6} is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, a heterocycle, acyl, carbalkoxy and carboxamido; said carbalkoxy, acyl and carboxamido are optionally substituted with one or two groups substituents, each of which is selected regardless of the group consisting of H, alkyl, aralkyl and a heterocycle

       \ vskip1.000000 \ baselineskip
    

In addition compositions are provided Pharmaceuticals comprising a compound of formula I, above, or one of its salts, solvates or stereoisomers, and at least one pharmaceutically acceptable vehicle. Optionally, the pharmaceutical composition may also comprise at least one agent additional therapeutic

Manufacturing uses are also provided of medications to treat proliferative diseases or inflammatory, in patients who need it, of a compound of formula I, above, or one of its salts, solvates or stereoisomers, and, optionally, at least one additional therapeutic agent.

Detailed description of the invention Definitions

The following definitions will apply to the terms used throughout this specification, unless otherwise limited in specific cases.

Unless stated otherwise, the terms "lower alkyl", "alkyl" or "alq" according are used herein, alone or in combination, for example, aralkyl or haloalkyl, include both hydrocarbons straight chain as branched, preferably containing 1 to 12 carbon atoms in the case of alkyl or alq, in the chain normal, and preferably 1 to 4 carbon atoms in the case of lower alkyl. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, Dodecil, and the like. Each alkyl group may optionally be substituted with 1 to 4 substituents that may include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogen, heterocycle, hydroxy, cyano, nitro, amino, monoalkylamino, dialkylamino, hydroxylamine, sulfonate, sulfonamide, cyano-guanidine, oxo, carbalkoxy, carboxamido, SO_ {n} where n is 0, 1 or 2, and / or acyl groups.

Unless stated otherwise, the term "cycloalkyl" as used herein document, alone or in combination includes hydrocarbon groups saturated or partially unsaturated cyclics (containing 1 or 2 double bonds), cyclic hydrocarbon groups, containing minus a ring and a total of 3 to 7 carbon atoms, of preference of 3 to 6 carbon atoms, forming the ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and the like. The cycloalkyl groups may be optionally substituted in the same manner as described above for alkyl groups.

The term "aryl" as used in the present document, alone or in combination, for example, aryloxy,  refers to monocyclic and bicyclic aromatic groups that they contain 6 to 10 carbon atoms in the part of the ring, such such as phenyl, indenyl, indanyl or naphthyl, including 1-naphthyl and 2-naphthyl, and the like. The aryl groups may be optionally substituted through available carbon atoms with 1, 2 or 3 groups selected hydrogen, halo, alkyl, cycloalkyl, aralkyl, heterocycle, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, carbalkoxy, acyl, hydroxylamine, sulfonate, sulfamide, cyano-guanidine, SO_ {n} where n is 0, 1 or 2, carboxamido, or monosubstituted amino, or disubstituted amino groups, in which amino substituents are independently groups alkyl, aralkyl, aryl, acyl or carbalkoxy.

The term "aralkyl" as used in This document refers to an aryl group, as defined previously, directly linked through an alkyl moiety, such as a benzyl group, for example. An aralkyl group may be optionally substituted with any group described herein document as an aryl or alkyl substituent.

Unless stated otherwise, the term "lower alkenyl" or "alkenyl" as used in this document itself or in combination, refers to straight or branched chain radicals from 2 to 12 carbon atoms, preferably 2 to 5 carbon atoms, in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and similar, which may be optionally substituted therein way described for the alkyl groups.

Unless stated otherwise, the term "lower alkynyl" or "alkynyl" as used in this document itself or in combination, refers to straight or branched chain radicals from 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, in the normal chain; which include a triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentinyl, 3-pentinyl, 2-hexinyl, 3-hexinyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 3-octinyl, 3-noninyl, 4-decinyl, 3-undecinyl, 4-dodecinyl and the like, which may be optionally substituted in the same manner as described for the alkyl groups.

The normal carbon chain of any group alkyl, alkenyl, alkynyl or aralkyl may optionally be interrupted by one or more heteroatoms.

As used herein, the term "acyl" refers to a group of the formula C (O) R, in which R represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group aralkyl

As used herein, the term "carbalkoxy" refers to a group of the formula C (O) OR, in which R represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group aralkyl

As used herein, the term "carboxamido" refers to a group of the formula C (O) NR_ {2}, in which the R groups, which can be same or different, they represent a hydrogen atom, a group alkyl, an aryl group, a heterocycle or an aralkyl group. How alternative, the two R groups, when taken together with the atom of nitrogen, they can form a heterocyclic group.

The terms "heterocycle" and "heterocyclic" as used herein, is refer to an aromatic or non-aromatic cyclic group, optionally substituted, which, for example, is a ring system  monocyclic 4 to 7 members, bicyclic 7 to 11 members or tricyclic 10 to 15 members, which has at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, of oxygen atoms and sulfur atoms, where the heteroatoms of nitrogen and sulfur can also be optionally oxidized and nitrogen heteroatoms may also be optionally quaternized The heterocyclic group may be attached to any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups Suitable include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, sulfoxide thiamorpholinyl, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thiethanyl, thiranyl, triazinyl, triazolyl, and the like.

Examples of bicyclic heterocyclic groups Suitable include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,1-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), bencisothiazolyl, bencisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, benzoxodiazole, benzothiodiazole, and the like.

In preferred embodiments, at minus one of the heteroatoms in the heterocycle is an atom of nitrogen.

Examples of substituents suitable for groups Heterocyclics include one or more alkyl groups as described. above or one or more groups described above as alkyl or aryl substituents. Groups are also suitable aryl and smaller heterocycles, such as epoxides and aziridines

The term "heteroatom" as used in this document, it includes oxygen, sulfur and nitrogen, where nitrogen and sulfur heteroatoms can also optionally be oxidized and nitrogen heteroatoms can also optionally be quaternized.

The term "halogen" or "halo" according is used in this document, alone or as part of another group, refers to fluorine, chlorine, bromine and iodine.

As used herein, the "optionally substituted" expression, as in "alkyl optionally substituted lower "," aryl optionally substituted "or the like" refers to an alkyl, aryl and others groups that may be unsubstituted or substituted with substituents mentioned above. Also, when in the this document describes a remainder as optionally substituted with more than one substituent, it is understood that each of Multiple substituents can be independently chosen from the substituents mentioned above.

       \ vskip1.000000 \ baselineskip
    

Compounds of the invention

In accordance with the present invention, they provide compounds having the following formula I.

       \ vskip1.000000 \ baselineskip
    

3

       \ vskip1.000000 \ baselineskip
    

In the compounds of formula I, R1 is selects from H, hydroxyl, alkyl, aralkyl, halogen, OR1 ', OC (O) R_ {1} ', OC (O) OR_ {1}', OC (O) NR_ {1} 'R_ {1}' ', OS (O) 2 R 1 '' 'and OS (O) 2 NR_ {1} 'R_ {1}' '. The R_ {1} 'and R1 '' can each independently be H, alkyl, aryl, aralkyl, heterocycle or cycloalkyl groups, or can be taken together to form a cycloalkyl, aryl or a heterocyclic group, any of which may be optionally substituted.

The group R1 '' 'is H, alkyl, aryl, aralkyl, heterocycle or a cycloalkyl group.

R 2 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R 1 'OC (O),
R_ {1} 'C (O), R_ {1}''R_{1}' NC (O), R_ {1} '''O (O) 2 S, R_ {1}' R_ { 1} '' N (O) 2 S and R 1 '''(O) n S where n is an integer selected from 1 or 2.

R_ {1} and R2_, when taken together they can forming a cycloalkyl, aryl or heterocyclic group, any of which may be optionally substituted.

Group X represents a valence bond, O, S and NR 2, and R 2 'is H, alkyl or aralkyl, C (O) R 1, C (O) OR 1, SO_ {NR} {1} 'R_ {1}' ', C (O) NR_ {1}' R_ {1} '', SO_ {2} R_ {1} '' '. With the limitation that when X is S, then R2 can only be selected from H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl.

R_ {3} is selected from the group consisting of H, hydroxyl, alkyl, cycloalkyl, a heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido, halogen, amine, amine substituted, OR 3 ', CH 2 OR 3', CH_ {NR} {3} 'R_ {3}' ', CH_ {2} SR_ {3}', OC (O) R_ {3} ', OC (O) OR_ {3}' ', OC (O) NR_ {3} 'R_ {3}' ', OS (O) 2 R 3 'and OS (O) 2 NR 3 'R 3'. The R_ {3} 'and R 3 '' are each independently H, alkyl, aralkyl, heterocycle, cycloalkyl or aryl. R_ {3} 'and R_ {3}' ', when they take together, they can form a cycloalkyl, aryl or heterocyclic, any of which may be optionally replaced.

When R 3 is a carbalkoxy, acyl or carboxamide, these groups are optionally substituted with one or two substituent groups, each of which is independently H, alkyl, aralkyl, heterocycle, cycloalkyl or aryl. Substituent groups, when taken together, can forming a group a cycloalkyl, aryl or heterocyclic group, any of which may be optionally substituted.

The R 2 and R 3 groups can also taken together to form a cycloalkyl, aryl or heterocyclic, any of which may be optionally replaced.

The group R_ {4} is selected from the group that It consists of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R_ {1} 'OC (O), R_ {'} C (O), R_ {1} '' R_ {1} 'NC (O), R_ {1}' 'O (O) 2 S, R 1 'R 1' N (O) 2 S and R_ {1} '' '(O) n S where n is a selected integer of 1 or 2.

And it is selected from the group consisting of a Valencia bond, O, S and NR_ {4} ', R_ {4}' is selected from H, alkyl, aralkyl, a heterocycle, C (O) R1, C (O) OR_ {1}, S (O_ {2}) NR_ {1} 'R_ {1}' ', C (O) NR_ {1} 'R_ {1}' 'and S (O 2) R 1. With the limitation that when Y is S, then R4 can be selected only from alkyl, cycloalkyl, aryl, heterocycle and aralkyl.

Also, when Y is a primary amine or secondary, can be taken together with R 3 to form a system of heterocyclic rings that may be optionally replaced.

R_ {5} is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, a heterocycle group, aryl, aralkyl, acyl, substituted alkylene, R1 'OC (O), R_ {1} 'C (O), R_ {1}' 'R_ {1}' NC (O), R 1 '' O (O) 2 S, R 1 'R 1' N (O) 2 S and R_ {1} '' '(O) n S where n is a selected integer of 1 or 2.

Z is selected from the group consisting of a Valencia bond, O, S and NR_ {5} ', with the conditions that when Z is a valence bond, then R_ {5} can selected only from H, halogen, a substituted alkylene group or a cyano group and when Z is S, then R_ {5} can be selected only of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl. He R 5 'group is H, alkyl, aralkyl or a heterocycle.

Finally, R_ {6} is selected from the group that It consists of H, alkyl, cycloalkyl, aryl, aralkyl, a heterocycle, acyl, carbalkoxy and carboxamido. The carbalkoxy groups, acyl and carboxamide are optionally substituted with one or two substituent groups, each of which is independently H, alkyl, aralkyl or a heterocycle.

Also included in the invention are salts, solvates and stereoisomers, enantiomers and diastereoisomers of the compounds of formula I.

All stereoisomers of the compounds of formula I, either as a mixture or pure, or substantially pure. A compound of formula I may have centers of asymmetry in any of its nitrogen or carbon atoms non-aromatic, including carbon atoms in any of its substituents Accordingly, the compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures of the same. Preparation procedures can use racemates, enantiomers or diastereomers as materials of departure. When diastereomeric products are prepared or enantiomeric, can be separated by procedures conventional, for example, chromatographic or crystallization fractional

The preferred compounds of the invention they are compounds of formula I in which Z is a valence bond and R 5 is cyano.

In some preferred embodiments, R 3 is an alkyl, aryl or heteroaryl, and is preferably methyl.

In some preferred embodiments, Y is N. In yet other embodiments, X is a link of Valencia, O or NR_2 '. R_ {2} 'is preferably R_ {1} 'C (O) or -C (O) NR_ {1}' R2_ 'or -C (O) OR_ {1} '.

According to some embodiments of The present invention, R 1 'and R 1' are independently alkyl, cycloalkyl or heterocycloalkyl.

Other preferred compounds are those compounds of formula I in which R 4 is phenoxyaniline. Too preference is given to compounds of formula I in which Y is NR_ {4} 'in which R_ {4}' is as defined above, or in which Y is O and R 4 is an aryl or heteroaryl group.

Other preferred compounds of the invention are the compounds of formula I in which Z is a bond of Valencia, R 5 is cyano and R 3 is methyl. Preferably, These compounds have one or more of the following substituents: Y is N; R1 'and R1' 'are independently alkyl, cycloalkyl or heterocycloalkyl; R 4 is alkyl, aryl or heteroaryl; X is a valence bond, O or NR2 '; and R2 is R_ {1} 'C (O), - (C (O) NR_ {1}' R2_ ', or -C (O) OR_ {1} '.

Other preferred compounds of formula I include those in which Z is a valence bond, R_ {5} is cyano, Y is NR_ {4} 'in which R_ {4}' is as defined above and R 4 is a phenyl group or a heteroaryl group with one or more substitutions.

Other preferred compounds are illustrated in The examples below.

       \ vskip1.000000 \ baselineskip
    

Procedures for producing the compounds

In general, the compounds of formula I can produced by reacting a pyrrole of formula II:

       \ vskip1.000000 \ baselineskip
    

4

in which X, R_ {1}, R2 and R_ {3} are as defined above, with an agent of amination in the presence of a base to produce the aminated pyrrole of formula III:

       \ vskip1.000000 \ baselineskip
    

5

in which X, R_ {1}, R2 and R_ {3} are as defined previously.

       \ vskip1.000000 \ baselineskip
    

The compound of formula III is reacted with a carbonyl of formula R 6 C (O) CH 2 ZR 5 or an acetal of the formula (RO) 2 CR 6 CH 2 ZR 5, in which R is a group alkyl and Z, R 5 and R 6 are as defined above, under ring closure conditions to produce a compound of formula IV

       \ vskip1.000000 \ baselineskip
    

6

The 4-oxo-pyrrolopyridazines of the formula IV can be reacted with a reagent that provides a leaving group, such as POCl3 or POCl5, to give a compound of formula V

7

in which L is a group outgoing.

       \ vskip1.000000 \ baselineskip
    

The compound of formula V can be made react with a compound of the formula HYR4, in which Y and R_ {4} are as defined above, to produce a compound of formula I, above.

The compounds of formula I can be prepared by the procedures described in the following reaction schemes. Examples of reagents and procedures suitable to carry out these reactions appear in what successive and in the examples of work. The protection and unprotection in the schemes in this document may be made through of procedures generally known in the art. (See, for example, T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, (1999)). In schemes A to D, unless otherwise indicated, X, Y, Z, R1, R2, R 3, R 4, R 5 and R 6 are as defined previously. The variables L and L 'represent outgoing groups. Variables designated with the suffix "a" or "b" have the same scope as, but chosen independently of, its variable original. For example, R_ {2a}, R_ {2a} 'and R_ {2a}' 'have the same scope, but not necessarily identical to, R2; R 2 and R 2, respectively.

       \ vskip1.000000 \ baselineskip
    

Scheme TO

8

The pyrroles of formula II can be obtained by means of the procedures described in the Cooperation Treaty in the field of patents (PCT) publication number WO 00/71129, United States (US) patent application pending number of US series 09/573829, PCT Publication Request in process number US 01/49982 and the US Patent Application in process number of US series 10/036293.

The treatment of a pyrrole of formula II with a base in a suitable reaction medium followed by the addition of an amination reagent generates an aminopyrrole of formula III. The Suitable bases include sodium hydride (NaH), n-BuLi, t-BuLi, NaOH, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS). Suitable reaction media include tetrahydrofuran (THF), CH 2 Cl 2, dimethylformamide (DMF), CH 3 CN and toluene. Suitable amination reagents include 2,4-dinitroaminophenol, NH 2 OSO 3 H and ClNCH_ {2}. Preferably, the amination reagent is ClNH2 or 2,4-dinitroaminophenol. Preferably, the base is NaH or LDA, the reaction medium is DMF or THF. More preferably, the base is NaH, the reaction medium is DMF and the amination reagent it is 2,4-dinitroaminophenol.

The condensation of the compound of formula III with an acetal followed by base-induced cyclization in a medium suitable reaction provides a pyrrolopyridazine of formula IV. Suitable bases include NaOH, LDA, diisopropylethylamine (DIPEA), 1,8-diazobicyclo [5.4.0] undec-7-eno (DBU) and K_ {2} CO_ {3}. Suitable reaction media include THF, CH 2 Cl 2, DMF and toluene. Preferably, the base is DBU, DIPEA or LDA and the reaction medium is toluene or DMF. The rest Preferably, the base is DBU or DIPEA, and the reaction medium is Toluene. Alternatively, the compounds of formula IV may Obtained through the reactions of the following Schemes H, J and K.

The conversion of the oxo group at position 4 of the compound of formula IV to a leaving group L, as in the compounds of formula V, can be achieved, then using a suitable halogenation reagent, such as SOCl2, POCl_ {3} or POCl_ {5}. More preferably, the reagent is POCl_ {3}.

The treatment of a compound of formula V with a reagent of formula HY-R4 in the presence of a base in a reaction medium then provides compounds of formula VI, which are compounds of formula I in which R 6 is H. Suitable bases include NaH, Et 3 N, DIPEA, K 2 CO 3 or Na 2 CO 3 and the reaction media Suitable include THF, DMF, CH 2 Cl 2 or CH 3 CN. From preferably, the base is NaH, Et 3 N or K 2 CO 3 and the Solvent is CH 3 CN or DMF. More preferably, the basis is triethylamine and the reaction medium is acetonitrile.

       \ vskip1.000000 \ baselineskip
    

Scheme B

9

The compounds of formula VIa, which are compounds of formula VI in which X is a valence bond, R 2 represents CO 2 R 2 ', ZR 5 represents CN and R 6 represents hydrogen, they can be saponified with a base to prepare carboxylic acids of formula VII as shown earlier in Scheme B. Suitable bases are NaOH, KOH, LiOH and Ba (OH) 2. Preferably, the base is a alkali metal hydroxide. More preferably, the basis is NaOH

The compounds of formula VIII, which are compounds of formula VI in which R 2 X is R_ {2a} 'R_ {2a}' 'NC (O), ZR_ {5} represents CN and R_ {6} represents hydrogen, can be prepared through the treatment of compounds of formula VII with a coupling reagent and a amine of formula NH 2 R 2 'R 2' in a medium of reaction. Suitable coupling agents include PyBOP [hexafluorophosphate benzotriazol-1-yloxytripyrrolidine-phosphonium],  BOP [hexafluorophosphate benzotriazol-1-yloxytris (dimethylamino) phosphonium], CDI (N, N'-carbonyldiimidazole), DCC (N, N'-dicyclohexylcarbodiimide), HBTU [hexafluorophosphate O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium],  HOAt (1-hydroxy-7-azabenzotriazole) and HOBt (1-hydroxybenzotriazole) and EDC [1-ethyl-3- (3-dimethylaminopropyl) carbodiimide].  Preferably, the coupling reagent is HOBt, PyBOP or EDC. More preferably, the coupling reagent is HOBt or PyBOP.

The compounds of formula IX, which are compounds of formula VI in which XR 2 is R 2a 'OC (O), ZR 5 represents CN and R 6 represents hydrogen, can be prepared to through the treatment of a compound of formula VII with an acid or a base and an alcohol of the formula R 2a 'OH. Acids Suitable include HCl, H2SO4, TsOH, acid 10-camphorsulfonic acid (CSA) and pyridinium p-toluenesulfonates (PPTs). The rest Preferably, the acid is hydrochloric acid.

The compounds of formula X, which are compounds of formula VI in which XR_ {2} is R_ {2a} 'OC (O) NR_ {2a}' ', ZR_ {5} represents CN and R 6 represents hydrogen, can be prepared through the treatment of compounds of formula VII with a reagent of azidation, that is, a source of N3, followed by the addition of an alcohol of formula R 2 'OH. Azidation reagents Suitable include diphenylphosphorylazide (DPPA) and NaN3. From Preferably, the reagent is DPPA.

       \ vskip1.000000 \ baselineskip
    

Scheme C

       \ vskip1.000000 \ baselineskip
    

10

       \ vskip1.000000 \ baselineskip
    

As shown in Scheme C, compounds of formula XII, which are compounds of formula I in which XR 2 is NH (R 2a) 2, can be prepared through compounds of formula X in which the carbalkoxy moiety of the compound of formula X functions as a removable protecting group. The intermediate compound of formula XI can be prepared by removing the carbalkoxy moiety of the compound of formula X. Preferably, the carbalkoxy group will be a t-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz or Z). Appropriate conditions to eliminate these and other protecting groups are disclosed in Green and Wuts, supra . Preferably, the deprotection reaction is an acid cleavage reaction or a hydrogenation reaction.

The compounds of formula XII are the result of the reductive amination of compounds of formula XI using a aldehyde of formula R 2 'CHO and a reducing agent in a medium of adequate reaction. Suitable reducing agents include NaBH_4, LiBH_ {4}, diisobutylaluminum hydride (DIBAL-H), lithium aluminum hydride (LAH) and NaBH (OAc) 3. Preferably, the reducing agent is NaBH (OAc) 3 or NaBH 4. More preferably, the reducing agent is NaBH (OAc) 3. The means of Suitable reactions include 1,2-dichloroethane, CH 2 Cl 2, THF and CH 3 CN. The reaction media of Preference include 1,2-dichloroethane and CH2CI2 and more preferably, the reduction is carried out in 1,2-dichloroethane.

As an alternative, the preparation of compounds of formula XII can be carried out by treating compounds of formula XI with a base and a reagent of formula R_ {2a} 'L. Suitable bases include K2CO3, NaHCO 3, Et 3 N, DIPEA, Cs 2 CO 3, DBU and pyridine. From preference, the base is selected from the group consisting of K 2 CO 3, NaHCO 3 and Et 3 N. More preferably, the base is baking soda.

       \ newpage
    

Scheme D

eleven

The compounds of formula XV can be prepared at through the procedure shown in Scheme D. The reduction net of compounds of formula VI in which XR2 is R 2 'OC (O) provides aldehydes of formula XIII. The suitable means to realize a net reduction of include the reaction with a reducing agent or the sequential reaction with a stronger reducing agent and a weaker oxidizing agent. The suitable reducing agents are generally known to skilled in the art and can be found in such references as Advanced Organic Chemistry III ed. Part B: Reactions and Synthesis, Francis A. Carey, Richard J. Sundberg, Plenum Publishing Corp., NY (1993) and in March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th ed., Wiley-InterScience, John Wiley & Sons, Inc., NY (2001).

The right combinations of oxidizing agents and reducing agents include diisobutylaluminum hydride (DIBAL-H) with MnO2. Preferably, the net reduction is carried out by sequential reduction and oxidation with a reducing agent such as DIBAL-H, LAH, NaBH_4 or LiBH4 {and an oxidizing agent such as MnO 2 SO 3 -pyridine, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical), Dess-Martin's periodic, or TPAP (tetrapropylammonium perrutenate) and NMO (N-oxide N-methylmorpholine) in combination. The rest preference, the reduction is carried out first with DIBAL-H to produce an intermediate compound, which at it is then oxidized with MnO2 to give the compound of formula XIII

Subsequent treatment with an oxidizing agent in a suitable reaction medium followed by etherification using a base in a suitable reaction medium and a reagent of formula R 2a gives the compounds of formula XV, which are compounds of formula VI in which XR 2 is OR 2 '. The suitable oxidizing agents include acid m-chloroperbenzoic acid (m-CPBA) and H 2 O 2. Suitable bases include NaH, Et3N, DIPEA and K 2 CO 3. Suitable reaction media include THF, DMF, CH 2 Cl 2 and CH 3 CN. More preferably, the agent oxidant is m-chloro perbenzoic acid (mCPBA), the base is NaH and the reaction medium is tetrahydrofuran (THF) or DMF

       \ vskip1.000000 \ baselineskip
    

Scheme AND

12

The halogenation of the group 5-methyl of a compound of formula V can be carried out by treatment with a halogenating agent. Suitable halogenating agents include, but are not limited to sulfuryl chloride, N-iodosuccinimide, N-Bromosuccinimide, N-chlorosuccinimide, oxalyl chloride. From Preferably, the halogenating agent is N-bromosuccinimide or sulfuryl chloride. The halogenation can be performed in an inert atmosphere, such as N2, in the presence of a catalyst, to produce a pyrrole intermediate halogenated of formula XVI. Preferably, the catalyst is dibenzoyl peroxide or 2,2'-azobisisobutyronitrile, or irradiation.

The treatment of a pyrrole of formula XVI with a thiol of formula HSR 3a, an intermediate alcohol of formula HOR_ {3a} ', or a primary or secondary amine of formula HNR_ {3a} 'R_ {3a}' 'in the presence of a base gives a pyrrole of formula XVII. Suitable bases include NaHCO3, diisopropyl ethylamine DBU, KHCO2 and trimethylamine. Preferably, the base is NaHCO3 or triethylamine. Acetonitrile is a means of Suitable reaction for this reaction.

The treatment of a pyrrole of formula XVII with a reagent of the formula HYR4, at room temperature in presence of a base, gives the compound of formula XVIII. From Preferably, the base is NaHCO3 or triethylamine. Acetonitrile It is a suitable reaction medium for this reaction. He heating the pyrrole of formula XVII with a reagent of formula HYR4 in the absence of bases also gives the compound of formula XVIII.

Scheme F

13

Compound XIX, which is a compound of formula VI, in which R_ {3} is -CH_ {SR} {3a} '(see Scheme A, above), can be oxidized to the sulfoxide of compound XX, in the that n = 1, or the sulfone of compound XX, in which n = 2. The suitable oxidizing agents include acid m-chloroperbenzoic acid (MCPDA), tBu-OOH, H2O2 NaIO4 and dimethyldioxyran. Preferably, the agent Oxidizer is MCPDA. The number of oxidizing agent equivalents that added to the reaction mixture determines the oxidation state End of the sulfur atom. A compound of formula XX, in which n = 1 or 2, can be heated with an excess of an alcohol of formula HOR 3b or a primary or secondary amine of formula HNR_ 3b} 'R 3b' 'to give a compound of formula XXI.

Scheme G

14

The compounds of formula VII, of scheme B, are undergo a Wittig reaction with a phosphonate in the presence of a base to give a compound of formula XXII. Can be used Suitable phosphonates known to those skilled in the art. From Preferably, the phosphonate is methyl diethylphosphonoacetate. He dichloroethane and the like are suitable organic reaction media for Wittig reactions. Suitable bases include KH, K 2 CO 3, N-butyllithium, sec-butyllithium, tert-butyllithium, NaH, preferably NaH.

The double bond in the R2 group of the compound of formula XXII can be hydrogenated in the presence of a catalyst to give a compound of formula XXIII. The Suitable catalysts include PtO2, palladium on carbon (Pd / C), Pd (OH) 2 and Ni Raney. Preferably, the catalyst is Pd / C.

Esters of formula XXIII can be hydrolyzed by techniques well known in the art, for example those taught in Green and Wuts, supra , the preference is for alkaline hydrolysis with NaOH. Subsequent coupling of the resulting acid with an amine in the presence of a coupling agent gives the amide of formula XXIV. Suitable coupling agents are known to those skilled in the art and include those described in The Practice of Peptide Synthesis, 2nd Ed., By Bodanszy, Miklos, Springer-Velag (1993). Preferably, the coupling agent is N, N'-dicyclohexylcarbodiimide (DCC).

       \ vskip1.000000 \ baselineskip
    

Scheme H

fifteen

Scheme H represents an alternative route for the synthesis of compounds of formula IV (see Scheme A, previous). The condensation of a pyrrole of formula III with a reagent of formula R 6 C (O) CH 2 ZR 5, followed by base-induced cyclization in a reaction medium suitable, give the intermediate of formula IV. The right bases include DBU, NaH, BuLi, Et3N and DIPEA. Reaction media Suitable include toluene, THF, CH2Cl2, DMF, toluene and CH 3 CN. Preferably, the base is NaH, DBU or DIPEA and the medium The reaction is DMF, toluene or THF. Formula reagents R 6 C (O) CH 2 ZR 5, particularly those in which R 6 is a substituted oxygen, nitrogen or a group alkyl and ZR5 is a nitrile group, can be purchased from commercial sources or can easily be synthesized by Those skilled in the art.

       \ vskip1.000000 \ baselineskip
    

Scheme I

16

As shown in Scheme I, a compound of formula XXV, which is a compound of formula VI in which ZR5 is a nitrile group (see Scheme A, above), can be reduced by presence of hydrogen and a catalyst to give a compound of XXVI formula. Suitable catalysts include PtO2, Pd / C, Pd (OH) 2 and Ni Raney. Preferably, the Catalyst is palladium on carbon (Pd / C).

The compounds of formula XXVI, when combined with a reagent of formula R5a L, in which L is a leaving group, for example, a halogen, in the presence of a base, give compounds of formula XXVII. Suitable bases are KH, K 2 CO 3, N-butyllithium, sec-butyllithium, tert-butyllithium and NaH Preferably, the base is NaH. Formula reagents R_ {5a} L are readily available from commercial sources.

In addition, a compound of formula XXVI can be treated with a reagent of formula (R 5b -Z b -C (O)) 2 O  or R_ {5b} -Z_ {b} -C (O) -L ', in which L 'is a leaving group, for example, a halogen, in presence of a base to give a compound of formula XXVII. The Suitable bases include NaHCO 3, diisopropylethylamine, DBU, KHCO 3, trimethylamine. Preferably, the base is triethylamine. Formula reagents R_ {5b} -Z_ {b} -C (O) -L '  or (R 5b -Z b -C (O)) 2 O They are easily available from commercial sources, or it can be synthesized by those skilled in the art.

Scheme J

17

Scheme J represents the synthesis of a compound of formula XXX, which is a compound of formula IV (see Scheme A, above) in which R 6 is hydrogen and ZR 5 is a nitrile group The treatment of a pyrrole of formula III with a reactive intermediate in a protic boiling solvent high results in an intermediate of formula XXIX. From preferably, dimethylformamide (DMF) and dimethylacetamide.

The intermediate treatment of formula XXIX with acetonitrile in the presence of a base results in cyclization to produce the compound of formula XXX. The bases Suitable include, but are not limited to KH, NaH, sec-butyllithium and preferably N-Butyllithium As shown in scheme A, above, the compounds of formula XXX are intermediate in the synthesis of compounds of formula I in which R 6 is hydrogen and ZR5 is a nitrile group.

Scheme K

18

The synthesis of compounds of formula XXXIV and XXXV is shown in Scheme K. The compounds of formula XXXIV and XXXV are intermediates of formula IV (see scheme A, above) in the that R 6 is hydrogen and ZR 5 is a nitrile group. He treatment of a pyrrole of formula XXXI with a reactive intermediate of formula XXXII in a high boiling solvent gives as a result an intermediate of formula XXXIII. Solvents Suitable include, but are not limited to, xylene, nitrobenzene and toluene, preferably toluene.

In addition the heating of an intermediate of formula XXXIII in a high boiling solvent gives as cyclization result to give intermediate products of formula XXXIV and XXXV. Suitable solvents include, but are not limited to. a, DMF, DMA, N-methylpyrolidinone, preferably Dowtherm? Or toluene in a high pressure apparatus.

       \ vskip1.000000 \ baselineskip
    

Scheme L

19

       \ vskip1.000000 \ baselineskip
    

The synthesis of compounds of formula XXXVI is Sample in Scheme L. The treatment of a compound of formula XXI, of Scheme F, with a reactive intermediate of formula X'C (O) X 'or X'C (O) OC (O) X', as described in Scheme L, in the presence of a base such as diisopropylethylamine or triethylamine, with or without heating, gives a compound of formula XXXVI. Suitable solvents include, but They are not limited to, methylene chloride, chloroform, tetrahydrofuran or ethyl acetate.

As shown in Scheme K, above, the compounds of formula XXXIV and XXXV are intermediate in the synthesis of compounds of formula I, wherein R 6 is hydrogen and ZR5 is a nitrile group. The intermediate reagent of formula XXXII and related reagents of this structure are easily available from commercial sources, or can be synthesized by Those skilled in the art.

Schemes 1 to 5, below, summary several preference procedures to produce some of the compounds of the invention. In schemes 1 to 5, unless indicate otherwise, X, Y, Z, R1, R2, R2, R 3, R 4, R 5 and R 6 are as defined above and L represents a leaving group. Variables designated with the subscript "a" or "b" have the same scope that, but are chosen independently of, the variable original.

       \ vskip1.000000 \ baselineskip
    

Scheme one

twenty

       \ vskip1.000000 \ baselineskip
    

The 3-cyanopyrrolopyridazines of Formula VI can be prepared according to Scheme 1. The Pyrroles of formula II can be obtained through the processes described in the Patent Cooperation Treaty (PCT) Publication number WO 00/71129, State patent application United (USA) pending serial number US 09/573829, Application for PCT publication in process number US 01/49982 and the Request for US patent pending serial number US 10/036293.

The treatment of a pyrrole of formula II with a base such as sodium hydride in a reaction medium such as DMF, followed by the addition of an amination reagent such as 2,4-Dinitroaminophenol generates an aminopyrrole of formula III. Condensation with an acetal such as 1,1-diethoxypropionitrile, followed by cyclization induced with bases using a base such as DBU or diisopropylethylamine, in a reaction medium such as toluene, provides the 3-cyanopyrrolopyridazine of formula IV. The conversion to the 4-chlorine compounds of formula V can then be carried out by a reagent of chlorination such as POCl3 or POCl5. The treatment of a compound of formula V with a reagent of formula HY-R4 in the presence of a base such as triethylamine in a reaction medium such as acetonitrile provides compounds of formula VI, which are compounds of formula I, in the which is XR_ {2} is C (O) OEt, Z is a link from valencia, R 5 is CN and R 6 is H.

       \ vskip1.000000 \ baselineskip
    

Scheme 2

twenty-one

The compounds of formula VI may saponify with a base such as NaOH to prepare acids carboxylics of formula VII as shown above in the Scheme 2. The compounds of formula VIII, which are compounds of formula I, in which XR2 is C (O) NHR2 ', Z is a valence bond, R5 is CN and R6 is H, can be prepared through the treatment of compounds of formula VII with a coupling agent such as EDC and an amine such as NHR 2a 'R 2a', in a reaction medium such as dichloromethane The compounds of formula IX, which are compounds of formula I in which XR 2 is C (O) OR 2, 'Z is a Valencia bond, R5 is CN and R6 is H, can be prepared through the treatment of a compound VII with an acid such as hydrochloric acid and an alcohol formula R2 'OH. The compounds of formula X, which are compounds of formula I in which XR2 is NHC (O) OR2 ', Z is a valence bond, R5 is CN and R6 is H, can be prepared through the treatment of compounds of formula VII with a reagent such as DPPA followed by the addition of an alcohol of the formula R 2 'OH.

       \ vskip1.000000 \ baselineskip
    

Scheme 3

22

As shown in Scheme 3, the compounds of formula XII, which are compounds of formula I, in which XR2 is NHR_ {2a} ', Z is a valence bond, R5 is CN and R6 is H, can be prepared from compounds of formula X in the that the carbalkoxy of the compound of formula X is a protective group removable (for example, R2 is t-butyl or benzyl). The compound of formula XI can be prepared by deprotection, that is, by acid cleavage or hydrogenation, respectively. Compounds of formula XII can be prepared also by reductive amination of compounds of formula XI using an aldehyde of formula R 2 'CHO and such a reducing agent as NaBH (OAc) 3 in a reaction medium such as 1,2-dichloroethane. As an alternative, the preparation of compounds of formula XII can be carried out by means of treatment of compounds of formula XI with a base such as NaHCO 3 and a reagent of formula R 2 'L.

Scheme 4

2. 3

The compounds of formula XV can be prepared at through the procedure shown in Scheme 4. The reduction of compounds of formula VI with a reducing agent such as DIBAL-H in reaction media such as dichloromethane or toluene, followed by oxidation with an agent oxidizer such as MnO2, provides aldehydes of formula XIII The treatment of compounds of formula XIII with a peracid such as m-CPBA in a reaction medium such as dichloromethane, followed by etherification using a base such as sodium hydride in reaction media such as tetrahydrofuran or DMF and a reagent of formula R 2 'L gives compounds of formula XV, which are compounds of formula I, in which XR2 is OR_ {2a} ', Z is a valence bond, R5 is CN and R6 is H.

Scheme 5

24

As shown in Scheme 5, an intermediate of formula XXV, which is a compound of formula I, in which R 6 is H and ZR5 is a nitrile group, it can be reduced in the presence of hydrogen, trifluoroacetic acid (TFA) and a catalyst such as Pd / C to give a compound of formula XXVI. The compound of formula XXVI can be treated with intermediate products of formula R_5b -Z_ {b} -C (O) -Cl or (R 5b -Z b -C (O)) 2 O in the presence of a base such as triethylamine to give the compound of formula XXVII. The formula intermediates R_ {5b} -Z_ {b} -C (O) -2O-Cl Y (R 5b -Z b -C (O)) 2 O they are easily available in commercial sources, or they can be synthesized by those skilled in the art.

The solvates (for example, hydrates) of compounds of formula I are also within the scope of the present invention Solvation procedures are known. Generally in the art. Therefore, the compounds of the The present invention may be in free or solvated form.

The compounds of formula I may be present as salts, in particular pharmaceutically salts acceptable. Compounds of formula I having, for example, at less a basic center can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a halide acid, with strong organic carboxylic acids, such as alkanocarboxylic acids of 1 to 4 carbon atoms, which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as dicarboxylic acids saturated or unsaturated, for example oxalic acid, malonic, succinic, maleic, fumaric, phthalic or terephthalic, such as hydroxycarboxylic acids, for example ascorbic, glycolic acid, lactic, malic, tartaric or citric, such as amino acids, (for example aspartic acid or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C 1 -C 4) alkyl or aryl sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methanesulfonic acid or acid p-toluenesulfonic. Salts of addition of corresponding acids with, if desired, a center additional basic.

The compounds of formula I which have at least an acid group (for example, COOH) can also form salts with bases. Suitable salts with bases are, for example, salts of metals, such as alkali metal salts or metals alkaline earth metals, for example sodium, potassium or magnesium salts or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or lower tri-alkylamine, for example ethyl, t-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine.

In addition, internal salts can be formed corresponding. Salts that are not suitable for pharmaceutical uses but that can be used, for example, for insulation or purification of free compounds of formula I or their salts Pharmaceutically acceptable, they are also included in the scope of the present invention.

Preferred salts of the compounds of Formula I, which includes a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate or nitrate.

Preferred salts of the compounds of formula I, which include an acid group include sodium salts, potassium and magnesium and pharmaceutically organic amines acceptable.

       \ vskip1.000000 \ baselineskip
    

Uses of the compounds

It has been discovered that the pyrrolopyridazines of The invention are protein kinase inhibitors. More concretely,  certain pyrrolopyridazines inhibit the effects of receptors tyrosine kinase and serine / threonine kinase, a valuable property in the treatment of disease states associated with hyperproliferation, angiogenesis, increased permeability vascular and inflammation, such as cancer and diseases inflammatory In particular, the compounds of formula I and its salts, solvates and stereoisomers inhibit the growth of primary and recurrent solid tumors by anti-proliferative and / or anti-angiogenic mechanisms. Tumors solids include, for example, bladder, cell cancers squamous, head, colorectal, esophagus, gynecological (such as ovarian), pancreas, breast, prostate, lung, vulva, skin, brain, genitourinary tract, system lymphatic (such as thyroid), stomach, larynx and lung.

In some embodiments of the present invention, uses are provided, in the manufacture of medicaments for the treatment of proliferative or inflammatory diseases in a patient who needs them, of a compound that has formula I, as described above.

The uses optionally comprise the use of al less another therapeutic agent, such as inhibitors of angiogenesis, antiestrogens, progestogens, inhibitors of aromatases, antihormones, antiprogestagens, antiandrogens, LHRH agonists and antagonists, testosterone inhibitors 5α-dihydroreductase inhibitors of farnesyl transferase, anti-invasion agents, growth factor inhibitors, antimetabolites, antitumor intercalator antibiotics, platinum derivatives, alkylating agents, antimitotic agents, inhibitors of topoisomerase, cell cycle inhibitors and modifiers of biological response, linomide, integrin function inhibitors αvβ3, angiostatin, razoxine, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, Anastrozole, Letrazole, Borazol, Exemestane, Flutamide, Nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, metalloproteinase inhibitors, urokinase activator receptor function inhibitors plasminogen, antibodies against growth factor, antibodies against the growth factor receptor, tyrosine kinase inhibitors, serine / threonine inhibitors kinase, methotrexate, 5-fluorouracil, analogs of purine and adenosine, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide nitrosoureas, thiotefan, vincristine, taxol, taxotere, epothilone analogues, discodermolide analogues, eleuterobin analogues, etoposide, tenipósido, amsacrine, topotecan, flavopyridoles and modifiers of The biological response In some embodiments of Preferably, the additional therapeutic agent is selected from Erbitux?, Taxol, paraplatin and Ifex.

More generally, the compounds of formula I are useful in treating a variety of cancers, including, but not limited to, the following:

carcinoma, including bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovaries, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma;

tumors hematopoietic lymphoid lineage, including leukemia, leukemia acute lymphocytic, acute lymphoblastic leukemia, cell lymphoma B, T-cell lymphoma, Hodgkin lymphoma, lymphoma non-Hodgkin, hair cell lymphoma and lymphoma Burkett;

tumors Myeloid lineage hematopoietics, including myelogenous leukemias acute and chronic myelodysplastic syndrome and leukemia promyelocytic;

tumors of mesenchemic origin, including fibrosarcoma and rhabdomyosarcoma;

tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; Y

other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigment, keratocantoma, follicular thyroid cancer and Kaposi's sarcoma.

       \ vskip1.000000 \ baselineskip
    

The compounds of formula I are especially useful in the treatment of tumors that have a high incidence of protein kinase activity, such as tumors of colon, lung, prostate, breast and pancreatic. Through administration of a composition comprising a compound of the invention, or a combination of these compounds, reduces the tumor development in a mammalian host.

The compounds of formula I may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways that act through receptors of growth factors. By example, due to the main function of kinases in the regulation of cell proliferation in general, inhibitors of kinases could act as reversible cytostatic agents that they can be useful in the treatment of any pathological process characterized by abnormal cell proliferation, by example, benign prostatic hyperplasia, adenomatous polyposis familial, neurofibromatosis, atherosclerosis, fibrosis pulmonary, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, the hypertrophic scar formation, inflammatory disease of intestine, transplant rejection, endotoxic shock and fungal infections

In addition, the compounds of formula I can induce or inhibit apoptosis. The apoptotic response is aberrant  in a diversity of human diseases. The compounds of formula I, as modulators of apoptosis, will be useful in the cancer treatment (including, but not limited to, types mentioned earlier in this document), infections viral (including, but not limited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of the development of AIDS in individuals infected by HIV, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, glomerulonephritis mediated by autoimmune disease, rheumatoid arthritis, psoriasis, disease inflammatory bowel and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, the Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, the retinitis pigmentosa, spinal muscular atrophy and degeneration cerebellar), myelodysplastic syndromes, aplastic anemia, injury ischemic associated with myocardial infarction, stroke and injury reperfusion, arrhythmia, atherosclerosis, liver diseases toxin-induced or alcohol-related diseases hematologic (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the system musculoskeletal (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, fibrosis cystic, multiple sclerosis, kidney diseases and pain Cancer.

As protein kinase inhibitors, the Compounds of the present invention have utility in the treatment of conditions associated with kinase activity inadequate Such conditions also include diseases in the that cytokine levels are modulated as a result of the intracellular signaling, and in particular, the diseases that are associated with an overproduction of cytokines such as IL-1, IL-4, IL-8 and FNT-? For example, the compounds of the Present invention are useful in the treatment and prevention from:

diseases mediated by IL-1 such as, for example, the rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and / or toxic shock syndrome, the inflammatory reaction induced by endotoxins, inflammatory bowel disease, the tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, diabetes, pancreatic β cell disease and Alzheimer disease;

diseases or IL-4 mediated conditions such as, by For example, allergic inflammatory processes, including those produce in asthma,

diseases or IL-8 mediated conditions such as, by example, those characterized by massive infiltration of neutrophils, such as psoriasis, inflammatory disease of the intestine, asthma, cardiac and renal reperfusion injury, adult respiratory failure syndrome, thrombosis and glomerulonephritis; Y

diseases or TNF-mediated conditions such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, shock syndrome septic, adult respiratory failure syndrome, the cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft reaction against receptor, allograft rejections, fever and myalgia due to infection, cachexia secondary to infection, AIDS, ARC or neoplasms, meloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, infections virals, such as HIV, CMV, flu and herpes; and infections veterinary virals, such as lentivirus infections, including, but not limited to infectious anemia virus equine; or retrovirus infections, including the virus feline immunodeficiency, bovine immunodeficiency virus or the canine immunodeficiency virus.

       \ vskip1.000000 \ baselineskip
    

P38-mediated diseases include rheumatoid arthritis (RA), obstructive pulmonary disease chronic (COPD), asthma, Crohn's disease, diseases neurological such as Alzheimer's disease and stroke and inflammatory bone diseases. Another analysis on p38 mediated diseases can be found in the PCT document pending Application number US01 / 49982 and in the Request for US Patent pending US Serial Number 10/036293.

Inhibitors of protein kinase activity, such as the compounds of the present invention, are useful in the treatment and prevention of other conditions and kinds of conditions, including, but not limited to, diseases inflammatory, autoimmune diseases, bone disorders destructive, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, viral diseases, allergies, myocardial ischemia, reperfusion / ischemia in heart attacks with stroke, hypoxia organic, vascular hyperplasia, cardiac hypertrophy, aggregation platelet-induced thrombin and conditions associated with prostaglandin endoperoxidase synthase-2.

The inflammatory diseases that can be treated or prevented include, but are not limited to, the acute pancreatitis, chronic pancreatitis, asthma, allergies and adult respiratory failure syndrome.

Autoimmune diseases that can be treated or prevented include, but are not limited to, the glomerulonephritis, rheumatoid arthritis, lupus erythematosus systemic, scleroderma, chronic thyroiditis, disease Graves, autoimmune gastritis, diabetes, anemia autoimmune hemolytic, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, active chronic hepatitis, myasthenia gravis, multiple sclerosis, disease inflammatory bowel, ulcerative colitis, disease Crohn, psoriasis or graft disease versus receiver.

Destructive bone disorders that can be treated or prevented include, but are not limited to, the osteoporosis, osteoarthritis and bone disorder related to multiple myeloma.

Proliferative diseases that can be treated or prevented include, but is not limited to, leukemia acute myelogenous, chronic myelogenous leukemia, melanoma metastatic, Kaposi's sarcoma and multiple myeloma.

Angiogenic disorders that can be treated or prevented include hemangiomas, psoriasis, Kaposi's sarcoma, ocular neovascularization, retinopathy of the premature, macular degeneration, diabetic retinopathy, diabetic nephropathy, rheumatoid arthritis, endometriosis, atherosclerosis, growth and tumor metastasis, the myocardial ischemia, peripheral ischemia, cerebral ischemia, wound healing disorders, certain disorders Female reproductive, organic hypoxia and disorders in the ulcer healing.

Infectious diseases that can be treated or prevented include, but are not limited to, sepsis, septic shock and shigellosis.

Neurodegenerative diseases can be treated or prevented by means of the compounds herein invention include, but are not limited to, the disease of Alzheimer's, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by injuries traumatic

Viral diseases that can be treated or prevented include, but are not limited to, acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and retinitis due to
CMV

The compounds of formula I can also prevent the implantation of blasts and, therefore, can be used as contraceptives in mammals.

In addition, protein kinase inhibitors of the present invention also show inhibition of expression of inducible proinflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also known as cyclooxygenase-2 (COX-2). By consequently, other conditions that can be treated or prevented by proper administration of the compounds of the invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by Cancer, dental pain and arthritis pain.

In the field of medical oncology, it is a normal practice combining different agents for the Treatment of cancer patients. Therefore a compound of formula I may optionally be combined with others components, such as antiproliferative, antiangiogenic agents and / or vascular permeability reducers. In addition, the surgery, the radiotherapy or chemotherapy can be used in combination with the administration of compounds of formula I. Therefore, the compound of formula I can be administered alone or in combination with the administration of another or other agents, substances and / or therapeutic treatments

Such joint treatment can be achieved by means of simultaneous, sequential or separate administration of individual components of the treatment. When they are not administered at the same time, component therapies can be administered in any order If formulated as a fixed dose, such combination products use the compounds of the present invention within the dose range described in then and the other pharmaceutically active agent is administered within its authorized dose range. The dose ranges of many pharmaceutically active agents They can be found in the Physician's Desk Reference, 55th Edition, Medical Economics Company (2001). The compounds of formula I can also be used sequentially with agents known anticancer or cytotoxic treatments and treatments, including radiation, when a combined formulation is inadequate.

In general, there are three main categories of chemotherapy agents:

(i)

antiangiogenic agents, for example, linomide, integrin? inhibitors (function 33, angiostatin and razoxine;

(ii)

cytostatic agents such as antiestrogens (by example tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, borazol, exemestane), antihormones, antiprogestagens, antiandrogens (for example, flutamide; nilutamide; bicalutamide; acetate cyproterone; salt mesylate (R) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-teienylsufonyl) -1H-1,4-benzodiazepin-7- carbonitrile; N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, hemi L-tartaric acid salt; cetuximab; molecules disclosed in US Patent Application Number of Ser 10 / 025.116, LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5α-dihydroreductase (by example finasteride), farnesyl transferase inhibitors, anti-invasion agents (for example inhibitors of metalloproteinases such as marimastat and function inhibitors urokinase receptor plasminogen activator) and inhibitors of growth factor function, (such growth factors include for example EGF, FGF, growth factor derived from platelets and hepatocyte growth factor, such inhibitors include antibodies against growth factors, antibodies against growth factor receptors, inhibitors of tyrosine kinase and serine / threonine kinase inhibitors); Y

(iii)

antiproliferative / antineoplastic drugs and their combinations, as used in medical oncology, such as antimetabolites (for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, analogs of purines and adenosine, cytosine arabinoside); antibiotics anti-tumor interleavers (for example anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin); derivatives of platinum (for example cisplatin, carboplatin); agents alkylating agents (eg nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide nitrosoureas, tiotefan); antimitotic agents (for example the alkaloids of the vinca as vincristine and taxoids such as taxol, taxotere and new microtubule stabilizing agents such as analogs of epothilone, discodermolide analogs and eleutherobin analogs); topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan); cycle inhibitors cellular (for example flavopyridols); and modifiers of the biological response Particular compounds may include N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, salt of hemi L-tartaric acid.

       \ newpage
    

The compounds of formula I and the compositions Pharmaceuticals comprising compounds of formula I may be administered by any means appropriate for the condition to treat, which may depend on the need for specific treatment of the site or the amount of drug to be administered. The compounds can be administered in a dose range of approximately 0.05 to 200 mg / kg / day, preferably less than 100 mg / kg / day, in single dose or in 2 to 4 separate doses.

Topical administration is generally of preference for skin-related diseases and Systematic treatment is preferred for cancerous conditions or precancerous, although other modes of administration are contemplated. For example, the compounds and compositions can be administered orally, such as tablets, capsules, granules, powders or liquid formulations, including syrups; by way topical, such as in the form of solutions, suspensions, gels or ointments; sublingually; orally; parenterally, such such as subcutaneously, intravenously, intramuscularly or by injection intrasternal or by infusion techniques (for example, as aqueous or non-aqueous injectable solutions or suspensions sterile); by nasal route such as by inhalation spray; by topical application, such as cream or ointment; by way rectal such as suppositories; or through liposomes

Pharmaceutical formulations can be administered. containing non-toxic vehicles or diluents, pharmaceutically acceptable. The compounds and compositions can be administered in a suitable form for immediate release or release prolonged Immediate release or prolonged release may be achieved with suitable pharmaceutical compositions or, in particular in the case of prolonged release, with devices such as subcutaneous implants or osmotic pumps. Other techniques for formulation and administration of the compounds and compositions of the This application can be found at "Remington's Pharmaceutical Sciences ", 18th Ed. (1990, Mack Publishing Co., Easton, PA).

       \ vskip1.000000 \ baselineskip
    

Abbreviations

The following abbreviations are among those used in this document:

\Delta

= heat

Ac

= acetyl

AcOH

= acetic acid

ac.

= aqueous

ATP

= adenosine triphosphate

BOP

= benzotriazol-1l-yloxytris (dimethylamino) -phosphonium

BSA

= bovine serum albumin

DBU

= 1,8-diazabicyclo [5.4.0] undec-7-eno

DCC

= dicyclohexylcarbodiimide

DCE

= dichloroethane

DEAD

= diethyl azodicarboxylate

DIBAL-H

= diisobutylaluminum hydride

DIPEA

= N, N-diisopropylethylamine

Dma

= dimethylacetamide

DME

= 1,2-dimethoxyethane

DMF

= dimethylformamide

DMSO

= dimethylsulfoxide

DPPA

= diphenylphosphoryl azide

DTT

= dithiothreitol

EDC

= hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EDTA

= ethylenediaminetetraacetic acid

Et

= ethyl

Et 2 O

= diethyl ether

EtOAc

= ethyl acetate

EtOH

= ethanol

GST

= glutathione S-transferase

h

= hours

Hexafluorophosphate

HOAt

= 1-hydroxy-7-azabenzotriazole

HOBt

= 1-hydroxybenzotriazole

Hünig Base

= N, N-diisopropylethylamine

KOtBu

= tert-butoxide of potassium

CL

= liquid chromatography

LDA

= lithium diisopropylamide

MBP

= myelin basic protein

mCPBA

= acid m-chloroperoxybenzoic

I

= methyl

MeI

= methyl iodide

MeOH

= methanol

MS (EV)

= electro mass spectrometry vaporization

n-BuLi

= n-butyllithium

Pd / C

= palladium on activated carbon

Ph

= phenyl

PhCH_ {3}

= toluene

pTSA

= acid para-toluenesulfonic

TR

= retention time

ta

= room temperature

sat.

= saturated

t-Bu

= tert-butyl

TCA

= trichloroacetic acid

TORCH

= triethylamine

TFA

= trifluoroacetic acid

THF

= tetrahydrofuran

FTA

= thin layer chromatography

Tris-HCl

= Tris [hydroxymethyl] aminomethane hydrochloride

Ts

= tosyl

TsCl

= tosyl chloride

TsOH

= tonic acid

       \ vskip1.000000 \ baselineskip
    

The following examples are provided for Describe the invention in more detail. These examples are intended illustrate and not limit the invention. All temperatures are given in degrees Celsius (° C) unless indicated otherwise. YMC Co., Ltd., is a column supplier for HPLC, based in Kyoto, Japan, and can be contacted through Waters Co. in Milford, MA.

       \ vskip1.000000 \ baselineskip
    

Example 1 Preparation of ethyl ester of acid 3-cyano-4- (cyclohexylamino) -5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid (1E)

25

       \ vskip1.000000 \ baselineskip
    

A. Preparation of diethyl ester of acid 3-methyl-1H-pyrrole-2,4-dicarboxylic (1A)

26

To a solution of ethyl isocyanoacetate (38.1 ml, 0.34 mol) and DBU (50.8 ml, 0.34 mol) in THF (400 ml) at 50 ° C a solution of acetaldehyde (9.5 ml, 0.17 mol) was added in THF (100 ml) for 25 min. The reaction mixture was stirred at 55 ° C. for 17 h, it was cooled to 25 ° C and acid was added slowly acetic (20 ml). The resulting mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (800 ml) and was washed with HCl (1 N, 3 x 300 ml). The combined aqueous washes are extracted with ethyl acetate (3 x 200 ml) and organic phases combined were washed with NaHCO3 (sat. aq., 3 x 200 ml), water (100 ml) and brine (100 ml) and then concentrated in vacuo giving a dark brown oil. Elution of this oil through a silica pad using ethyl acetate / hexanes (1: 1) and the concentration in vacuo provided compound 1A (16 g, 42% yield) as a yellow solid. HPLC: 100% to 3,536 minutes (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 226.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

B. Preparation of diethyl ester of acid 1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic (1 B)

27

To a suspension of NaH (60% suspension in mineral oil, 213 mg, 5.33 mmol) in DMF (15 ml) at 0 ° C was added compound 1A (1.0 g, 4.44 mmol), in portions. The mixture of reaction was stirred at 0 ° C for 5 min and then heated to 25 ° C and stirred another hour. Then the mixture of reaction was cooled to 10 ° C and added 2,4-dinitro-aminophenol (972 mg, 4.88 mmol) in two portions. The resulting mixture was heated to 25 ° C, stirred for 12 h, poured into water (40 ml) and dichloromethane (50 ml), and the phases were separated. The aqueous phase was extracted with dichloromethane (3 x 20 ml) and the combined organic extracts are washed with NaOH (1N, 3 x 20 ml), water (20 ml) and brine (20 ml) and then dried over MgSO4, filtered and concentrated empty The resulting reddish brown residue was concentrated again for 12 h under high vacuum giving 800 mg (yield 75%) of compound 2B, which was used without further purification. HPLC: 100% at 3,488 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol that contained 0.2% phosphoric acid for 4 min, 4 ml / min, with 220 nm control). MS (EV): m / z 241.17 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

C. Preparation of ethyl ester of acid 3-cyano-1,4-dihydro-5-methyl-4-oxopyrrolo [1,2-b] pyridazine-6-carboxylic (1 C)

28

To a diethyl ester solution of the acid 1-amino-3-methyl-1H-pyrrole-2, 4-dicarboxylic (1.08 g, 4.50 mmol) in toluene (15 ml) 1,1-diethoxypropionitrile (2.02 ml, 1.93 g, 13.5 mmol) and TsOH-H2O (171 mg, 0.90 mmol). The reaction mixture was heated at reflux for 12 h and at then cooled to 25 ° C. DBU (0.81 ml, 0.822 g, was added, 5.40 mmol) and the resulting dark brown mixture was heated at 80 ° C for 1 h and then cooled to temperature ambient. The reaction mixture was poured onto dichloromethane (50 ml) and NH 4 Cl (aq. sat., 50 ml) and the phases were separated. The phase Aqueous was extracted with dichloromethane (2 x 30 ml) and extracts Combined organics were washed with water (30 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified. by silica gel column chromatography (methanol at 10-30% / dichloromethane) giving 441 mg (40%) of compound 1C as a brown solid. HPLC: 100% at 3,383 min (time of retention) (YMC S5 ODS column, 4.6 x 50 mm, eluting with methanol 10-90% aqueous containing phosphoric acid at 0.2% for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 246.09 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

D. Preparation of ethyl ester of acid 4-Chloro-3-cyano-5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic (1D)

29

A 15 ml round base flask was loaded which contained compound 1C (370 mg, 1.51 mmol) with POCl3 (1 ml) and It was heated at 75 ° C for 2 h. The reaction mixture was concentrated in vacuum and the resulting yellow residue was dissolved in dichloromethane (10 ml) and was added, by means of a pipette, to a solution saturated aqueous NaHCO3 with stirring at 0 ° C. Mix Heterogeneous was stirred for 10 min at 0 ° C then heated to room temperature and stirred for another hour. Mix It was poured into a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 20 ml) and the extracts Combined organics were washed with NaHCO 3 (sat. aq., 1 x 20 ml), dried over Na2SO4, filtered and concentrated on empty. The resulting residue was dissolved in EtOAc (20 ml) and was filtered through a silica pad using EtOAc (100 ml) to wash the silica pad. The filtrate was concentrated in vacuum giving compound 1D as a yellow solid, which was used without Other purification HPLC: 100% at 4,160 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with aqueous methanol at 10-90% containing 0.2% phosphoric acid for 4 min, 4 ml / min, with control at 220 nm).

       \ vskip1.000000 \ baselineskip
    

E. Preparation of ethyl ester of acid 3-cyano-4- (cyclohexylamino) -5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid (1E)

To a solution of compound 1D (20 mg, 0.076 mmol) in acetonitrile (1 ml) was added Et3N (32 µl, 0.228 mmol) and cyclohexylamine (10 µL, 0.084 mmol) and the mixture of reaction was stirred at 25 ° C. After 24 h, another 10 µl of cyclohexylamine and the reaction mixture was stirred for another 1.5 hours after what was poured onto NaHCO3 (ac. sat., 20 ml) and dichloromethane The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 10 ml). The combined organic phases are washed with water (20 ml), dried over MgSO4, filtered and concentrated in vacuo to give 18 mg (75%) of compound 1E as a solid yellow, which was used without further purification. HPLC: 100% at 4.60 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing acid 0.2% phosphoric for 4 min, 4 ml / min, with control at 220 nm). EM (EV): m / z 327.2 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 2 Preparation of ethyl ester of acid 3-cyano-5-methyl-4-phenoxypyrrolo [1,2-b] pyridazin-6-carboxylic

       \ vskip1.000000 \ baselineskip
    

30

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 1D (18 mg, 0.068 mmol) in acetonitrile (0.5 ml) at room temperature was added Et 3 N (21 ul, 0.205 mmol) and phenol (7 mg, 0.075 mmol). Mix The reaction was stirred for 24 h and then poured onto dichloromethane (10 ml) and NaHCO3 (ac. sat., 10 ml). They separated the phases, the aqueous phase was extracted with dichloromethane (3 x 5 ml) and The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the compound 2 (15 mg, 68%) as a yellow solid. HPLC: 100% at 4.35 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing acid 0.2% phosphoric for 4 min, 4 ml / min, with MS control (EV): m / z 340.0 [M + NH4] +.

       \ vskip1.000000 \ baselineskip
    

Example 3 Preparation of 6- (methoxymethyl) -5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile (3C)

       \ vskip1.000000 \ baselineskip
    

31

       \ vskip1.000000 \ baselineskip
    

A. Preparation of ethyl ester of acid 3-cyano-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-6-carboxylic (3A)

       \ vskip1.000000 \ baselineskip
    

32

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 ml) was added K2CO3 (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25 ° C. The reaction mixture was stirred for 12 h and then diluted with dichloromethane (15 ml) and washed with water (10 ml) and brine (10 ml) The organic phase was dried over Na2SO4 and concentrated and the resulting residue was triturated with methanol to give 31 mg. (76% yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol that contained 0.2% phosphoric acid for 4 min, 4 ml / min, with 220 nm control). MS (EV): m / z 413.12 [M + H] +.

Compound 3A can also be prepared from the as follows: at a solution of 1D (1.00 g, 3.79 mmol) in THF (10 ml) 4-phenoxyaniline (0.84 g, 4.53) was added mmol) and triethylamine (1.06 ml, 7.58 mmol). The reaction mixture is heated at 60 ° C for 3 days, after which it cooled to room temperature and diluted with MeOH (50 ml). The solids resulting were filtered, washed with MeOH and dried to give 1.50 g (96% yield) of 3A as a yellow powder.

       \ vskip1.000000 \ baselineskip
    

B. Preparation of 6- (hydroxymethyl) -5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile (3B)

       \ vskip1.000000 \ baselineskip
    

33

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 3A (41 mg, 0.10 mmol) in THF (2 ml) at -78 ° C was added DIBAL-H (1.5 M in toluene, 0.13 ml, 0.20 mmol). The reaction mixture is stirred for 6 h at -78 ° C, heated to 0 ° C and stirred for another 2 h. The reaction mixture was quenched by the addition of methanol (3 ml) and Na2CO3ac. sat. (3 ml) and then It was poured onto dichloromethane (20 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 15 ml) and the extracts The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification by means of preparative HPLC (YMC S5 ODS 20 x 100 mm, eluting with aqueous methanol at 30-100% for 15 min containing 0.1% TFA, 20 ml / min) gave 33 mg (90% yield) of compound 3B as a yellow solid HPLC: 100% at 3.98 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with aqueous methanol at 10-90% containing 0.2% phosphoric acid for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 371.19 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

C. Preparation of 6- (methoxymethyl) -5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile (3C)

To a solution of compound 3B (9.0 mg, 0.025 mmol) in DMF: THF (1: 1, 1 ml) at 0 ° C was added KOtBu (1.5 M in THF, 0.025 ml, 0.038 mmol). After stirring for 45 min at 0 ° C, it is added methyl iodide (2 µL, 0.025 mmol) and the mixture of reaction was stirred for another hour, heated to 25 ° C and was stirred for 3 h. During this time, none were observed reaction. The reaction mixture was cooled once more to 0 ° C, added more KOtBu (1.5 M in THF, 0.25 ml, 0.38 mmol) and the mixture of reaction was stirred for 30 min, after which more iodide was added of methyl (20 µL, 0.25 mmol). After stirring for another 2 h at 0 ° C, the reaction was quenched by the addition of aqueous NH4Cl saturated (10 ml) and dichloromethane (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and extracts The combined organics were dried over MgSO4, filtered, dried. concentrated and purified by means of preparative HPLC (YMC S5 ODS 20 x 100 mm, eluting with 30-100% aqueous methanol that contained 0.1% TFA for 15 min, 20 ml / min) giving the product desired as a yellow semi-solid. HPLC: 100% a 4.27 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 385.21 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 4 Acid preparation 4 - [(2-Chloro-4-iodophenyl) amino] -3-cyano-5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid

       \ vskip1.000000 \ baselineskip
    

3. 4

       \ vskip1.000000 \ baselineskip
    

To an ethyl ester solution of the acid 4 - [(2-Chloro-4-iodophenyl) amino] -3-cyano-5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid (59 mg, 0.123 mmol, prepared as described in Example 1) in THF (1 ml) was added NaOH (1N, 1 ml). The reaction mixture is stirred at 25 ° C for 72 h and then poured over NaHCO 3 (30 ml) and EtOAc (30 ml). The phases and the aqueous phase was acidified to pH = 2 and extracted with dichloromethane (2 x 20 ml). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuum giving 20 mg (36% yield) of compound 4, which was used Without other purification. 1 H NMR (DMSO-d 6) δ 8.99 (s, 1 H), 8.18 (s, 1 H), 8.03 (s, 1 H), 7.97 (s, 1 H), 7.75 (d, 1 H), 7.29 (d, 1H), 2.78 (s, 3 H). HPLC: 100% at 4.04 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing acid 0.2% phosphoric for 4 min, 4 ml / min, with control at 220 nm).

       \ vskip1.000000 \ baselineskip
    

Example 5 Preparation of 4 - [(2-Chloro-4-iodophenyl) amino] -3-cyano-5-methyl-N- (2-methylpropoxy) pyrrolo [1,2-b] pyridazine-6-carboxamide

35

To a solution of compound 4 (20 mg, 0.442 mmol) in THF: dichloromethane (1: 1, 1 ml) was added Isopropylhydroxylamine HCl (7 mg, 0.053 mmol), Hüning base (18 mul, 0.106 mmol) and PyBOP (hexafluorophosphate) benzotriazol-1-yl oxytripyrrolidinophosphonium) (28 mg, 0.0531 mmol). The mixture of The reaction was stirred for 1 h, concentrated in vacuo and diluted with 10% HCl (15 ml) and Et2O (15 ml). The phases and the Organic phase was washed with 1N NaOH (15 ml) and brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo. The phase Aqueous was made alkaline by the addition of 1N NaOH and extracted with EtOAc (2 x 15 ml). The organic extracts were dried over MgSO4, filtered, concentrated in vacuo and added to the phases organic combined from the first extractions. HPLC preparative (YMC S5 ODS 20 x 100 mm, eluting with aqueous methanol at 30-100% containing 0.1% TFA for 15 min, 20 ml / min) gave 1.1 mg of compound 5. HPLC: 100% at 3.68 min (time of retention) (YMC S5 ODS column, 4.6 x 50 mm, eluting with methanol 10-90% aqueous containing 0.1% TFA for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 524.02 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 6 Acid preparation 3-cyano-4 - [[5 - [(methoxyamino) carbonyl] -2-methylphenyl] amino] -5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid

36

To an ethyl ester solution of the acid 3-cyano-4 - [[5 - [(methoxyamino) carbonyl] -2-methylphenyl] amino] -5-methylpyrrolo [1,2-b] pyridazine-6-carboxylic acid (160 mg, 0.393 mmol, prepared as described in Example 1) in THF (2 ml) 1N NaOH (4 ml) was added. The reaction mixture is stirred at 25 ° C for 2 days and then neutralized with acid 1M citrus and poured onto dichloromethane. The organic phase is separated and extracted with dichloromethane and organic extracts combined were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by means of Preparative HPLC (YMC S5 ODS 20 x 100 mm, eluting with methanol 30-100% aqueous containing 0.1% TFA for 15 min, 20 ml / min) giving 36 mg (39% yield) of the compound 6. HPLC: 100% at 3.33 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid for 4 min, 4 ml / min, with 220 nm control). MS (EV): m / z 380.24 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 7 Preparation of 3-cyano-4 - [[5 - [(methoxyamino) carbonyl] -2-methylphenyl] amino] -5-methyl-N - [(1S) -1-phenylethyl] pyrrolo [1,2-b] pyridazin-6 -carboxamide

37

To a solution of compound 6 (19 mg, 0.05 mmol) in DMF (2 ml) EDC (14.4 mg, 0.075 mmol), HOBt was added (10.1 mg, 0.075 mmol) and DIPEA (12.9 mg, 0.10 mmol) and the mixture of The reaction was stirred for 30 min at 25 ° C. Then it was added (S) -methylbenzylamine (7.3 mg, 0.06 mmol) and the mixture The reaction was stirred for another 16 h at 25 ° C. Then the The reaction was diluted with dichloromethane and poured into water. Be the phases were separated and the organic phase dried over Na 2 SO 4, was filtered and concentrated in vacuo. The residue is purified by means of preparative HPLC (YMC S5 ODS 20 x 100 mm, eluting with 30-100% aqueous methanol for 15 min containing 0.1% TFA, 20 ml / min) gave 21 mg (yield of 87%) of compound 7 as a yellow semi-solid. HPLC: 100% at 3.79 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm, eluting with 10-90% aqueous methanol that contained 0.2% phosphoric acid for 4 min, 4 ml / min, with 220 nm control). MS (EV): m / z 483.36 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 8 Preparation of 6-formyl-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile

       \ vskip1.000000 \ baselineskip
    

38

To a solution of compound 3B (266 mg, 0.72 mmol) in dichloroethane (30 ml) was added MnO2 (200 mg, 2.0 mmol). The reaction mixture was heated at 60 ° C for 3 h, it was cooled to 25 ° C, diluted with dichloromethane and filtered through from Celite. The filtrate was concentrated in vacuo and purified by means. column chromatography on silica gel (MeOH at 0.5% / CH2CI2) giving 238 mg (90% yield) of compound 8 as a yellow solid. HPLC: 100% at 3.37 min (time of retention) (YMC S5 ODS column, 4.6 x 50 mm, eluting with methanol 10-90% aqueous containing phosphoric acid at 0.2% for 4 min, 4 ml / min, with control at 220 nm). MS (EV): m / z 369.08 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 9 Acid preparation 3-cyano-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-6-carboxylic

       \ vskip1.000000 \ baselineskip
    

39

To a solution of compound 3A (1.50 g, 3.64 mmol) in THF (50 ml) was added NaOH (1 M, 20.0 ml) and EtOH (25 ml) The reaction was heated to 80 ° C, evaporating THF so effective, and, after 1 h, the reaction mixture became homogeneous. Be continued heating for another 6 h, after which the reaction was cooled to rt and neutralized with HCl (1 M, 20.0 ml). The solids resulting were filtered, washed with water and dried giving the compound 9 (1.33 g, 95% yield) as a yellow solid. HPLC: 100% at 1.84 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm eluting with 10-90% MeOH / H2O which contained 0.1% TFA for 2 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 489.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 10 Preparation of an amide library Preparation of 3-cyano-5-methyl-4 - [(4-phenoxyphenyl) amino] -N-phenylpyrrolo [1,2-b] pyridazine-6-carboxamide

       \ vskip1.000000 \ baselineskip
    

40

To a solution of compound 9 (11.5 mg, 0.030 mmol) and HOAt (6.1 mg, 0.045 mmol) in THF (0.60 ml) was added a solution of aniline (14 mg, 0.15 mmol) in THF (0.15 ml) followed by a solution of EDC (11.5 mg, 0.06 mmol) in chloroform (0.30 ml) The reaction mixture was heated at 60 overnight and at It was then cooled to rt and diluted with MeOH (0.4 ml). The resulting mixture was purified by elution through a SCX / SAX cartridge (500 mg / 500 mg) SCX ion exchange cartridges Silica-binding SAX, supplied by United Chemical Technologies, Inc., Bristol, PA, with MeOH, followed by concentration of the solvent in vacuo, giving 13.2 mg (yield 96%) of compound 10 as a yellow solid. HPLC: 100% at 2.05 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% MeOH / H2O containing acid 0.2% phosphoric for 4 minutes, 4 ml / min, with control at 220 nm). MS (EV): m / z 460.0 [M + H] +.

The above procedure was used to prepare a library of 68 amide compounds by means of the replacement of the aniline reagent with other amines. The compounds are purified using the above procedure or through HPLC preparative (Shimadzu VP-ODS 20.0 x 50.0 mm eluting with 25-90% MeOH / H2O containing 0.1% TFA for 7 minutes, 10 ml / min, with control at 220 nm).

       \ vskip1.000000 \ baselineskip
    

Example 11 Preparation of 6-amino-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile (11B)

       \ vskip1.000000 \ baselineskip
    

41

       \ vskip1.000000 \ baselineskip
    

A. Preparation of acid phenylmethyl ester [3-cyano-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1, 2-b] pyridazin-6-yl] carbamic, (11A)

       \ vskip1.000000 \ baselineskip
    

42

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 9 (192 mg, 0.50 mmol) in dioxane (anhydrous, 4 ml) under an atmosphere of N 2 is given added triethylamine (0.134 ml, 1.00 mmol) and DPPA (0.216 ml, 1.00 mmol) and the mixture was stirred overnight. Then you added benzyl alcohol (0.310 ml, 3.00 mmol) and the mixture of The reaction was heated at 75 ° C for 4 h, concentrated in vacuo and purified by silica gel column chromatography. (20-30% EtOAc / hexanes) giving compound 11A as an oil yellow (172 mg, 70%). HPLC: 100% at 4.01 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 490.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

B. Preparation of 6-amino-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-3-carbonitrile (11B)

To a solution of compound 11A (40 mg, 0.082 mmol) in MeOH (4ml) was added Pd / C (12 mg) and the mixture of reaction was stirred under hydrogen (1 atm) for 30 minutes, after which HCl (4M in dioxane, 0.1 ml) was added. The mixture of reaction was filtered and the filtrate was concentrated in vacuo giving 32 mg of compound 11B as an orange solid (quantitative yield as HCl salt). HPLC: 100% at 2.90 min (retention time) (column YMC S5 ODS, 4.6 x 50 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 356.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 12 Preparation of N- [3-cyano-5-methyl-4 - [(4-phenoxyphenyl) aminolpyrrolo [1,2-b] pyridazin-6-yl] acetamide

43

To a solution of compound 11B (HCl salt, 32 mg, 0.082 mmol) in THF (2 ml) was added acetic anhydride (11 mg, 0.11 mmol) followed by triethylamine (33 mg, 0.33 mmol) and the reaction stirred at rt for 30 min. After extinguishing with MeOH, the mixture of The reaction was stirred for another 30 min, concentrated in vacuo and purified by means of flash chromatography on gel silica (40 to 50% EtOAc / dichloromethane) giving compound 12 as a yellow oil (30 mg, 92% yield). HPLC: 100% to 3.46 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm eluting with 10-90% MeOH / H2O containing 0.1% TFA for 2 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 398.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 13 Acid preparation 3- (aminomethyl) -5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazine-6-carboxylic acid

44

To a solution of compound 9 (27 mg, 0.070 mmol) in MeOH: THF (2: 1 v / v, 6 ml) TFA (30 mg) was added followed by Pd / C (10 mg). The reaction mixture was stirred under hydrogen (1 atm) overnight and then filtered through a Celite pad. The filtrate was concentrated in vacuo and the residue was purified by means of several azeotropic distillations with MeOH to remove excess TFA. This procedure gave the compound 13 as a yellow solid (35 mg, quantitative). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm eluting with 10-90% MeOH / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). EM (EV): m / z 389. 0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 14 Acid preparation 3 - [(acetylamino) methyl] -5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazine-6-carboxylic

Four. Five

To a solution of compound 13 (10 mg, 0.02 mmol) in THF was added triethylamine (1 drop, about 10 mg) followed by acetic anhydride (1 drop, approximately 10 mg). The reaction was stirred at rt for 10 min and then concentrated in vacuo. The residue was redissolved in THF and was NaOH (1M, 2 drops) added. The resulting mixture was stirred at rt for 2 hours, it was neutralized with HCl (1M) and purified by means Preparative HPLC (Shimadzu VP-ODS 20.0 x 50.0 mm eluting with 25-90% MeOH / H2O containing 0.1% TFA for 7 minutes, 10 ml / min, with control at 220 nm) giving compound 14 as a yellow solid (7 mg, yield of 81%) HPLC: 100% at 3.46 min (retention time) (YMC S5 column ODS, 4.6 x 50 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 431.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 15 Preparation of N- [3-cyano-5-methyl-4 - [(4-phenoxyphenyl) amino] pyrrolo [1,2-b] pyridazin-6-yl] -N'-methylurea

       \ vskip1.000000 \ baselineskip
    

46

A solution of compound 9 (19 mg, 0.05 mmol), triethylamine (0.014 ml, 0.10 mmol) and DPPA (0.022 ml, 0.10 mmol) in dry dioxane (1 ml) under N2 for 12 h. The reaction was then heated to 80 ° C for 1 h and subsequently allowed to cool to 25 ° C at rest. Was added methylamine (solution in 2.0 M THF, 0.30 ml, 0.60 mmol) and the The reaction was stirred at 25 ° C for 1 h, concentrated in vacuo and purified by means of flash column chromatography silica gel (50 to 70% EtOAc / dichloromethane) giving the compound 15 (15 mg, 73%) as a yellow solid. HPLC: 100% to 3.44 min (retention time) (YMC S5 ODS column, 4.6 x 50 mm eluting with 10-90% MeOH / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 413.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 16 Preparation of ethyl ester of acid 3-cyano-5-hydroxymethyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid (16C)

       \ vskip1.000000 \ baselineskip
    

47

       \ vskip1.000000 \ baselineskip
    

A. Acid ethyl ester 5-bromomethyl-4-chloro-3-cyano-pyrrolo [1,2-b] pyridazin-6-carboxylic (16A)

48

A suspension of compound 1D was heated (79 mg, 0.30 mmol), NBS (59 mg, 0.33 mmol) and benzoyl peroxide (5 mg, 0.02 mmol) in CCl4 (2 ml) at 77 ° C for 3 hours. After cooling until room temperature, the reaction was purified by means of a short column of silica gel (eluted with CH2Cl2) giving compound 16A as a yellow solid (102 mg, 99%).

       \ vskip1.000000 \ baselineskip
    

B. 4-Ethyl ester of acid chloro-3-cyano-5-hydroxymethyl-pyrrolo [1,2-b] pyridazine-6-carboxylic (16B)

49

To a solution of compound 16A (102 mg, 0.30 mmol) in THF (12 ml) water (3 ml) was added dropwise. The reaction was maintained at room temperature for 3 days and at It was then heated at 50 ° C for 3 hours. Once cooled until room temperature, NaHCO3 (70 mg) was added to the reaction mixture. The reaction was concentrated to dryness, dissolved again in CH2Cl2 and filtered. The filtrate is concentrated giving compound 16B as a yellow solid (84 mg, 100%) This compound was used in the following stages without other purification.

       \ vskip1.000000 \ baselineskip
    

C. Acid ethyl ester 3-cyano-5-hydroxymethyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid (16C)

A solution of compound 16B was heated (84 mg, 0.30 mmol), 4-phenoxyaniline (72 mg, 0.39 mmol) and triethylamine (0.083 ml, 0.60 mmol) in THF (2.5 ml) at 70 ° C for 30 min. After cooling to room temperature, the reaction is concentrated to about 0.5 ml, diluted with MeOH (2 ml) and leaked The solid was washed with MeOH and dried to give the compound 16C as a yellow solid (118 mg, 92%). HPLC: 92% at 2.12 min (retention time) (column 5u C18-HC of PrimeSphere, 4.6 x 30 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 2 minutes; 5 ml / min, with control at 220 nm). MS (EV): m / z 429.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 17 Preparation of ethyl ester of acid 3-cyano-5-methoxymethyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid (17B)

       \ vskip1.000000 \ baselineskip
    

fifty

       \ vskip1.000000 \ baselineskip
    

A. Acid ethyl ester 4-Chloro-3-cyano-5-methoxymethyl-pyrrolo [1,2-b] pyridazine-6-carboxylic (17A)

       \ vskip1.000000 \ baselineskip
    

51

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 16A (31 mg, 0.09 mmol) in 1: 1 MeOH: CH 2 Cl 2 (2 ml) NaHCO 3 was added (30 mg, 0.36 mmol). The reaction was maintained at room temperature. for 3 h, heated at 70 ° C for 1 h, cooled to room temperature, concentrated to dryness, returned to Dissolve in CH2Cl2 and filtered. The filtrate was concentrated. giving compound 17A as a yellow solid (26 mg, 98%).

       \ vskip1.000000 \ baselineskip
    

B. Acid ethyl ester 3-cyano-5-methoxymethyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid (17B)

Compound 17B was prepared according to procedure described in Example 16C. HPLC: 96% at 2.24 min (retention time) (column 5u C18-HC PrimeSphere, 4.6 x 30 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 2 minutes; 5 ml / min, with control at 220 nm). MS (EV): m / z 443.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 18 Preparation of ethyl ester of acid 3-cyano-5-formyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid (18)

       \ vskip1.000000 \ baselineskip
    

52

To a solution of compound 16C (21.4 mg, 0.05 mmol) in chloroform (1 ml) was added MnO2 (<5 micrometers, activated, 17 mg, 0.20 mmol). The reaction was heated to 55 ° C overnight, cooled to room temperature and purified by means of flash chromatography on a silica gel column (EtOAc al 0-2% / CH 2 Cl 2) giving compound 18 as a yellow solid (20 mg, 94%). HPLC: 94% at 2.20 min (time of retention) (PrimeSphere column 5uC18-HC, 4.6 x 30 mm eluting with 10-90% MeOH / H2O which contained 0.1% TFA for 2 minutes; 5 ml / min, with control at 220 nm). MS (EV): m / z 427.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 19 Preparation of 1- [3-Cyano-5-methyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazin-6-yl] -3- (2-morpholin-4-yl-ethyl) - urea (19-1) and 5-methyl-6- (5-oxo-4,5-dihydro-tetrazol-1-yl) -4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazin-3-carbonitrile (19-2)

53

A solution of compound 9 (115 mg, 0.30 mmol), triethylamine (0.063 ml, 0.45 mmol) and DPPA (0.097 ml, 0.45 mmol) in dioxane (5 ml) overnight. The next day is added TMS-azide (0.080 ml, 0.60 mmol) and the reaction temperature was brought to 80 ° C. The reaction was heated to 80 ° C for 2 hours, cooled to room temperature and added 4- (2-aminoethyl) morpholine (0.079 ml, 0.60 mmol). The reaction was stirred at room temperature for 1 h, concentrated and purified by means of resolution chromatography fast on a silica gel column (MeOH at 3-6% / CH 2 Cl 2) giving a mixture of the compounds 19-1 and 19-2 as a yellow oil This oil recrystallized from MeOH giving compound 19-1 as a yellow solid (116 mg, 76%). 19-1: HPLC: 97% at 3.11 min (time of retention) (YMC S5 ODS column, 4.6 x 50 mm eluting with MeOH at 10-90% / H2O containing 0.1% TFA for 4 minutes; 4 ml / min, with control at 220 nm). MS (EV): m / z 512.0 [M + H] +.

The mother liquor of the previous recrystallization It was passed through an SCX cartridge (500 mg) and eluted with MeOH (5 ml). The eluent was concentrated to give the compound. 19-2 as a yellow solid (9 mg, 7%). 19-2: HPLC: 94% at 1.93 min (retention time) (PrimeSphere C18-HC column 5u, 4.6 x 30 mm eluting with 10-90% MeOH / H2O containing 0.1% TFA for 2 minutes; 5 ml / min, with control at 220 nm). EM (EV): m / z 424.0 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Examples 20 A 144

Other compounds of the present invention are prepared by procedures analogous to those described previously. Table 1 provides the name and structure of representative compounds and their retention times, as well as the Example number of the procedure on which the compound preparation The chromatography techniques used to determine the retention time of the compounds that are presented in Table 1 are the following:

CLEM =

YMC S5 ODS column, 4.6 x 50 mm eluting with MeOH at 10-90% / H2O for 4 minutes containing the TFA 0.1%; 4 ml / min, with control at 220 nm.

CLEM * =

YMC S5 ODS column, 4.6 x 50 mm eluting with MeOH 10-90% / H2O containing 0.1% TFA for 2 minutes; 4 ml / min, with control at 220 nm.

CLEM-1 =

PrimeSphere C18-HC 5u column, 4.6 x 30 mm eluting with 10-90% MeOH / H2O which contained 0.1% TFA for 2 minutes; 5 ml / min, with control at 220 nm.

CL =

YMC S5 ODS 4.6 x 50 mm column eluting with MeOH at 10-90% / H2O containing 0.2% phosphoric acid for 4 minutes, 4 ml / min, with control at 220 nm.

CL * =

YMC S5 ODS 4.6 x 50 mm column eluting with 10-90% MeOH / H2O containing phosphoric acid at 0.2% for 4 minutes, 4 ml / min, with control at 220 nm.

       \ vskip1.000000 \ baselineskip
    

The molecular mass of the compounds that are presented in Table 1 was determined by MS (EV) by means of the formula m / z.

TABLE 1

54

TABLE 1 (continued)

55

TABLE 1 (continued)

56

TABLE 1 (continued)

57

TABLE 1 (continued)

58

TABLE 1 (continued)

59

TABLE 1 (continued)

60

TABLE 1 (continued)

61

TABLE 1 (continued)

62

TABLE 1 (continued)

63

TABLE 1 (continued)

64

TABLE 1 (continued)

65

TABLE 1 (continued)

66

TABLE 1 (continued)

67

TABLE 1 (continued)

68

TABLE 1 (continued)

69

TABLE 1 (continued)

70

TABLE 1 (continued)

71

TABLE 1 (continued)

72

       \ vskip1.000000 \ baselineskip
    

Example 145 6- (1-Hydroxy-1-methyl-ethyl) -5-methyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazin-3-carbonitrile

73

To a solution of compound 3A (124 mg, 0.30 mmol) in THF (5 ml) at 0 ° C a solution of slowly added 3.0M MeMgBr in ether (0.40 ml, 1.20 mmol). The reaction was heated to room temperature and then heated to 50 ° C for 1 h. After cooling to room temperature, the reaction is quenched with EtOAc (20 ml) and saturated aqueous NH4Cl was added (20 ml). The resulting two phases were separated and the organic phase washed with brine, dried over Na2SO4 and concentrated until you get an orange oil. This crude oil was purified by silica gel rapid chromatography medium (eluted with EtOAc 14-17% / CH 2 Cl 2) giving compound 145 as a yellow solid (76 mg, 64%). HPLC: 97% at 1.97 min (time retention) (column S5 C18 Phenom-Prime, 4.6 x 30 mm, eluting with 10-90% aqueous methanol that contained 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 399 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 146 6-Hydroxy-5-methyl-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazin-3-carbonitrile

       \ vskip1.000000 \ baselineskip
    

74

To a mixture of H2O2 (50% by weight in H 2 O, 0.0115 ml, 0.20 mmol) and CH 2 Cl 2 (2 ml) at -5 ° C BF_ {3} \ cdotOEt_ {2} was added. The reaction was stirred at -5 ° C. for 40 min before adding a solution of compound 145 (56 mg, 0.14 mmol) in CH 2 Cl 2 (3 ml). The reaction was maintained at -5 ° C for 10 min and was quenched with an aqueous solution of Na 2 SO 3 (2 g, 10 ml). The reaction was diluted with CH 2 Cl 2 and the two phases separated. The aqueous phase is extracted with CH 2 Cl 2 (2x10 ml). The phases of CH 2 Cl 2 were combined and concentrated in vacuo giving a brown oil This crude product was purified by means of silica gel flash chromatography (eluted with EtOAc at 10% / CH 2 Cl 2) giving compound 146 as a solid yellow (32 mg, 64%). HPLC: 90% at 1.89 min (retention time) (column C18 Phenom-Prime S5, 4.6 x 30 mm, eluting with 10-90% aqueous methanol containing TFA at 0.1% for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 357 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 147 5-Methyl-6- (2-morpholin-4-yl-ethoxy) -4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazin-3-carbonitrile

       \ vskip1.000000 \ baselineskip
    

75

To a solution of compound 146 (8.9 mg, 0.025 mmol), PPh3 (13.1 mg, 0.05 mmol) and 4- (2-hydroxyethyl) -morpholin (6.6 mg, 0.05 mmol) in dry THF (0.3 ml) under N2 at 0 ° C was added DEAD (8.7 mg, 0.05 mmol). The reaction was stirred at 0 ° C for 5 min, it was heated to room temperature for 2 h, concentrated to dryness and purified by means of rapid gel chromatography of silica (eluted with 1-5% MeOH / CH 2 Cl 2) giving compound 147 as a yellow oil (10 mg, 85%). HPLC: 96% at 1.69 min (retention time) (Column C10 S5 Phenom-Prime, 4.6 x 30 mm, eluting with methanol 10-90% aqueous containing 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 470 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 148 Acid ethyl ester 5-cyano-7-oxo-6- (4-phenoxy-phenyl) -6,7-dihydro-9H-8-oxa-2a, 3,6-triaza-benzo [cd] azulen-1-carboxylic

       \ vskip1.000000 \ baselineskip
    

76

To a solution of compound 16C (26 mg, 0.061 mmol) and DIPEA (63 mg, 0.485 mmol) in CH 2 Cl 2 (6 ml) at -50 ° C triphosgene (30 mg, 0. 101 mmol) was added. The reaction was heated slowly to 10 ° C for 1 h, quenched with MeOH (1 ml), concentrated to dryness in vacuo and purified by means of silica gel flash chromatography (eluted with EtOAc at 1-2% / CH 2 Cl 2) giving compound 148 as a yellow solid (16 mg, 58%). HPLC: 91% at 2.09 min (time of retention) (column C10 S5 Phenom-Prime, 4.6 x 30 mm, eluting with 10-90% aqueous methanol that contained 0.1% TFA, 5 ml / min for 2 min, with control at 220 nm). MS (EV): m / z 455 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 149 Acid ethyl ester 5-azidomethyl-3-cyano-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid

       \ vskip1.000000 \ baselineskip
    

77

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 148 (21 mg, 0.05 mmol) in THF (0.6 ml) DPPA (22 mg, 0.08 mmol) was added followed by DBU (9 mg, 0.06 mmol). The reaction was stirred at temperature. ambient for 4 h, concentrated and purified by means of flash chromatography on a silica gel column (0.5-1% EtOAc / CH 2 Cl 2) giving the compound 149 as a yellow oil (14 mg, 63%). HPLC: 99% to 2.16 min (retention time) (column 5u C18-HC of PrimeSphere, 4.6 x 30 mm, eluting with aqueous methanol at 10-90% containing 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 454 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 150 Acid ethyl ester 5-aminomethyl-3-cyano-4- (4-phenoxy-phenylamino) -pyrrolo [1,2-b] pyridazine-6-carboxylic acid

       \ vskip1.000000 \ baselineskip
    

78

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 149 (12 mg, 0.026 mmol) in a mixture of THF: MeOH 1: 2 (3 ml) Pd / C (5 mg) The reaction was hydrogenated under a hydrogen balloon at room temperature for 30 min and filtered. The filtrate is concentrated giving 8 as a yellow solid (9 mg, 80%). I dont know They required more purifications. HPLC: 92% at 1.71 min (time of retention) (PrimeSphere C18-HC column 5u, 4.6 x 30 mm, eluting with 10-90% aqueous methanol which contained 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 428 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Example 151 Acid ethyl ester 5-cyano-7-oxo-6- (4-phenoxy-phenyl) -6,7,8,9-tetrahydro-2a, 3,6,8-tetraaza-benzo [cd] azulen-1-carboxylic

       \ vskip1.000000 \ baselineskip
    

79

       \ vskip1.000000 \ baselineskip
    

To a solution of compound 150 (7 mg, 0.016 mmol) and DIPEA (17 mg, 0.13 mmol) in CH2Cl2 (1.5 mL) at -70 ° C triphosgene (9.5 mg, 0.032 mmol) was added. The reaction is slowly heated to -5 ° C for 1 h, quenched with MeOH (0.5 ml), concentrated to dryness and purified by means of silica gel flash chromatography (eluted with EtOAc at 6-8% / CH 2 Cl 2) giving 9 as a solid yellow (6 mg, 81%). HPLC: 98% at 1.97 min (retention time) (PrimeSphere C18-HC 5u column, 4.6 x 30 mm, eluting with 10-90% aqueous methanol containing 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm). MS (EV): m / z 454 [M + H] +.

       \ vskip1.000000 \ baselineskip
    

Examples 152 A 367

Other compounds of the present invention are prepared by procedures analogous to those described previously. Table 2 provides the name and structure of representative compounds and their retention times, as well as the Example number of the procedure on which the compound preparation The chromatography techniques used to determine the retention times of the compounds presented in Table 2 are as follows:

CL =

YMC S5 ODS column, 3.6 x 50 mm, eluting with 10-90% aqueous methanol containing 0.1% TFA for 2 min, 5 ml / min, with control at 220 nm

CL * =

YMC S5 ODS 4.6 x 50 mm column eluting with MeOH at 10-90% / H2O containing 0.2% phosphoric acid for 4 minutes, 4 ml / min, with control at 220 nm.

       \ vskip1.000000 \ baselineskip
    

The molecular mass of the compounds presented in Table 2 it was determined by MS (EV) by means of the formula m / z

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

       \ vskip1.000000 \ baselineskip
    

Example 368 VEGFR-2 and FGFR-1 assays kinases

148

The incubation mixtures used for the assay of VEGFR-2 or FGFR-1 contained the synthetic poly-Glu substrate: Tyr (4: 1), ATP, ATP-? - 33 P and buffer which contains Mn ++ and / or Mg ++, dithiothreitol (DTT), albumin of Bovine serum (BSA) and Tris buffer. The reaction was initiated by the enzyme addition and after 60 minutes it was terminated by addition of trichloroacetic acid (TCA) at a concentration of 30% in volume percentage. The inhibitors according to the invention are led to a concentration of 10 mM in DMSO. Rehearsals are They prepared in a 96-well format. The compounds were diluted 1: 500 in DMSO and then 1:10 in water for a concentration final in DMSO of 10%. 10 µl aliquots were added to the B-H rows in a 96-well format of DMSO at 10% Aliquots of 20 µl of inhibitor solution were added to row A with a concentration 5 times higher than the conditions of the experiment 10 µl aliquots were transferred to each row with 10 pipette phases to mix, and 10 µl was discarded in row F. Row G was a control without compound and row H was a control without compound and without enzyme. The enzyme and the substrate are supplied using a Tomtec Quadra equipment.

The plates were covered with plate covers adhesives, incubated at 27 ° C for 60 minutes, and then were precipitated with acid with TCA for 20 minutes in ice. The precipitate was transferred to GF / C microplates UniFilter-96 using a FilterMate Packard collector or Tomtec. The activity was determined by quantifying the built-in radioactivity using a scintillation counter Packard TopCount microplates, after cocktail addition Microscint-20 in each dry well of the UniFilter microplates.

The compounds of formula I tested inhibited VEGFR-2 and FGFR-1 kinases with IC_ {50} values \ leq 80 µM.

       \ vskip1.000000 \ baselineskip
    

Example 369 HER1, HER2 or HER4 kinase assays

Compounds of interest were tested in a kinase buffer containing 20 mM Tris.HCl, pH 7.5, MnCl2 mM, 0.5 mM dithiothreitol, 0.1 mg / ml bovine serum albumin, poly (glu / tyr, 4: 1), 0.1 mg / ml, 1 µM ATP and [γ - 33 P] -ATP 4 µCi / ml. Poly (glu / tyr, 4: 1) is a synthetic polymer that It serves as a phosphoryl acceptor and was purchased from Sigma Chemicals. The kinase reaction was initiated by the addition of enzyme and the reaction mixtures were incubated at 26 ° C for 1 hour. The reaction it was terminated by the addition of 50 mM EDTA and the proteins were made precipitate by adding 5% trichloroacetic acid. Proteins precipitates were recovered by filtration in Packard plates Unifilter and the amount of radioactivity incorporated into a TopCount scintillation counter.

To prepare recombinant HER1 and HER4, expressed the cytoplasmic sequences of the receptors in insect cells as fusion proteins with GST, which purified by affinity chromatography. Sequence HER2 cytoplasmic was subcloned into the expression vector of baculovirus pBluBac4 (Invitrogen) and expressed as a protein Unmarked in insect cells. The recombinant protein is partially purified by ion exchange chromatography.

The present compounds inhibit HER-1, HER-2 and HER4 kinases with IC 50 values between 0.001 and 25 µM. Preferably the compounds have IC 50 values between 0.001 and 5.0 µM. The most preferred compounds have IC 50 values between 0.001 and 1.0 µM. The most preferred compounds have IC 50 values between 0.001 and
0.1 µM.

To select the compounds according to their HERG activity an HERG potassium channel test can be used (see Caballero R, et al., "Direct Effects of Candesartan and Eprosartan on Human Cloned Potassium Channels Involved in Cardiac Repolarization ", Molecular Pharmacology, 59 (4), 825-836, (2001)). Therefore, the compounds preferably have lower activity in the channel test HERG

To prepare recombinant HER1, the cytoplasmic sequence of the receptor in insect cells as a fusion protein with GST, which was purified by chromatography of affinity. The cytoplasmic sequence of HER2 was subcloned into the baculovirus expression vector pBluBac4 (Invitrogen) and se expressed as an unlabeled protein in insect cells. The Recombinant protein was partially purified by chromatography of ion exchange

The compounds of formula I tested inhibited HER-1 and HER-2 kinases with values of IC_ {50} \ leq 100 µM.

       \ vskip1.000000 \ baselineskip
    

Example 370 MEK-ERK kinase cascade test

An in vitro 96-well plate assay was described as described in Example 388, above, with several modifications. Each well contained 30 µl assay buffer (Tris-HCl, pH 7.5, MgCl 2, DTT, BSA, myelin basic protein (MBP), ATP and [γ-33 P] ATP) , dilutions of 10 µl inhibitor or empty DMSO solvent and mixture of 10 µ enzymes (MEK-EE 5-10 ng and ERK 100-200 ng). The final concentrations in the assay were 20 mM Tris-HCl, pH 7.5, 10 mM MgCl 2, 0.3 mM DTT, 50 µg BSA, 50 µg basic myelin protein (MBP), 10 ATP muM and [γ-33 P] ATP 200 nCi. The plates were incubated at room temperature for 60 minutes and the reactions were terminated by the addition of 10 µl stop mixture containing 300 mM EDTA and 25 µg BSA. The samples were subjected to precipitation with TCA containing ATP (final concentrations: TCA, 3.2% and ATP, 2.3 mM). The samples were transferred to Packard 96-well Unifilter GF / C plates using a Packard Filter Mate 196 collector. After drying under light, the radioactivity count of the residues in the wells was performed with a Packard microplate counter
Top Count

Since this assay is a cascade assay, MEK and ERK inhibitors are expected to be identified. Another in vitro analysis was required to determine if the "successes" were attributable to the inhibition of MEK (using MEK and ERK deficient kinase activity) or ERK inhibitors (using activated ERK and MBP). However, the compounds of formula I tested inhibited MEK and / or ERK with IC50 values? 10 µM.

       \ vskip1.000000 \ baselineskip
    

Example 371 Generation of p38 kinases

The cDNAs of the human p38?,? And?? Isoenzymes were cloned by PCR. These cDNAs were subcloned into the expression vector pGEX (Pharmacia). The GST-p38 fusion protein was expressed in E. coli and purified from bacterial sediments by affinity chromatography using glutathione agarose. The p38 fusion protein was activated by incubating with constitutively active MKK6. The active p38 was separated from MKK6 by affinity chromatography. The constitutively active MKK6 was generated according to Raingeaud et al. [Mol. Cell Biol., 1247-1255
(nineteen ninety six)].

       \ vskip1.000000 \ baselineskip
    

Example 372 Production of TNF-? By stimulated PBMC with LPS

Heparinized human blood was obtained from Healthy volunteers Peripheral blood mononuclear cells (PBMC) were purified from human blood by centrifugation in density gradient with Ficol-Hypaque and it resuspended in a concentration of 5 x 10 6 / ml in the middle of assay (RPMI medium containing 10% fetal calf serum). Be incubated 50 µl of cell suspension with 50 µl of compound test (4X concentration in test medium containing DMSO at 0.2%) in 96-well tissue culture plates for 5 minutes to TA. Then 100 ul of LPS (solution was added mother 200 ng / ml) to the cell suspension and the plate was incubated for 6 hours at 37 ° C. After incubation, the medium was collected from culture and stored at -20 ° C. The concentration of TNF-? In the medium by an ELISA kit conventional (Pharmingen - San Diego, CA). The concentrations of TNF-? And IC 50 values for the test compounds (concentration of the compound that inhibits the production of TNF-? stimulated by LPS in a 50%) were calculated by means of linear regression analysis.

       \ vskip1.000000 \ baselineskip
    

Example 373 P38 test

The tests were performed on 96 plates V-bottom wells The final assay volume was 60 µl prepared from three additions of 20 µl of enzyme, substrates (MBP and ATP) and test compounds in the assay buffer (50 mM Tris, pH 7.5, 10 mM MgCl 2, 50 mM NaCl and 1 mM DTT). The activated p38, expressed in bacteria, was pre-incubated with the test compounds for 10 minutes before the start of the reaction with substrates. The reaction was incubated at 25 ° C for 45 minutes and ended by adding 5 µl of 0.5 M EDTA to each sample. The reaction mixture was aspirated into a pre-moistened filter. using a Skatron Micro96 cell collector (Skatron, Inc.), then washed with PBS. Subsequently the filter in a microwave oven for 1 minute, treated with wax MeltilLex A (Wallac) scintillation and counting was performed with a Model 1450 Microbeta scintillation counter (Wallac). Were analyzed nonlinear least squares regression inhibition data using Prizm (GraphPadSoftware). The final concentration of Reagents in the assays were: ATP, 1, µM; [γ - 33 P] ATP, 3 nM, MBP (Sigma, number of catalog M1891), 2 µg / well; p38, 10 nM; and DMSO, 0.3%.

       \ vskip1.000000 \ baselineskip
    

Example 374 TNF-? Production by mice stimulated with LPS

Mice (Balb / c females, 6-8 weeks old, Harlan Labs; n = 8 / treatment group) were injected intraperitoneally with 50 ug / kg lipopolysaccharide (LPS; E. coli strain 0111: B4, Sigma ) suspended in sterile saline solution. Ninety minutes later, the mice were sedated by inhalation of CO2: O2 and blood samples were obtained. Serum was prepared and analyzed for TNF-α concentrations by means of a commercial ELISA according to the manufacturer's instructions (R&D Systems, Minneapolis, MN).

Test compounds were administered by orally at various times before the injection of LPS. The compounds were administered as suspensions or as solutions in various vehicles or solubilizing agents.

Claims (18)

1. A compound of formula (I): 149 including its enantiomers, pharmaceutically acceptable diastereomers, salts and solvates, in the that:

R_ {1} se select from the group consisting of H, hydroxyl, alkyl, aralkyl, halogen, OR1 ', OC (O) R1', OC (O) OR_ {1} ', OC (O) NR_ {1}' R_ {1} '', OS (O) 2 R 1 '' 'and OS (O) 2 NR 1 'R 1'; in which R_ {1} 'and R_ {1} '' are each independently selected from the group that It consists of groups H, alkyl, aryl, aralkyl, heterocycle and cycloalkyl; R_ {1} 'and R_ {1}' 'can also be taken together from one of a cycloalkyl, an aryl and a heterocyclic group; R_ {1} '' 'is selected from the group consisting of alkyl, aryl, aralkyl, heterocycle and cycloalkyl;

R2 is select from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R1 'OC (O), R_ {1} 'C (O), R_ {1}' 'R_ {1}' NC (O), R 1 '' 'O (O) 2 S, R 1 'R 1' N (O) 2 S and R_ {1} '' (O) n S, where n is the integer selected from 1 or 2;

R_ {1} and R2 can be taken together to form a cycloalkyl group, aryl or heterocyclic;

X is selected from the group consisting of a valence bond, O, S and NR2 '; Y R 2 'is selected from the group consisting of H, alkyl, aralkyl, C (O) R1, C (O) OR1, SO_ {2} NR_ {1} 'R_ {1}' ', C (O) NR_ {1}' R_ {1} '' and SO_ {R} {1} '' '; with the proviso that when X is S, R2 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl;

R 3 is select from the group consisting of H, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido, halogen, amine, substituted amine, OR 3 ', CH_ {OR} {3} ', CH_ {NR} {3}' R_ {3} '', CH_ {SR} {3} ', OC (O) R_ {3} ', OC (O) OR_ {3}' ', OC (O) NR_ {3} 'R_ {3}' ', OS (O) 2 R 3 'and OS (O) 2 NR 3 'R 3' '; in which R_ {3} 'and R_ {3} '' are each independently selected from the group that It consists of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; R_ {3} 'and R_ {3}' 'can also be taken together to forming a cycloalkyl, aryl or heterocyclic group; when R_ {3} is a carbalkoxy, acyl or carboxamido group, these groups are optionally substituted with one or two substituent groups, said substituent groups are independently selected from the group that It consists of H, alkyl, aralkyl, heterocycle, cycloalkyl and aryl; said substituent groups can also be taken together to form a cycloalkyl, aryl or heterocyclic group;

R2 and R 3 can also be taken together to form a group cycloalkyl, aryl or heterocyclic;

R4 is select from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R1 'OC (O), R_ {1} 'C (O), R_ {1}' 'R_ {1}' NC (O), R 1 '' O (O) 2 S, R 1 'R 1' N (O) 2 S and R_ {1} '' (O) n S, where n is the integer selected from 1 or 2;

And it is selected from the group consisting of a valence bond, O, S and NR4 '; R 4 'is selected from the group consisting of H, alkyl, aralkyl, a heterocycle, C (O) R1, C (O) OR_ {1}, S (O_ {2}) NR_ {1} 'R_ {1}' ', C (O) NR_ {1} 'R_ {1}' 'and S (O2) R1; with the proviso that when Y is S, R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle and aralkyl; when Y is NR_ {4} ', R_ {4} 'can be taken together with R_ {3} to form a system of heterocyclic ring;

R5 se select from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, a heterocycle, aryl, aralkyl, acyl group, substituted alkylene, R 1 'OC (O), R 1' C (O), R_ {1} '' R_ {1} 'NC (O), R_ {1}' 'O (O) 2 S, R 1 'R 1' N (O) 2 S and R 1 '' (O) n S; where n is the integer 1 or 2;

Z is selected from the group consisting of a valence bond, O, S and NR5 '; R 5 'is selected from the group consisting of H, alkyl, aralkyl and a heterocycle; with the proviso that when Z is a Valencia link, R5 is selected from the group consisting of H, halogen, a substituted alkylene group and a cyano group; and with the other condition that when Z is S, R_ {5} is selected from group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl; Y

R 6 is select from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, a heterocycle, acyl, carbalkoxy and carboxamido; said carbalkoxy, acyl and carboxamido groups are optionally substituted with one or two substituent groups, each of the which is independently selected from the group consisting of H, alkyl, aralkyl and a heterocycle,

in which, "alkyl" or "alq" in reference to R1, R1 ', R_ {1} '', R_ {1} '' ', R_ {2}, R_ {2}', R_ {3}, R_ {3} ', R_ {3} '', R_ {4}, R_ {4} ', R_ {5}, R_ {5}' and R_ {6}, are refers to straight or branched chain hydrocarbon radicals, optionally substituted with 1 to 4 substituents that may include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogen, heterocycle, hydroxy, cyano, nitro, amino, monoalkylamino, dialkylamino, hydroxylamine, sulfonate, sulfamide, cyano-guanidine, oxo, carbalkoxy, carboxamido, SO_ {n}, in which n is 0, 1 or 2, and / or acyl groups.

         \ vskip1.000000 \ baselineskip
      

2. The compound of claim 1, in the that Z is a valence bond and R5 is cyano. 3. The compound of claim 2, in the that R 3 is methyl. 4. The compound of claim 3, in the that Y is N. 5. The compound of claim 4, in the that R 4 is alkyl, aryl or heterocycle. 6. The compound of claim 5, in the that X is a valence bond, O or NR_ {2} '. 7. The compound of claim 6, in the that R2 is R1 'C (O). 8. The compound of claim 6, in the that R_ {2} 'is -C (O) NR_ {1}' R_ {2} 'or -C (O) OR_ {1} '. 9. The compound of claim 8, in the that R 1 'and R 1' 'are independently alkyl, cycloalkyl or heterocycle. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and at less a pharmaceutically acceptable vehicle. 11. The pharmaceutical composition of the claim 10, further comprising at least one agent additional therapeutic 12. The pharmaceutical composition of the claim 11, wherein the additional therapeutic agent is select from the group consisting of angiogenesis inhibitors, antiestrogens, progestogens, aromatase inhibitors, antihormones, antiprogestogens, antiandrogens, agonists and LHRH antagonists, testosterone inhibitors 5α-dihydroreductase inhibitors of farnesyl transferase, anti-invasion agents, growth factor inhibitors, antimetabolites, antibiotics anti-tumor interleavers, platinum derivatives, agents alkylating agents, antimitotic agents, topoisomerase inhibitors, cell cycle inhibitors and response modifiers biological 13. The pharmaceutical composition of the claim 11, wherein the additional therapeutic agent is select from the group consisting of linomide, inhibitors of integrin αvβ3 function, angiostatin, razoxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, acetate of megestrol, anastrozole, letrazole, borazol, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, acetate goserelin, luprolide, finasteride, metalloproteinase inhibitors, urokinase receptor activator function inhibitors plasminogen, antibodies against growth factor, antibodies against the growth factor receptor, tyrosine kinase inhibitors, serine / threonine inhibitors kinase, methotrexate, 5-fluorouracil, analogs of purine and adenosine, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide nitrosoureas, thiotefan, vincristine, taxol, taxotere, epothilone analogues, discodermolide analogs, eleuterobin analogues, etoposide, Tenipósido, amsacrine, topotecan and flavopyridoles. 14. The pharmaceutical composition of the claim 11, wherein the additional therapeutic agent is select from the group consisting of taxol, Erbitux?, paraplatin and Ifex. 15. A compound according to any of the claims 1 to 9 as active agent for the treatment of a proliferative or inflammatory disease 16. Use of a compound according to any of the claims 1 to 9 in the manufacture of a medicament for the Treatment of a proliferative or inflammatory disease. 17. Use of a compound according to any of the claims 1 to 9 in combination with at least one other agent additional therapeutic in the manufacture of a medicine for Treatment of a proliferative or inflammatory disease.

         \ newpage
      

18. Use according to claim 17, wherein the Additional therapeutic agent is selected from the group consisting of angiogenesis inhibitors, antiestrogens, progestogens, aromatase inhibitors, antihormones, antiprogestogens, LHRH antiandrogens, agonists and antagonists, inhibitors of testosterone 5α-dihydroreductase, farnesyl transferase inhibitors, agents anti-invasion factor inhibitors growth, antimetabolites, intercalator antibiotics antitumor agents, platinum derivatives, alkylating agents, agents antimitotics, topoisomerase inhibitors, inhibitors of cell cycle and biological response modifiers.