ES2292329B2 - QUINASE INHIBITORS FOR THE TREATMENT OF DISEASES. - Google Patents

Abstract

Kinase inhibitors for the treatment of diseases.

The present invention relates to molecules organic capable of modulating signal transduction of tyrosine kinase to regulate, modulate and / or inhibit abnormal cell proliferation

Scheme one

one

Description

Kinase inhibitors for the treatment of diseases.

Background of the invention 1. Field of the invention

The present invention relates to prodrugs of compounds capable of modulating, regulating and / or inhibiting the tyrosine kinase signal transduction. The The present invention is also directed to methods for regulating, modulating or inhibit tyrosine kinases, of the recipient class or non-recipient, for the prevention and / or treatment of disorders related to deregulated signal transduction of tyrosine kinase, including disorders of cell, metabolic and vessel proliferation growth blood.

2. Description of the related technique

The protein tyrosine kinases (TTK) comprise a broad and diverse class of proteins that have enzymatic activity. PTKs play an important role in growth control and cell differentiation.

For example, the transduction of mediated signals by receptor tyrosine kinases is initiated by an extracellular interaction with a specific growth factor  (ligand), followed by receptor dimerization, stimulation transient intrinsic protein activity tyrosine kinase and phosphorylation. The sites of binding are therefore created for transduction molecules of intracellular signals and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (for example, division, homeostasis metabolic and responses to the extracellular microenvironment).

With respect to receptor tyrosine kinases, has been shown also that tyrosine phosphorylation sites function as high affinity binding sites for SH2 domains (homology src) of signaling molecules. Several have been identified intracellular substrate proteins that are associated with receptor tyrosine kinases (RTK). They may be divided into two main groups: (1) substrates that have a catalytic domain; and (2) substrates that lack this domain but they serve as adapters and are associated with catalytically molecules active. The specificity of interactions between recipients of SH2 protein and domains of its substrates is determined by the amino acid residues immediately surrounding the residue of phosphorylated tyrosine. Differences in binding affinities between the SH2 domains and the surrounding amino acid sequences phosphotyrosine residues in particular receptors are congruent with the differences observed in their profiles of phosphorylation of substrates. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its expression model and its availability of ligands, but also by the ordering of signal transduction paths in the downward direction that They are activated by a particular receiver. Therefore, the phosphorylation provides an important regulatory stage that determines the selectivity of signaling paths recruited by specific growth factor receptors, as well as receptors of differentiation factors.

Aberrant expression or mutations in PTK It has been shown to lead to uncontrolled cell proliferation (for example, malignant tumor growth) or defects in key development procedures. Consequently, the community Biomedical has dedicated significant resources to discover the function specific biological of members of the PTK family, their role in Differentiation procedures, their relationship with genesis tumor and other diseases, the biochemical mechanisms that underlie their transduction trajectories of activated signals after stimulation by ligands and the development of new drugs

Tyrosine kinases can be receptor type (which have extracellular domains, of transmembrane and intracellular) or non-receptor type (which are completely intracellular).

RTKs comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated after ligand binding, which results in phosphorylation of the receptor and multiple substrates cell phones, and subsequently to a variety of responses cell phones.

At present, they have been identified at minus nineteen (19) subfamilies other than RTK. A subfammilia RTK, called the subfamily HER, is believed to be comprised of by EGFR, HER2, HER3 and HER4. The ligands for the subfamily Her de receptors include epithelial growth factor (EGF), TGF-?, Anfirregulin, HB-EGF, betacellulin and heregulin.

A second family of RTK, called the insulin subfamily, is comprised of the INS-R, IGF-1R and IR-R. A third family, the subfamily "PDGF" includes PDGF? and? receptors, CSFIR, c-kit and FLK-II. Another subfamily of RTK, identified as the FLK family, is believed to be comprised by insertion domain receiver of fetal liver kinase / kinase-1 (KDR / FLK-1), fetal liver kinase 4 (FLK-4) and fms type tyrosine kinase 1 (flt-1). Each of these receptors was believed initially they were receptors for growth factors hematopoietic Two other RTK subfamilies have been named the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Due to the analogies between the PDGF and FLK subfamilies, the two subfamilies are often considered together. Known RTK subfamilies are identified by Plowman et al , 1994, DN&P 7 (6): 334-339, which are incorporated by reference to the present specification.

Tyrosine kinases do not receptors represent a collection of cellular enzymes that they lack extracellular and transmembrane sequences. In the Currently, they have been identified more than twenty four individual non-receptor tyrosine kinases, which they comprise eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes7Fps, Fak, Jak, Ack and LIMK). Currently, the Src subfamily of non-receptor tyrosine kinases is comprised by the largest number of PTK and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been associated with Oncogenesis A more detailed exposure of tyrosine kinases does not Receivers is provided by Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated as a reference to the Present descriptive report.

Many of the tyrosine kinases, whether it is a RTK or a tyrosine kinase no recipient, it has been found that they are related to trajectories cell signaling devices that lead to cell signal cascades leading to pathogenic conditions, which include cancer, psoriasis and hyper-immune response.

Given the supposed importance of PTKs in the control, regulation and modulation of cell proliferation and the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify "inhibitors" of receptor and non-receptor tyrosine kinases using a variety of approaches, including the use of mutant ligands (U.S. Patent No. 4,966,849), soluble receptors and antibodies (PCT application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al , 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al , Biochemistry 33: 10450-56); Takano, et al , 1993, Mol. Bio. Cell 4: 358A; Kinsella, et al , 1992, Exp. Cell Res. 199: 56-62; Wright, et al , 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCT applications No. WO 94/03427, WO 92/21660, WO 91/15495, WO 94/14808 and patent U.S. 5,330,992; Mariani, et al , 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).

More recently, attempts have been made to identify small molecules that act as inhibitors of tyrosine kinase For example, the compounds of bis-monocyclic, bicyclic or heterocyclic aryl (PCT application No. WO 92/20642), derived from vinyl azaindole (PCT application No. WO 94/14808) and 1-cyclopropyl-4-pyridyl quinolones (U.S. Patent No. 5,330,992) have been generally described as tyrosine kinase inhibitors. The compounds  styryls (U.S. Patent No. 5,217,999), compounds of pyridyl substituted with styryl (US Patent No. 5,302,606), certain quinazoline derivatives (European patent application no. 0.566.266 A1), selenoindoles and selenides (PCT application No. WO 94/03427), tricyclic polyhydroxy compounds (PCT application no. WO 92/21660) and benzylphosphonic acid compounds (PCT application No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors to be used in the treatment of cancer.

The identification of small compounds effective that specifically inhibit signal transduction modulating tyrosine kinase activity receptors and non-recipients to regulate and modulate proliferation abnormal or inappropriate cell phone is therefore desirable and is an object of this invention.

Finally, certain small compounds are described in US Pat. 5,792,783, 5,834,504, 5,883,113, 5,883,116 and 5,886,020 as useful for the treatment of  diseases related to deregulated transduction of TKS. These patents are incorporated by reference herein fully descriptive for the purpose of describing materials of starting and methods for its preparation, selections and tests for determine the ability of a claimed compound to modulate, regulate and / or inhibit cell proliferation, indications that are treatable with said compounds, formulations and routes of administration, effective dosages, etc.

As a foundation of the present invention is the concept of prodrugs that is well known in the art. Prodrugs are derived from drugs that, after administration, undergo a conversion in physiologically active species. This conversion may be due or caused by a hydrolysis in the physiological environment, or it may be due to an enzymatic hydrolysis. The following bibliography is cited: Design of Pro-drugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers BV (Biomedical Devision), chapter 1; design of prodrug derivatives: bioreversible for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al . Int.J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al Int. J. of Pharmaceutics 29 (1986) 19-28 (Elsevier); Bundgaard et al . J. Med. Chem. 32 (1989) 2503-2507 Chem. Abstracts 95, 138493f (Bungaard et al .); Chem. Abstracts 95, 138592n (Bundgaard et al .); Chem Abstracts 110, 57664p (Alminger et al .) Chem. Abstracts 115, 64029s (Buur et al .); Chem Abstracts 115, 189582y (Hansen et al .); Chem.Abstracts 117, 14347q (Bundgaard et al .); Chem. Abstracts 117, 55790x (Jensen et al .); and Chem Abstracts 123, 17593b (Thomsen et al ).

Brief description of the drawings and figures

Figure 1 shows the general scheme for preparation of the compounds of this invention, in particular the compounds of Examples 2-6, 8 and 9.

Figure 2 shows the general scheme for preparation of the compounds of this invention, in particular the compounds of Examples 12 and 13.

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Figure 3 shows the general scheme for preparation of the compounds of this invention, in particular the compounds of Examples 15, 16, 19 and 21.

Brief summary of the invention

The present invention relates to molecules organic capable of modulating, regulating and / or inhibiting transduction of tyrosine kinase signals. These compounds they are useful for the treatment of diseases related to deregulated TKS transduction, including diseases of cell proliferation such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic pulmonary obstruction disease, vascular proliferation disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of the prematurity, autoimmune diseases and rejection of transplants

Detailed description of the invention

In an illustrative embodiment, the compounds of the present invention have the formula I:

2

in which fragment B represents a tyrosine kinase inhibitor or an inhibitor of serine-threonine-kinase that contains a nitrogen atom capable of reacting with formaldehyde, a substituted aldehyde or substituted ketone and a amine, to provide a compound of formula I, in the which

R 3 and R 4 are selected independently among the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl radicals, wherein said hydrocarbyl may be substituted with selected heteroatoms between the group consisting of halogens, for example, fluorine, chlorine,  bromine or iodine, nitrogen, phosphorus, sulfur and oxygen, or R3 and R 4 together with the nitrogen atom can form a cyclic ring, ring that may be substituted with said heteroatoms, for example, R 3 and R 4 can be selected from the group consisting of hydrogen, alkyl, alkoxy, alkyloxyalkyl, aryl, aryloxy, alkylaryl and alkaryloxy; Y

R 5 and R 6 are selected independently among the group consisting of hydrogen, alkyl and aryl radicals; with the proviso that said radicals alkyl or phenyl may be substituted with one to three radicals halo, hydroxyl, lower alkyloxy or (alkyl lower) -amino. Preferably, R 5 and R 6 They are hydrogen.

In a preferred embodiment, the compounds of The present invention has the formula II or III:

3

in the that:

X is O or C (R2) 2;

And it is [C (R 2) 2] c;

A is NR2 or is absent;

R1 is selected from the group that consists of halogen, hydroxy, NO2, CN, hydrocarbyl radicals and substituted hydrocarbyl, wherein said substituted hydrocarbyl it may be substituted with heteroatoms selected from the group consisting of halogen, for example, fluorine, chlorine, bromine or iodine, nitrogen, phosphorus, sulfur and oxygen, for example, alkyl C 1 to C 4 and aryl, for example, phenyl, and when b is 1 R1 is preferably chlorine;

R 2 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, (CR 8 R 9) d C (O) OR 10 }, COCH 3, CH 2 CH 2
OH, CH 2 CH 2 CH 2 OH and phenyl;

R is selected from the group consisting of halogen, hydrocarbyl radicals and substituted hydrocarbyl, in which said substituted hydrocarbyl can be substituted with heteroatoms selected from the group consisting of halogen, for example, fluorine, chlorine, bromine or iodine, nitrogen, phosphorus , sulfur and oxygen, for example, R may be selected from the group consisting of halogen, C 1 to C 8 alkyl, CF 3, OCF 3, OCF 2 H, CH 2 CN, CN, SR 2, (CR 8 R 9) d C (O) OR 2, (CR 8 R 9) _ {d C (O) N (R 2) 2, (CR 8 R 9) d OR 2, HNC (O) R 2 , HN-C (O) OR 2, (CR 8 R 9) 6 N (R 2) 2, SO 2 (CR ^ {8 R9) d
N (R 2) 2, OP (O) (OR 2) 2, OC (O) OR 2, OCH 2 O, HN-CH = CH , -N (COR 2) CH 2 CH 2, HC = N-NH, N = CH-S, O (CR 8 R 9) c R ^ {7}, (CR 8 R 9) d R 7 and -NR 2 (CR 8 R 9) e R ^ {7}, wherein R7 is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, isonipecotate methyl, N- (2-methoxyethyl) -N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N- (2-methoxyethyl) ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro- (1H) -1,4-diazepinyl-5 (4H) -one, N-methylhomopiperazinyl, (3-dimethylamino) pyrrolidinyl, N- (2-methoxyethyl) - N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3- (diethylamino) pyrrolidinyl, 1,4 -dioxa-8-azaspiro [4,5] decaninyl, 1- (2-methoxyethyl) -piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3- (methylsulfonyl) pyrrolidinyl, 3-picolylmethylaminyl, 2- (2-Methylaminoethyl) pyridinyl, 1- (2-pyrimidyl) -piperazinyl, 1- (2-pyrazinyl) -piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2- (N-methyl-2-aminoethyl) -1,3-dioxolane, 3- (N-acetyl-N-methylamino) pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1- (3-aminopropyl) imidazole , histamyl, N, N-diisopropylethylene diamine, 1-benzyl-3-aminopyrrolidyl 2- (aminomethyl) -5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R) -3-amino- 1-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran, ethanolamine and its alkyl substituted derivatives; with the proviso that said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower-amino alkyl radicals;

in which R 8 and R 9 can be selected among the group consisting of H, halogen, for example, F, hydroxy and C 1 -C 4 alkyl or CR 8 R 9 can represent a carbocyclic ring of 3 to 6 carbon atoms, preferably R 8 and R 9 are H or CH 3, preferably in the compounds of formula III when a is 1, R is dimethylamino and in the compounds of formula II when a is 1, R is morpholinyl;

R 3, R 4, R 5 and R 6 are as follows defined above;

R 10 is hydrogen, C 1 to C 8 alkyl or arylalkyl;

a is 0 or an integer from 1 to 3;

b is 0 or an integer from 1 to 3;

c is an integer from 1 to 2;

d is 0 or an integer from 1 to 5;

e is an integer from 2 to 5;

the wavy line represents an E or Z link; Y

Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl, in that said substituted hydrocarbyl or said substituted heteroaryl they may be substituted with heteroatoms selected from the group consisting of halogen, for example, fluorine, chlorine, bromine or iodine, nitrogen, phosphorus, sulfur and oxygen, for example, Ar can be selected from the group consisting of aryl and heteroaryl monocyclic and bicyclic, including aryl or bicyclic heteroaryl condensed or non-condensed, for example, phenyl, naphthyl, pyridyl,  pyrrolyl, furyl, thienyl, etc. and its substituted derivatives; and their pharmaceutically acceptable salts. Preferably, Ar is an aryl or monocyclic heteroaryl, for example, phenyl or pyrrolyl.

Preferably R 5 and R 6 are hydrogen.

Preferably R 3 is H and R 4 is select from the group consisting of alkyl, for example, n-butyl or alkyloxyalkyl, for example, Methyloxypropyl, or R 3 and R 4, together with the atom of nitrogen, forms a cyclic ring that has 5 or 6 members, for example, a 6-member ring, which can include an atom of chained oxygen or nitrogen, for example, R 3 and R 4 they can be, together with the nitrogen atom, morpholinyl or piperidinyl and said morpholinyl or piperidinyl ring may be substituted with one or more lower alkyl groups, by example, methyl.

Preferably, X is O and Y is CH2 and R it can be di- (lower alkyl) amino, for example, dimethylamino

Preferably, Ar is phenyl or pyrrolyl and R it can be lower alkyl, for example, methyl or morpholinyl.

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In a preferred embodiment of the invention, the R 3 and R 4 together with the nitrogen atom form a ring cyclic that has 3 to 8, for example, 5 or 6 members and, more preferably, said cyclic ring includes an oxygen atom chained or a second nitrogen atom. That is, R3 and R 4 together with the nitrogen atom can be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In another preferred embodiment, R 3 is hydrogen and R 4 is alkyl or alkyloxyalkyl.

In another embodiment of the invention, or R 8 and R 9 are hydrogen or d is 0, and R is selected among the group consisting of halogen, C 1 to C 8 alkyl, CF 3, OCF 3, OCF 2 H, CN, SR 2, (CH 2) d C (O) OR 2, C (O) N (R 2) 2, (CH 2) d OR 2, HNC (O) R 2, HN-C (O) OR2, (CH 2) d N (R 2) 2, SO 2 N (R 2) 2, OP (O) (OR 2) 2, OC (O) OR 2, OCH 2 O, HN-CH = CH, -N (COR 2) CH 2 CH 2, HC = N-NH, N = CH-S, O (CH 2) c -R 7 and (CH 2) d -R 7, wherein R 7 is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl and its substituted derivatives with lower alkyl; with the proviso that R 7 and / or said alkyl or phenyl radicals may be substituted with one to three halo, hydroxyl, lower alkyloxy or (alkyl) radicals lower) -amino.

In a preferred embodiment of formula II, A is -NH-, a is 0, Ar is

4

in which R_ {3} 'and R_ {4}' are each independently selected from the group consisting in hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S (O) R2, SO 2 (R 2) 2, SO 3 R 2, SR 2, NO 2, N (R 2) 2, OH, CN, C (O) R2, OC (O) R2, NHC (O) R 2, (CH 2) d CO 2 R 2, Y (CH 2) d CON (R 2) 2;

R 'is hydrogen, alkyl, aryl, alkylaryl, haloalkyl, (CR 8 R 9) d C (O) OR 2, (CR 8 R 9) e OR 2 O (CR 8 R 9) e N (R 2) 2, or (CR 8 R 9) e R 7, wherein d, e, R 2, R 7, R 8 and R 9 are as defined above.

In another preferred embodiment of formula II, A is -NH-, a is 0, Ar is

5

where R_ {3} 'and R_ {4}' are as defined above, R 11 is R 1 or R 11 taken together with the nitrogen atom can be a ring 5 or 6 members that can have a chained oxygen atom or a second nitrogen atom, for example, morpholinyl, piperidinyl, piperazinyl, etc.

Still, in another preferred embodiment of formula II, A is absent, Ar is a five-membered heteroaryl ring selected from the group consisting of furyl, thiophene, pyrrole, 2,4-dimethylpyrrole, 2,4-dimethyl-3 acid -pyrrol-propionic, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazol, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1 , 2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole , 1,2,4-thiadiazole, 1,2,5-thiatriazole and tetrazole, optionally substituted in one or more positions with R 2, O (CR 8 R 9) e
N (R 2) 2, (CR 8 R 9) d N (R 2) 2 or NR 2 (CR ^ {8 R 9) e N (R 2) 2 (CR 8 R 9 C (O) OR 2, O (CR 8 R 9) e R 7, (CR 8 R 9) d R 7 and NR 2 (CR 8 R 9) e R 7, wherein d, e, R 2, R 7, R 8 and R 9 } are as defined above.

Still, in another preferred embodiment of the formula II, A is -NH, Ar is a five-membered heteroaryl ring  selected from the group consisting of furyl, thiophene, pyrrole, 2,4-dimethylpyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiatriazole and tetrazole, optionally substituted in one or more positions with R2, O (CR 8 R 9) e N (R 2) 2, (CR 8 R 9) d N (R 2) 2, NR 2 (CR 8 R 9) e N (R 2) 2, (CR 8 R 9) d C (O) OR 2, O (CR 8 R 9) e R 7, (CR 8 R 9) d R 7 and NR 2 (CR 8 R 9) e R 7 where d, e, R2, R7, R8 and R9 are as defined previously.

In a preferred embodiment of formula III X is O or CH2;

And it is [C (R 2) 2] c;

R1 is selected from the group that it consists of halogen, hydroxy or C 1 to C 4 alkyl;

R2 is selected from the group that consists of hydrogen, C 1 to C 8 alkyl, (CR 8 R 9) d C (O) OR 10;

R is selected from the group consisting of halogen, C 1 to C 8 alkyl, CF 3, OCF 3, OCF_2H, (CR 8 R 9) d C (O) OR 2, (CR 8 R 9) d C (O) N (R 2) 2, HNC (O) R2, HN-C (O) OR2, (CR 8 R 9) d N (R 2) 2, SO 2 (CR 8 R 9) d N (R 2) 2, O (CR 8 R 9) e R 7 and (CR 8 R 9) d R 7, NR 2 (CR 8 R 9) e R 7 where d, e, R2, R7, R8 and R9 are as defined previously.

The present invention is further directed to pharmaceutical compositions comprising an amount pharmaceutically effective of the compounds described above and a pharmaceutically acceptable carrier or excipient. This composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or the ability to interact With a substrate.

More particularly, the compositions of the Present invention can be included in methods for treating diseases that include proliferation, fibrotic disorders or metabolic, for example, cancer, fibrosis, psoriasis, atherosclerosis, arthritis and other disorders related to one vasculogenesis and / or abnormal angiogenesis, such as retinopathy diabetic

"Pharmaceutically acceptable salt" is refers to salts that retain efficacy and properties biological of the free bases and that are obtained by reaction with inorganic acids such as hydrochloric acid, acid hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acid methanesulfonic acid, ethanesulfonic acid, acid p-toluenesulfonic acid, salicylic acid and Similar.

"Alkyl" refers to a hydrocarbon saturated linear, branched or cyclic chain aliphatic. Preferably, the alkyl group has 1 to 12 carbon atoms. More preferably, it is a lower alkyl of 1 to 7 atoms of carbon, most preferably 1 to 4 carbon atoms. Normally the alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and Similar. The alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, = O, = S, NO2, halogen, dimethylamino and SH.

"Alkenyl" refers to a group unsaturated linear, branched or cyclic chain hydrocarbon that It contains at least one carbon-carbon double bond. Preferably, the alkenyl group has 1 to 12 carbon atoms. More preferably it is a lower alkenyl of 1 to 7 atoms of carbon, most preferably 1 to 4 carbon atoms. The group alkenyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, = O, = S, NO2, halogen, dimethylamino and SH.

"Alkynyl" refers to a hydrocarbon unsaturated linear, branched or cyclic chain containing the minus a triple carbon-carbon bond. Preferably, the alkynyl group has 1 to 12 carbon atoms. More preferably it is a lower alkynyl of 1 to 7 atoms of carbon, most preferably 1 to 4 carbon atoms. The group alkynyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, = O, = S, NO2, halogen, dimethylamino and SH.

"Alkoxy" refers to a group "O-alkyl".

"Aryl" refers to an aromatic group that it has at least one ring that has an electron system po conjugates and includes carbocyclic aryl groups, aryl heterocyclic and biaryl. The aryl group may optionally be substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2, amino, thioether, cyano, alkoxy, alkyl and amino.

"Alkaryl" refers to an alkyl that is covalently bound to an aryl group. Preferably, the group alkyl is a lower alkyl.

"Carbocyclic aryl" refers to a group aryl in which the ring atoms are carbon atoms.

"Heterocyclic aryl" refers to a group aryl having 1 to 3 heteroatoms as ring atoms, and the The rest of the ring atoms are carbon atoms. The Heteroatoms include oxygen, sulfur and nitrogen. Therefore, the heterocyclic groups include furanyl, thienyl, pyridyl, pyrrolyl, N-alkyl lower-pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.

"Hydrocarbyl" refers to a radical hydrocarbon 3 having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has 1 to 20 atoms of carbon, more preferably 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.

"Substituted hydrocarbyl" refers to a hydrocarbyl radical in which one or more, but not all, atoms  of hydrogen and / or carbon are substituted with an atom of halogen, nitrogen, oxygen, sulfur or phosphorus or a radical that includes a halogen, nitrogen, oxygen, sulfur or phosphorus atom, for example, fluorine, chlorine, cyano, nitro, hydroxyl, oxa, oxo, phosphate, thiol, etc.

"Amido" refers to C (O) -NH-R, where R is alkyl, aryl, alkylaryl or hydrogen.

"Thioamido" refers to C (S) -NH-R, where R is alkyl, aryl, alkylaryl or hydrogen.

"Amino" refers to a group -N (R ') R' ', where R' and R '' are selected independently between the group consisting of alkyl, aryl and rented.

"Thioether" refers to -S-R, where R is alkyl, aryl or rented.

"Sulfonyl" refers to -S (O) 2 -R where R is aryl, C (CN) = C-aryl, CH2CN, alkylaryl, sulfonamido, NH-alkyl, NH-alkylaryl or NH-aryl.

In particular, the compounds of the present invention are selected from the compounds of the Table 1-Table 3, later.

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TABLE 1 Analogues of 1-aminomethyl-3- (1H-pyrrole-2-ylmethylene) -1,3-dihydro-indole-2-one replaced

6

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7

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TABLE 2 Analogues of 1-aminomethyl-3 - [(4-morpholin-4-yl-phenylamino) -methylene] -1,3-dihydro-indole-2-one replaced

8

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9

TABLE 3 Analogues of 1-aminomethyl-3- (3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one replaced

10

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eleven

It should be noted that in Examples 15, 16 and 19 b is 0, therefore R1 is provided as H. In the Examples  15 and 16 a is 0, therefore R is provided as H.

The present invention relates to compounds capable of regulating and / or modulating the signal transduction of tyrosine kinase and, more particularly, the tyrosine-quinine signal transduction receiving and not receiving.

The transduction of signals mediated by tyrosine-receptor kinase is initiated by a extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, stimulation transient intrinsic protein activity tyrosine kinase and phosphorylation. The sites of binding are created well for signal transduction molecules intracellular and lead to complex formation with a spectrum of cytoplasmic signaling molecules that facilitate appropriate cell response (e.g. cell division, effects metabolic and responses to the extracellular microenvironment).

Phosphorylation sites have been shown of tyrosine in growth factor receptors work as high affinity binding sites for SH2 domains (src homology) of signaling molecules. Have been identified various intracellular substrate proteins that are associated with receptor tyrosine kinases. They can be divided into Two main groups: (1) substrates that have a domain catalytic; and (2) substrates that lack this domain but serve as adapters and are associated with catalytically molecules active. The specificity of interactions between receptors and SH2 domains of its substrates is determined by the residues of amino acids that immediately surround the tyrosine residue phosphorylated Differences in binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues in particular receptors are congruent with the differences observed in their profiles of phosphorylation of substrates. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its expression and availability model of ligands, but also by arranging the trajectories of transduction of downward signals that are activated by a particular receiver. Therefore, phosphorylation provides an important regulatory stage that determines the selectivity of signaling trajectories recruited by specific receptors of the growth factor, as well as of the receptors of the factor of differentiation.

The signal transduction of tyrosine kinase results, among other responses, to cell proliferation, differentiation and metabolism. The abnormal cell proliferation can lead to a wide range of disorders and diseases, which include the development of neoplasia like carcinoma, sarcoma, leukemia, gliobastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (u other diseases related to angiogenesis and / or uncontrolled vasculogenesis, for example, degeneration macular)

Therefore, this invention is directed to compounds that regulate, modulate and / or inhibit the transduction of thyroid kinase signals by affecting the enzymatic activity of RTK and / or non-receptor tyrosine kinases and interfering with the signal transduced by these proteins More particularly, the present invention is directed to compounds that regulate, modulate and / or inhibit signal transduction pathways mediated by RTK and / or non-receptor tyrosine kinase as a therapeutic approach to cure many types of solid tumors, including, but without limitation, carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to, brain cancers, bladder cancers, ovarian cancers, cancers
gastric, pancreatic cancers, colon cancers, blood cancers, lung cancers and bone cancers.

Chemical stability

The chemical stability of Example 12 of the The invention has been studied using buffers at pH 1, pH 3 and pH 7. The  Example 12 was prepared in acetonitrile at 200 µg / ml and diluted to 20 ng / ml in buffers at pH 1, pH 3 and pH 7. Example 12 was measured so that it had a half-life (t_ {1/2}) of approximately 20 hours at pH 3 and 38 hours at pH 1. The half-life (t 1/2) of the Example 12 at pH 7.4 was less than 30 minutes.

Biological data for the compounds of the Present invention were generated by using the following essays.

Ca ++ signal stimulated by VEGF in vitro

FLIPR technology (plate reader of automated fluorometric imaging) to select VEGF inhibitors that induce increases in calcium levels intracellular in endothelial cells with dye content fluorescent. HUVEC (endothelial vein cells were seeded Human umbilicals (Clonetics) on a black-walled plate coated with 96-well fibronectin overnight 37 ° C / 5% CO2. In the cells an indicator of calcium fluorine-4 for 45 minutes at 37 ° C. The cells were washed 4 times (original cell wash, Labsystems) to separate the extracellular dye. Test compounds were reconstituted in 100% DMSO and added to the cells to provide a final concentration in DMSO of 0.1%. For the selection, the cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 µM) or at concentrations that varied in the range of 0.01 at 10.0 µM followed by stimulation with VEGF (5 ng / ml). Be they measured the fluorescence changes at 516 nm simultaneously in all 96 wells using a cooled CCD chamber. The data were generated by determining fluorescence levels maximum-minimum for samples without stimulation, stimulated and treated with drug. The IC_ {50} values for test compounds were calculated from% inhibition of responses stimulated by VEGF in the absence of inhibitor.

VEGFR2 kinase assay

The cytoplasmic domain of the human VEGF receptor  (VEGFR-2) was expressed as a fusion protein with histidine tag following a cell infection insects using a baculovirus treated by genetic engineering. He His-VEGFR-2 was purified until homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. The kinase assays are performed in 96-well microtiter plates that were coated overnight with 30 \ mug of poly-Glu-Tyr (4: 1) in solution 10 mM phosphate buffered saline (PBS), pH 7.2-7.4. Plates were incubated with 1% BSA and They were then washed four times with PBS before starting the reaction. The reactions were carried out in volumes of 120 µl reaction containing 3.6 µM ATP and buffer kinase (50 mM Hepes buffer, pH 7.4, 20 mM MgCl 2, MnCl 2 0.1 mM and Na 3 VO 4 0.2 mM). The test compounds were reconstituted in 100% DMSO and added to the reaction to provide a final concentration in DMSO of 5%. The reactions were initiated by the addition of 0.5 mg of purified protein. Following a ten minute incubation at 25 ° C, the reactions were washed four times with PBS containing 0.05% of Tween-20 One hundred l of an antibody conjugate monoclonal anti-phosphotyrosine peroxidase se diluted 1: 10,000 in PBS-Tween-20 and They were added to the wells for 30 minutes. After four washed with PBS-Tween 200, 100 µl of O-phenylenediamine dihydrochloride in buffer phosphate citrate, which contained urea-hydrogen peroxide, were added to the wells for 7 minutes in the form of a colorimetric substrate for peroxidase. The reaction was terminated by the addition of 100 µL of H 2 SO 4 2.5 N to each well and read using an ELISA microplate reader set at 492 nm. The values of IC 50 for compound inhibition were calculated directly from graphs of optical density (units arbitrary) versus compound concentration after subtraction of blank values.

Dermal extravasation induced by VEGF in guinea pig ( Thousands)

Hartley male guinea pigs were anesthetized (300-600 g) with isofluoran, were shaved and provided them with a single dose of drug or vehicle respective. The guinea pigs were dosed orally unless indicate otherwise in Table 3. Ten minutes before the end of drug treatment, guinea pigs were anesthetized conisofluorane, and blue dye was injected intravenously 0.5% Evans (EBD) in PBS (13-15 mg / kg dose of EBD) After 5 minutes injections were administered on the side intradermal triplicate of 100 ng of rhVEGF_ {165} in 100 µl of PBS and 100 µl of PBS alone. After 20 minutes each animal was sacrificed with Pentosol, and the skin that contained the Intradermal injection sites were removed for an analysis of images.

Using an analog video camera attached to one PC, an image of each skin sample was captured with transverse lighting, and the integrated optical density of each Injection site was measured using an ImagePro 4 device. To Each skin sample, the difference between the average optical density of VEGF sites and the average optical density of the sites of PBS is the measure of EBD extravasation induced by VEGF in that animal. These measured values were averaged by group of study to determine the extravasation of EBD induced by VEGF mean for each experimental state, and the means of the groups were then compared to assess the inhibition of EBV-induced EBD extravasation in groups treated with drug in relation to controls treated with vehicle.

To determine the dose required for a 50% inhibition (ID 50), the percentage data of inhibition were plotted as a function of the oral dose, using a "best fit" analysis in the Excel software from MicroSoft. The value of ID_ {50} was verified visually using the data represented graphically (line horizontal from the value of 50% of y, at the intersection with the vertical drop line of the best fit line to the x axis (dose)).

Laser-induced choroidal-induced neovascularization (CNV) in rat (CNV test)

A CNV was induced and quantified in this model as previously described (Edelman and Castro. Exp. Eye Res. 2000; 71: 523-533). On day 0, Brown male rats Norway (200-300 g) were anesthetized with 100 mg / kg of ketamine and 10 mg / kg of xylazine, and the pupils were dilated with 1% tropicamide. Using a setting blue-green of a Coherent Novus argon laser, it provided 3 laser burns (90 mW for 0.1 s; 100 um diameter) to each eye between the retinal vessels around of the optic nerve head. The rats were dosed with test compounds and their orally indicated vehicles once a day.

On day 10, the rats were sacrificed with 100% CO2, and the blood vessels were marked by vascular perfusion with 100 mg / ml of FITC-dextran (P.M. 2 x 10 6). Using a hepifluorescence microscope (20x) coupled to a digital point camera and a PC, were obtained  images of the smooth amounts of RPE-choroid-sclera of each eye and the area occupied by new hyperfluorescent vessels was measured in each laser lesion using ImagePro 4 software.

To determine the dose required for a 50% inhibition (ID 50), the graphs were plotted percentage inhibition data as a function of dose oral, using the "best fit" analysis in the software Microsoft Excel. The value of ID_ {50} was visually verified using the data represented graphically (horizontal line from the value and 50%, at the intersection with the vertical drop line from the line of best fit to the x-axis (dose).

The results of these tests are set out in Tables 4-6 below.

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TABLE 4 Ca ++ signal assay stimulated with VEGF and VEGF kinase assay data

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12

TABLE 5 Dermal extravasation induced by VEGF in guinea pig. Results (Thousands trial)

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TABLE 6 Results of the choroidal angiogenesis test of rat laser

fifteen

sid = dosage once a day

The invention is further illustrated by The following non-limiting examples.

Example 1 Preparation of Z- (1H-Pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one

A mixture of oxindole (137 mg, 1.03 mmol), pyrrol-2-carboxaldehyde (115.1 mg, 1.21 mmol) and piperidine (40 µL, 0.404 mmol) in 2.0 ml of MeOH is heated to reflux for 3 h. The mixture was cooled in a bath with ice and the solid that formed was collected by filtration to provide the title compounds (208 mg, 96%) in the form of a yellow solid

Example 2 Preparation of 1-Piperidin-1-ylmethyl-3- (1-H-pyrrole-2-ylmethylene) -1,3-dihydro-indole-2-one

A solution of Z- (lH-pyrrole-2-ylmethylene) -1,3-dihydro-indole-2-one (0.60 g, 2.85 mmol), paraformaldehyde (0.13 g, 4.28 mmol) and Piperidine (0.24 g, 2.85 mmol) in EtOH (5 mL) was heated to 60-70 ° C for 14 h. The reaction mixture is cooled to -209 ° C for 1 h and the fine yellow solid present is collected by filtration. The collected solid was dried under vacuum to provide the title compound as a yellow solid (0.68 g, 77%).

H 1 NMR (500 MHz, d 6 -DMSO) δ (wide s, 111), 7.81 (s, 1H), 7.67 (d, J = 7.3 Hz, 111 ), 7.37 (m, 111), 7.22 (m, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.06 (ddd, J = 7, 3, 7, 3, 1.2 Hz, 1H), 6.88 (m, 1H), 6.37 (m, 1H), 4.58 (s, 2H), 2.54 (wide s, 4H), 1.46 (m, 4H), 1.33 (wide m, 2H).

Example 3 Preparation of 1-morpholin-4-ylmethyl-3- (1 H -pyrrol-2-ylmethylene) -1,3-dihydroindole-2-one

A mix of Z- (1H-Pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one (120 mg, 0.57 mmol), paraformaldehyde (32 mg, 1.1 mmol) and morpholine (62.2 µL, 0.71 mmol) in 8.0 ml of 20% dioxane in EtOH is heated to reflux for 19.5 h. The reaction mixture is concentrated and paraformaldehyde (10.0 mg, 0.33 mmol) was added, morpholine (15 µL, 0.17 mmol) and EtOH (7 ml). The mixture of reaction was refluxed for 24 h. The reaction mixture is cooled to room temperature and concentrated. The residue dissolved in 15 ml of CHCl3 and treated with activated carbon. The The resulting suspension was filtered and the filtrate was concentrated. He residue was crystallized from ethyl acetate / hexane to provide the title compound 88.0 mg, 50%) as a solid light yellow.

H 1 NMR (500 MHz, d 6 -DMSO) δ 13.03 (wide s, 111), 7.80 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.35 (wide s, 1H), 7.19 (m, 211), 7.05 (m, 111), 6.86 (m, 1H), 6.35 (m, 111) , 4.56 (s, 211), 3.52 (m, 4H), 2.53 (m, 411).

Example 4 Preparation of 1- (4-Methyl-piperazin-1-ylmethyl) -3- (1 H -pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one

A mix of Z- (1H-Pyrrole-2-ylmethylene) -1,3-dihydro-indole-2-one (120 mg, 0.57 mmol), paraformaldehyde (17 mg, 0.57 mmol), and 1-methylpiperazine (63 µL, 0.57 mmol) in 4.0 ml of EtOH was heated at reflux for 6.5 h. After leaving in stand at room temperature for 23 h, the mixture was concentrated to 3 ml of solvent and 1 ml of hexane was added. The solution resulting was cooled to 0 ° C and the yellow solid that formed was collected by filtration. The collected solid was divided into parts between 30 ml of diluted HCl and 20 ml of ethyl acetate. The layer organic was separated and the aqueous layer was washed with ethyl acetate (15 ml) The aqueous layer was made basic at pH 8 with saturated NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer is washed with H2O, brine and dried with Na2SO4. The layer organic was concentrated and the residue was crystallized from acetate ethyl / hexane to provide the title compound (38 mg, 21%) in the form of a light yellow solid.

H 1 NMR (500 MHz, CDCl 3) δ 13.35 (s wide, 1H), 7.46 (d, J = 7.6 Hz, 111), 7.42 (s, 111), 7.19 (dd, J = 7, 8, 7.6 Hz, 111), 7.14 (wide s, 1H), 7.06 (dd, J = 7.6, 7.6 Hz, 1H), 7.02 (d, J = 7.8 Hz, 111), 6.75 (m, 1H), 6.36 (m, 1H), 4.57 (s, 211), 2.69 (wide s, 4H), 2.41 (wide s, 411), 2.24 (s, 311).

Example 5 Preparation of 1- (3-Methoxy-propylamino) -methyl-3- (1H-pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one

A mix of Z- (1H-Pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one (120.0 mg, 0.571 mmol), paraformaldehyde (17.1 mg, 0.571 mmol), and 3-methoxypropylamine (58.2 µL, 0.571 mmol) in 4.0 ml of EtOH was heated at reflux for 6.5 h. The mixture of reaction was cooled to room temperature and allowed to stand for 22 h. The reaction mixture was filtered and the cake filtration was rinsed with 30% ethyl acetate in hexane. He The filtrate was concentrated in vacuo and 4 ml of EtOH was added. The reaction was refluxed for an additional 19.5 h. The mixture of reaction was cooled to room temperature and partitioned between 30 ml of diluted HCl and 20 ml of ethyl acetate. The layer Organic was separated and the aqueous layer was washed with 15 ml of acetate  ethyl. The aqueous layer was made basic at pH 8 with NaHCO 3 saturated and extracted with ethyl acetate. The acetate layer of ethyl was washed with H2O, brine and dried over Anhydrous Na 2 SO 4. The ethyl acetate layer was filtered and He then concentrated. The solid obtained (42.5 mg) was dissolved in CHCl3 and purified by chromatography (silica gel, 1: 1 / hexane: acetone) to provide the title compound (1.5 mg, 1%).

H 1 NMR (500 MHz, CDCl 3) δ 13.40 (s wide, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.44 (s, 111), 7.21 (m, 111), 7.16 (m, 111), 7.07 (m, 111), 6.95 (d, J = 7.7 Hz, 111), 6.77 (m, 111), 6.38 (m, 111), 4.81 (s, 2H), 3.37 (t, J = 6.3 Hz, 2H), 3.24 (s, 311), 2.69 (t, J 6.7 Hz, 211), 1.72 (quintet, J = 6.5 Hz, 2H)

Example 6 Preparation of 1-Butylaminomethyl-3- (1H-pyrrole-2-ylmethylene) -1,3-dihydroindole-2-one

A mix of Z- (1H-Pyrrol-2-ylmethylene) -1,3-dihydro-indole-2-one (120.0 mg, 0.571 mmol), paraformaldehyde (17.1 mg, 0.571 mmol), and Butylamine (56.4 µL, 0.571 mmol) in 5.5 ml of EtOH was heated to reflux for 2.5 h. Then the reaction mixture was treated with 2 ml of hexane and then cooled to 0 ° C. The mixture of reaction was then filtered to separate Z- (1H-pyrrole-2-ylmethylene) -1,3-dihydro-indole-2-one. The filtrate was partitioned between dilute HCl and acetate. ethyl. The organic layer was separated and the aqueous layer was washed with 15 ml of ethyl acetate The aqueous phase was made basic at pH 8 with Saturated NaHCO3 and extracted with ethyl acetate. The layer of ethyl acetate was washed with H2O, brine and dried over Anhydrous Na 2 SO 4. The solvent was removed in vacuo to provide 58 mg of yellow oil. The oil was purified by chromatography (silica gel, 1: 1 / hexane: ethyl acetate) to provide the title compound (51.6 mg, 31%) in the form of a yellow solid

H 1 NMR (500 MHz, CDCl 3) δ 13.41 (s wide, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.23 (m, 1H), 7.17 (wide s, 1H), 7.09 (m, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.78 (m, 1H), 6.39 (m, 1H), 4.83 (s, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.43 (m, 2H), 1.29 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).

Example 7 Preparation of 5-Chloro-3- (1H-pyrrole-2-yl-methylene) -1,3-dihydro-indole-2-one

A mixture of 5-Chloroxoindole (6.98 g, 41.6 mmol), 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (5.12 g, 41.6 mmol) and piperidine (410 µL, 4.16 mmol) in 200 ml of EtOH was heated at reflux for 8 h. The reaction mixture is cooled to room temperature and filtered to provide the title compound (4.50 g, 40%) in the form of a solid Orange Red.

Example 8 Preparation of 5-Chloro-3- (3,5-dimethyl-1H-pyrrole-2-ylmethylene) -1-piperidin-lylmethyl-1,3-dihydro-indole-2-one

A suspension of 5-Chloro-3- (1H-pyrrole-2-yl-methylene) -1,3-dihydro-indole-2-one (260 mg, 0.96 mmol), piperidine (95 µL, 0.96 mmol) and paraformaldehyde (43 mg, 1.44 mmol) in 5 ml of dioxane and 5 ml of EtOH was heated at 80 ° C for 15 h. The resulting solution is cooled to room temperature followed by cooling to -20 ° C for 1 h. The solid that formed was collected by filtration and rinsed with EtOH (previously cooled to -20 ° C). The solid collected dried under vacuum to provide the title compound (180 mg, 51%) in the form of a yellow-orange solid.

Example 9 Preparation of 5-Chloro-3- (3,5-dimethyl-1H-pyrrole-2-ylmethylene) -1-morpholin-4-ylmethyl-1,3-dihydro-indole-2-one

A suspension of 5-Chloro-3- (1H-pyrrole-2-yl-methylene) -1,3-dihydro-indole-2-one (120 mg, 0.44 mmol), morpholine (39 µL, 0.44 mmol) and paraformaldehyde (20 mg, 0.66 mmol) in 8 ml of dioxane and 2 ml of EtOH was heated at 80 ° C for 15 h. The reaction mixture is cooled to room temperature and treated with morpholine (25 µl, 0.28 mmol) and paraformaldehyde (16 mg, 0.50 mmol). The mixture of reaction was heated at 80 ° C for 4 h. The reaction mixture is cooled to room temperature and partially concentrated under a nitrogen stream The reaction mixture was cooled to -20 ° C. He solid that formed was collected by filtration and rinsed with EtOH (previously cooled to -20 ° C). The collected solid was dried under vacuum to provide the title compound (85 mg, 52%) in Shape of an orange solid.

Example 10 Preparation of 3-Hydroxymethylene-1,3-dihydro-indole-2-one

To an oxindole suspension (1.33 g, 10.0 mmol) and ethyl formate (2.42 ml, 30.0 mmol) 4.85 ml of 21% NaOEt by weight in EtOH. The thick solution was stirred for 30 minutes at room temperature and then heated to reflux for 30 minutes. The solution was acidified to pH = 3 with 10% aqueous HCl and 5 ml of H2O was added. The solid that is formed was filtered and rinsed with H2O to provide the title compound (1.34 g, 83%) in the form of a yellow solid pale.

Example 11 Preparation of 3 - [(4-morpholinophenylamino) -methylene] -1,3-dihydroindole-2-one

A solution of 4-morpholinoaniline (8.3 g, 51.5 mmol) in 100 ml of tetrahydrofuran was treated with 3-hydroxymethylene-1,3-dihydro-indole-2-one (5.5 g, 30.9 mmol) in one part. The reaction mixture was heated to reflux for 3 h. The reaction mixture was concentrated. The residue  it was treated with 125 ml of ethyl acetate and the resulting suspension It was heated at 40 ° C for 2 h. The suspension was cooled to room temperature and the solid was collected by filtration with suction and washed with ethyl acetate. The solid obtained was dried under vacuum to provide the title compound (10.1 g, 92%) in the form of a yellow solid.

Example 12 Preparation of 3 - [(4-Morpholin-4-yl-phenylamino) -methylene-1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one

A solution of 3 - [(4-morpholinophenylamino) -methylene] -1,3-dihydroindole-2-once (17.3 g, 53.8 mmol) and paraformaldehyde (2.43 g, 80.9 mmol) in 125 ml of EtOH was treated with piperidine (5.87 ml, 59.3 mmol). The mixture of reaction was then heated to reflux temperature for 5 hours, during which time a yellow precipitate formed. The reaction mixture was allowed to cool to room temperature and the solid was collected by filtration and washed with EtOH and dried under vacuum to provide the title compound (21.5 g, 95%) in form of a yellow solid.

Example 13 Preparation of 1-morpholin-4-ylmethyl-3 - [(4-morpholin-4-ylphenylamino) -methylene] -1,3-dihydro-indole-2-one

A solution of 3 - [(4-morpholinophenylamino) -methylene] -1,3-dihydroindole-2-one (0.71 g, 2.21 mmol) and paraformaldehyde (0.10 g, 3.33 mmol) in 8 ml of EtOH was treated with morpholine (213 µL, 2.44 mmol). The mixture of reaction was then heated to reflux temperature for one night, during which time a yellow precipitate formed. The reaction mixture was allowed to cool to room temperature and the solid was collected by filtration and washed with EtOH and dried under vacuum to provide the title compound (0.769 g, 83%) in form of a yellow solid.

Example 14 Preparation of 3- (3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one

To a suspension of sodium hydride (6.0 g, 150 mmol, 60% in mineral oil) in 300 ml of DMF oxindole was added (10.0 g, 75.1 mmol) in 50 ml of DMF for 8 minutes. After stir for 15 minutes at room temperature, a phthalate solution (13.1 g, 97.6 mmol) in 50 ml of DMF for 1 minute. The mixture was stirred for 1.25 h and then poured in 1,100 ml of H2O. The addition of a 4% aqueous solution of HCl provided a yellow solid that was filtered and rinsed with H2O to provide the title compound (8.75 g, 47%)

H 1 NMR (500 MHz, d 6 -DMSO) δ 10.41 (s, 1H), 9.65 (d, J = 8.1 Hz, 111), 7.83 (d , J = 7.6 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 11I), 7.10 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 6.95 (ddd, J = 7, 6, 7, 6, 1.0 Hz, 111), 6.81 (d, J = 7.6 Hz, 1H), 5.81 (s, 2H ).

Example 15 Preparation of 3- (3H-isobenzofuran-1-ylidene) -1-piperidin-1-ylmethyl-1,3-dihydroindole-2-one

A mix of 3- (3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one (4.32 g, 17.3 mmol), paraformaldehyde (0.99 g, 32.9 mmol) and piperidine (2.14 ml, 21.7 mmol) in 192 ml of EtOH and 48 ml of Dioxane was heated at reflux for 18.5 h. The solution is concentrated in vacuo to a volume of 100 ml and then brought at reflux for 1 h to dissolve the precipitate. The mixture is allowed to cool to room temperature and the precipitate was filtered to provide the title compound (3.728 g) in the form of a light yellow solid. An additional 0.52 g of the title compound by crystallization of the filtrate in acetate ethyl. The two batches were combined to provide 4,248 g (71%) of the title compound as a light yellow solid.

H 1 NMR (500 MHz, d 6 -DMSO) δ 9.67 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 111 ), 7.68 (m, 2H), 7.58 (m, 111), 7.18 (dd, J 7.8, 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.6, 7.6 Hz , 1H), 5.83 (s, 211), 4.50 (s, 211), 2.52 (s wide, 411), 1.45 (m, 4H), 1.32 (wide s, 211).

Example 16 Preparation of 3- (3H-isobenzofuran-1-ylidene) -1-morpholin-4-ylmethyl-1,3-dihydro-indole-2-one

A mix of 3- (3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one (4.32 g, 17.3 mmol), paraformaldehyde (0.99 g, 32.9 mmol) and Morpholine (1.89 ml, 21.7 mmol) in 192 ml of EtOH and 48 ml of dioxane It was heated at reflux for 18.5 h. The solution was concentrated to vacuum to a volume of 100 ml and then refluxed for 1 h to dissolve the precipitate. The mixture was allowed to cool. at room temperature and the solid that formed was collected by filtration to provide 4.19 g of a light yellow solid. Be obtained an additional 0.72 g of yellow solid by crystallization of the filtrate in ethyl acetate. The material combined was crystallized from ethyl acetate to provide the title compound (2.49 g, 41%) in the form of yellow needles fine

H 1 NMR (500 MHz, d 6 -DMSO) δ 9.67 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.6Hz, 1H) , 7.68 (m, 2H), 7.58 (m, 1H), 7.19 (m, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.05 (m, 1H), 5.84 (s, 2H), 4.53 (s, 2H), 3.53 (m, 4H), 2.54 (wide s, 4H).

Example 17 Preparation of 5-dimethylaminophthalide

Sodium cyanoborohydride (8.42 g, 134 was added mmol) to a stirred suspension of 5-aminophthalide (5.0 g, 33.5 mmol) and 37% solution of CH 2 O / H 2 O (24.9 ml, 335 mmol) in 120 ml of acetonitrile. The mixture was stirred at room temperature for 1 hour, cooled to 0 ° C and added 120 ml of 10% aqueous solution of acetic acid. The mixture is it was then stirred at room temperature for 1 hour, and it was evaporated under low pressure until no acetonitrile remained. Mix The resulting was extracted with ethyl acetate (2 x 125 ml). The Combined organic extracts were washed with saturated solution of NaHCO 3 (125 ml) and brine (125 ml), dried over Na 2 SO 4 and evaporated to dryness to provide a light brown solid, which was triturated with hot MeOH (10 ml) to provide the title compound (3.9 g, 66%) as a white solid off.

Example 18 Preparation of 3- (5-Dimethylamino-3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one

A solution of oxindole (938 mg, 7.05 mmol) in 20 ml of DME was cooled to 0 ° C and treated with 6.2 ml of a solution 2.5 M n-BuLi / hexane (15.5 mmol) dropwise under nitrogen. The mixture was stirred at 0 ° C for 10 minutes. Was added 5-dimethylaminophthalide (1.0 g, 5.64 mmol) in one part. The mixture was allowed to warm to room temperature under nitrogen and stirring was continued for 3 hours. Mix cloudy was then added slowly to a 0.5 aqueous solution M HCl (0 ° C) with vigorous stirring. The resulting mixture is neutralized with 1 M NaOH solution until pH = 9. The precipitate Yellow that formed was collected by filtration, washed with water and It dried under vacuum. The solid obtained was triturated with hot MeOH (20 ml), was collected by filtration and dried to provide the title compound (990 mg, 60%) in the form of a yellow powder Sure.

Example 19 Preparation of 3- (5-Dimethylamino-3H-isobenzofuran-1-ylidene) -1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one

A mix of 3- (5-Dimethylamino-3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one (550 mg, 1.88 mmol), para-formaldehyde (141 mg, 4.7 mmol) and piperidine (240 mg, 2.82 mmol) in 20 ml of EtOH was stirred at reflux overnight and cooled to room temperature. He solid that formed after cooling was collected by filtration, washed with EtOH (5 ml) and dried under vacuum to provide the compound of the title (655 mg, 89%) in the form of yellow crystals clear.

Example 20 Preparation of 5-Chloro-3- (5-dimethylamino-3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one

A solution of 5-Chloroxyindole (1.18 mg, 7.05 mmol) in 20 ml of DME was cooled to 0 ° C and treated with 6.2 ml of 2.5 M solution of n-BuLi / hexane (15.5 mmol) dropwise under nitrogen. The mixture was stirred at 0 ° C for 10 minutes. 5-dimethylaminophthalide (1.0 g, 5.64 mmol) in one part. The mixture was allowed to warm to temperature. ambient under nitrogen and stirring was continued for 3 hours. The cloudy mixture was then slowly added to a solution 0.5 M aqueous HCl (0 ° C) with vigorous stirring. Mix The resulting was neutralized with 1 M NaOH solution until pH = 9. The Yellow precipitate that formed was collected by filtration, washed with water and dried under vacuum. The solid obtained was triturated with Hot MeOH (20 ml) followed by ethyl acetate (10 ml), is collected by filtration and dried to provide the compound of title (900 mg, 49%) in the form of a light yellow powder.

Example 21 Preparation of 5-Chloro-3- (5-dimethylamino-3H-isobenzofuran-1-ylidene) -1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one

A mix of 5-Chloro-3- (5-dimethylamino-3H-isobenzofuran-1-ylidene) -1,3-dihydro-indole-2-one (400 mg, 1.22 mmol), paraformaldehyde (91 mg, 3.05 mmol) and Piperidine (156 mg, 1.83 mmol) in 20 ml of EtOH was stirred at reflux overnight and cooled to room temperature. The solid that formed on cooling was collected by filtration, washed with EtOH (5 ml) and dried under vacuum to provide the title compound (500 mg, 97%) in the form of light yellow crystals.

The present invention is not limited in its scope for the illustrated embodiments, which are intended to be illustrations of unique aspects of the invention only. From In fact, various modifications of the invention in addition to the described herein will be apparent. for those skilled in the art from the description that precedes. These modifications are intended to fall within the scope of the appended claims.

All references cited herein Descriptive report is incorporated as a reference to it in your whole.

Claims (25)

1. A compound, represented by the formula general II or III: 16

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in the that: X is O or C (R2) 2; And it is [C (R 2) 2] c; A is NR2; R1 is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, radicals  hydrocarbyl and substituted hydrocarbyl, wherein said hydrocarbyl substituted may be substituted with selected heteroatoms between the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R 2 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, (CR 8 R 9) d C (O) OR 10 }, COCH 3, CH 2 CH 2
OH, CH 2 CH 2 CH 2 OH and phenyl; R is selected from the group consisting of halogen, hydrocarbyl radicals and substituted hydrocarbyl, in which said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R 3 and R 4 are selected independently among the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl radicals, wherein said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogens, nitrogen, phosphorus, sulfur and oxygen, or R 3 and R 4 together with the nitrogen atom can form a cyclic ring, ring that may be substituted with said heteroatoms, R 5 and R 6 are selected independently among the group consisting of hydrogen, alkyl and aryl radicals; with the proviso that said radicals alkyl or phenyl may be substituted with one to three radicals halo, hydroxyl, lower alkyloxy or (alkyl lower) -amino; R 10 is hydrogen, C 1 to C 8 alkyl or arylalkyl; a is 0 or an integer from 1 to 3; b is 0 or an integer from 1 to 3; c is an integer from 1 to 2; d is 0 or an integer from 1 to 5; the wavy line represents an E or Z link and Ar is selected from the group consisting of aryl, aryl substituted, heteroaryl and substituted heteroaryl, wherein said aryl or substituted heteroaryl may be substituted with heteroatoms selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen. 2. The compound of claim 1, in the that R is selected from the group consisting of halogen, C 1 to C 8 alkyl, CF 3, OCF 3, OCF 2 H, CH 2 CN, CN, SR 2, (CR 8 R 9) d C (O) OR 2, (CR 8 R 9) d C (O) N (R 2) 2, (CR 8 R 9) d OR 2, HNC (O) R 2, HN-C (O) OR2, (CR 8 R 9) 6 N (R 2) 2, SO 2 (CR 8 R 9) d N (R 2) 2, OP (O) (OR 2) 2, OC (O) OR 2, OCH 2 O, HN-CH = CH, -N (COR 2) CH 2 CH 2, HC = N-NH, N = CH-S, O (CR 8 R 9) c R 7, (CR 8 R 9) d R 7, -NR 2 (CR 8 R 9) e R 7, in which R 7 is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, methyl isonipecotate, N- (2-methoxyethyl) -N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N- (2-methoxyethyl) ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro- (1H) -1,4-diazepinyl-5 (4H) -one, N-methylhomopiperazinyl, (3-dimethylamino) pyrrolidinyl, N- (2-methoxyethyl) -N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3- (diethylamino) pyrrolidinyl, 1,4-dioxa-8-azaspiro [4,5] decaninyl, 1- (2-methoxyethyl) -piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3- (methylsulfonyl) pyrrolidinyl, 3-picolylmethylaminyl, 2- (2-methylaminoethyl) pyridinyl, 1- (2-pyrimidyl) -piperazinyl, 1- (2-pyrazinyl) -piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2- (N-methyl-2-aminoethyl) -1,3-dioxolane, 3- (N-acetyl-N-methylamino) pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1- (3-aminopropyl) imidazole, histamyl, N, N-diisopropylethylene diamine, 1-benzyl-3-aminopyrrolidyl 2- (aminomethyl) -5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R) -3-amino-1-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran, ethanolamino and its alkyl substituted derivatives; with the proviso that said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or (alkyl) radicals lower) -amino; wherein R 8 and R 9 can be select from the group consisting of H, halogen, hydroxy and C 1 -C 4 alkyl or CR 8 R 9 can represent a carbocyclic ring of 3 to 6 carbon atoms; Y e is an integer from 2 to 5. 3. The compound of claim 2, in the that R 5 and R 6 are hydrogen. 4. The compound of claim 3, in the that R 3 and R 4, together with the nitrogen atom, form a 5 or 6 member ring. 5. The compound of claim 4, in the that R 3 and R 4, together with the nitrogen atom, form a ring selected from the group consisting of morpholinyl or piperidinyl 6. The compound of claim 3, in the that R 3 is H and R 4 is selected from the group that It consists of alkyl or alkyloxyalkyl. 7. The compound of claim 3, in the which either R 8 and R 9 are H or d is 0, and R is selected among the group consisting of halogen, C 1 to C 8 alkyl, CF 3, OCF 3, OCF 2 H, CN, SR 2, (CH 2) d C (O) OR 2, C (O) N (R 2) 2, (CH 2) d OR 2, HNC (O) R 2, HN-C (O) OR2, (CH 2) d N (R 2) 2, SO 2 N (R 2) 2, OP (O) (OR 2) 2, OC (O) OR 2, OCH 2 O, HN-CH = CH, -N (COR 2) CH 2 CH 2, HC = N-NH, N = CH-S, O (CH 2) c -R 7 and (CH 2) d -R 7, wherein R 7 is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl and its substituted derivatives with lower alkyl; with the proviso that R 7 and / or said alkyl or phenyl radicals may be substituted with one to three halo, hydroxyl, lower alkyloxy or (alkyl) radicals lower) -amino. 8. The compound of claim 3, in the that Ar is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrrolyl, furyl, thienyl and its derivatives replaced. 9. The compound of claim 8, wherein Ar is phenyl or pyrrolyl. 10. The compound of claim 3, in the that said compound is represented by formula II. 11. The compound of claim 10, in the that A is -NH- and Ar is phenyl. 12. The compound of claim 11, in the that a is 1 and R is morpholinyl. 13. The compound of claim 3, in the that said compound is represented by formula III. 14. The compound of claim 13, in the that X is O and Y is CH_ {2}. 15. The compound of claim 14, in the that a and b are 0. 16. The compound of claim 14, in the that a is 1 and R is dimethylamino. 17. The compound of claim 3, selected from the group consisting of 3 - [(4-morpholin-4-yl-phenylamino) -methylene] -1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one Y 1-morpholin-4-ylmethyl-3 - [(4-morpholin-4-yl-phenylamino) -methylene] -1,3-dihydro-indole-2-one. 18. The compound of claim 3, selected from the group consisting of 3- (5-dimethylamino-3H-isobenzofuran-1-ylidene) -1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one Y 5-Chloro-3- (5-dimethylamino-3H-isobenzofuran-1-ylidene) -1-piperidin-1-ylmethyl-1,3-dihydro-indole-2-one.

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19. A compound, represented by the formula general II: 17 in the that: A is absent; R1 is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, radicals  hydrocarbyl and substituted hydrocarbyl, wherein said hydrocarbyl substituted may be substituted with selected heteroatoms between the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R 2 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, (CR 8 R 9) d C (O) OR 10 }, COCH 3, CH 2 CH 2
OH, CH 2 CH 2 CH 2 OH and phenyl; R is selected from the group consisting of halogen, hydrocarbyl radicals and substituted hydrocarbyl, in which said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen, R 3 and R 4 are selected independently among the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl radicals, wherein said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen, or R 3 and R 4 together with the nitrogen atom can form a cyclic ring, ring that may be substituted with said heteroatoms, R 5 and R 6 are selected independently among the group consisting of hydrogen, alkyl and aryl radicals; with the proviso that said radicals alkyl or phenyl may be substituted with one to three radicals halo, hydroxyl, lower alkyloxy or (alkyl lower) -amino; R 10 is hydrogen, C 1 to C 8 alkyl or arylalkyl; a is 0 or an integer from 1 to 3; b is 0 or an integer from 1 to 3; d is 0 or an integer from 1 to 5; the wavy line represents an E or Z link and Ar is aryl or substituted aryl, wherein said substituted aryl it may be substituted with heteroatoms selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen. 20. Use of a compound according to claim 1 to prepare a medicine for the treatment of diseases related to deregulated signal transduction of tyrosine kinase 21. The use of claim 20, wherein said disease is selected from the group consisting of cancer, blood vessel proliferation disorders, disorders fibrotic, mesangial cell proliferation disorders and Metabolic diseases. 22. The use of claim 21, wherein the blood vessel proliferation disorder is selected from the group consisting of diabetic retinopathy, macular degeneration related to age, retinopathy of prematurity, arthritis and restenosis 23. The use of claim 21, wherein the fibrotic disorder is selected from the group consisting of liver cirrhosis, atherosclerosis and surgical adhesions. 24. The use of claim 21, wherein the mesangial cell proliferation disorder is selected between the group consisting of glomerulonephritis, nephropathy diabetic, malignant nephrosclerosis, microangiopathy syndromes thrombotic, transplant rejection and glomerulopathies. 25. The use of claim 21, wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.