SK15882003A3 - Pyrrolopyrimidines as protein kinase inhibitors - Google Patents

Abstract

This invention is directed to compounds of the formula (I) to N-oxides, prodrugs, acid bioisosteres, pharmaceutically acceptable salts or solvates of such compounds, or N-oxides, prodrugs, or acid bioisosteres of such salts or solvates, to compositions comprising such compounds, and to methods of treatment comprising administering, to a patient in need thereof, such compounds and compositions.

Description

Technical field

The present invention is directed to the salified pyrrolopyrimidines, to a process for their preparation, to pharmaceutical compositions containing the compounds, and to their pharmaceutical use in the treatment of diseases which can be influenced by protein kinase inhibition.

BACKGROUND OF THE INVENTION

Protein kinases are involved in the signaling pathway that controls cell activation, growth and differentiation in response to extracellular mediators and environmental changes. Generally, these kinases fall into several groups: kinases that preferentially phosphorylate serine and / or threonine residues and kinases that preferentially phosphorylate tyrosine residues [S.K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576-596]. Serine / threonine kinases include, for example, protein kinase C isoforms [A.C. Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases (cyclin-dependent kinases) such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197], Tyrosine kinases include membrane-crossing (membrane) growth factor receptors, such as the epicermal growth factor receptor [S. Iwashita and M. Kobayashi, Cellular Signalling, 1992, 4, pages 123-132] and cytosolic non-receptor kinases (lacking receptor function) such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan et al., Ann. Rev. Immunol., 1994, 12, pages 555-592].

Inadequately high protein kinase activity is implicated in many diseases resulting from abnormal cellular function. This may occur either directly or indirectly, for example, by disrupting the proper kinase control mechanisms associated, for example, with mutation, overexpression or inappropriate activation of the enzyme, or over or under-production of cytokines or growth factors also involved in upstream or downstream transduction signals. kinase. In all of these examples, it can be expected that selective inhibition of the action of cy kinase cy may have a beneficial effect.

Syk is a 72 kDa cytoplasmic protein tyrosine kinase that is expressed in a number of hematopoietic cells and is an essential element in several (signaling) cascades that associate antigen receptors with cellular responses. Thus, Syk has a critical role in signaling the high affinity IgS receptor, FcεR1, in mast cells, and in the signaling of an anisogenic receptor in T and B cells. The signal transduction pathways present in mast cells, T and B lymphocytes, have common features. The ligand receptor binding domain does not have its own (internal) tyrosine kinase activity. However, they interact with transducing pcduns which contain tyrosine activation motifs based on immunoreceptor tyrosine based activation mctifs -ΙΤΆΝ [M. Reth, Nature, 1989, 338, pages 38 3-36 4 i. They are also present in both the β and γ subunits of the FcsR1, in the ξ-subunit of the T cell receptor (TCR) and in the IgG and α IgG β subunits of the B cell receptor (BCR; [NS van Oers and A. Weiss, Seminars in Immunology, 1995, 7, pages 227-236} · In antigen binding and multimerization, ITAR residues are phosphorylated by Src family prozeinzyrosine kinases, Sy <belonging to a unique class of tyrosine kinases having two tandem domains with Src homology 2 (3H2) and a C terminal catalytic comene. binds with high affinity to ITAM, and the SH2-sorbed-mediated association of Syk with activated receptor down-regulates Syk kinase activity and localizes Syk to the plasma membrane.

Syk deficient mice inhibit mast cell degranulation, suggesting that this is an important target for the development of mast cell stabilizing agents [P.S. Costello, Oncogene, 1996, 13, pp. 2595-2605j. Similar studies have demonstrated the critical role of Syk in BCR and TCR signaling. [A.M. Cheng, Nature, 1995, 378, pp. 303-306, 1995, and D.H. Chu et al., Immunological Reviews, 1998, 165, pages 167-180], Syk also appears to be involved in eosinophil survival in response to IL-5 and GM-CSF [S. Ycusefi et al., J. Exp. Med., 1996, 183, pages 1407-1414]. Despite the key role of Syk in signaling mast cells, BCR and T lymphocytes, little is known about the mechanism by which Syk transmits the signal downstream to effectors. Two adapter proteins, ELNKs (B-lymphocyte linker, SLP-65) and SLP-76, have been shown to be substrates of Syk in B cells and mast cells, respectively, and are thought to link Syk downstream of the signaling pathway with efektormi [M. Ishiai et al., Imrcuniuy, 1999, 10, pages 117-125 and L.R. Hendricks-Taylor et al., J. Biol. Chem., 1997, 272, pages 1363-1367], In addition, Syk appears to play an important role in the CD40 signaling pathway, which has an important role in B cell proliferation [M. Faris et al., J. Exp. Med., 1994, 179, pp. 1923-1931],

Syk is further involved in the activation of platelets stimulated by a low affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F. Yanaga et al., Biochem. J., 1995, 311, (Pt.2) pages 471-478].

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways. FAK occurs together with integrins at focal contact sites and FAK activation and tyrosine phosphorylation in many cell types has been shown to be dependent on the binding of integrins to their extracellular ligands. The results from several studies support the hypothesis that FAK inhibitors might be useful in the treatment of cancer. For example, FAK-deficient cells migrate poorly in response to chemotactic signals, and overexpression of the FAK C-terminal domain blocks cell proliferation as well as chemotactic migration (Sieg et al., J. Cell Science, 1999, 112, 2677-2691, Richardson A And Parsons T., Cell, 1997, 97, 221-231), in addition, tumor cells treated with FAK antisense oligonucleocides lost their attachment (adhesion) and overcome apopoosis Xu et al., Cell Growth Differ. 1996, 4, 413-418). FAK has been reported to be overexpressed in cancers of the prostate, breast, thyroid, colon and lung. FAK expression levels correlate directly with tumors showing the most aggressive phenocype.

Angiogenesis or the formation of new blood vessels by rapid growth from a previous vascular supply is of central importance for embryonic development and organogenesis. Abnormally enhanced rheovascularization is observed in rheumatoid arthritis, diabetic retinopathy and during tumor development (Folkman, Hat. Med., 1995, 1, 27-31). Angiogenesis is a complex multistep process that involves activation, migration, proliferation, and survival of erothelial cells. Extensive studies in the field of tumor a.ngicgenesis over the past two decades have identified a large number of therapeutic targets, including kinases, proteases and integrins, which have resulted in the discovery of many new angiogenic agents, including KDR inhibitors, some of which are currently in clinical assays (Jekunen et al., Cancer Treatment Rev. 1997, 23, 263-286). The angiogenesis inhibitors can be used in the medicament as first-line medicaments, as an adjuvant and even to prevent the emergence or regrowth of malignancies.

Several proteins involved in nucleosome segregation and mitotic spindle assembly have been identified in yeast and drosophila. Disruption of these proteins results in poor chromosome segregation and formation of a monopolar or broken spindle. Among these kinases, Ipli and aurorakinases from S. cerevisiae and Drosophila, respectively, are necessary for centrosome seoarchy and chromosome segregation. One human homologue of yeast Ipli has recently been cloned and charaxterized by various laboratories. This kinase, called Aurora2, STK15 or 3TAK, carries a serine / threonine kinase. Bischoff et al. has shown that Aurora2 is oncogenic and is amplified in human colorectal carcinoma cells (EMBO J, 1998, 17, 3052-3065). It has also been shown in cancers involving epithelial tumors, such as breast cancer.

SUMMARY OF THE INVENTION

The present invention relates to substituted pyrrolopyrimidines of the formula I which are capable of inhibiting one or more protein kinases, in particular FAK, KDR, Syk or Aurora2 kinases, in particular Syk kinase,

where

R ¹ is hydrogen, -C (= O) -ΝΥ'ύ ² , -C (O) -OR ⁵ , -SO2-NY * Y ² , -SO2-R ⁷ , -C (= O) R ⁷ , or R can be alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycioalkylalkyl, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO (or a five, six or seven-membered cyclic acetal derivative thereof), -C (= 0) ^ ¹ -NY ² group, -C (= O) -OR ^5, -NY group G ^2, -N (R ⁶⁾ -C (= 0) -R ⁷ group,

N, R ^€ C (= 0) -NY ^J Y ^{and the} group -K (R) -SCy -R ', -OR', -C (O) -R, OH with kuρ

-N (R ⁶ ) -SO ₂ -NY ³ Y ' ^: a, alkoxy and carboxyl;

R ² is one or more selected from the group consisting of hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, kyancskupina, halo, hydroxy, heteroaryl, heterocycloalkyl, nitroskupma group, R y -C (= O) -NY'Y ² , -C (= O) -OR ^2> , -NY ^X Y ^Z , -N (R 0) -C (= O) -R ', -N (R ^e ) -C (= C) -NY ³ Y ", -N (R 0) -C (= O) -OR ', -N (R ⁰ ) -SO 2 -R', - N (R &apos;) - SO2-NY ^J Y &apos;, -5-2-ΝΥ ³ Υ ^Ζ and -ZR ³ ;

R ³ is hydrogen, oxygen, halogen, hydroxyl, nitro, R ', NY * Y ^Z , -ZR', -C; = O) -OR ', -C (= Oj-R ³ , -C (= 0) -NY ¹ ^, N (R ^a) -C (= 0) ^-R3, -K (R ⁸⁾ -C (= 0) -NY ³ Y ^2, siupma - N (R ⁸⁾ -C (= 0) -OR ^5, a group -SO 2 NY ^J Y 'aiebo -N (R ⁸ i-SCY-R ^7, R ^J aiebo is an aryl, heteroaryl, alkenyl an alkynyl group, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cyano, nalogen, hydroxyl, heteroaryl, heterocycloalkyl, nitro, -C (= O) -NY ³ Y ^Z , -3; = O) -OR ⁵ , -NY ³ Y ^Z , -N (R ^c ) -C (= O 1 -R ', -N (R 0) -C (= O) ) -NY ³ Y \ -N (R ⁶⁾ -C (= 0) -OR, -N (R ^c j-S02-R, N (R ⁶⁾ -SO 2 NY ^J Yg group -SO2 -NY ³ Y ^Z or -ZR group ·

R ³ is an allyl, cycloalkyl or cycloalkylalkyl group, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cycloalkyl, cyano, halogen, heteroaryl, heterocycloalkyl, hydroxyl, CHO (or a 5-membered, 6-membered or 7-membered acetal derivative), -C (= O) -NY ² Y ² , -C (= O) -OR ⁵ , -NY ^X Y ² , -N (R ⁶⁾ ) -C (= O) -R ⁷ , -N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , -N (R ⁶ ) -SO 2 -R ⁷ , -N (R ⁶ ) -SO 2 NY ³ Y b -OR ^7, and -C (= O) -R ^7; R ⁴ may also contain a group selected from the group consisting of oxygen, S (O) _n , -NR ⁶ ;

R ⁵ is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

R ⁶ is hydrogen or lower alkyl;

R ⁷ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R ⁸ is hydrogen or lower alkyl;

Y ¹ and Y ² are, independently of one another, a hydrogen atom, an alkenyl group, an aryl group, a cycloalkyl group, a heteroaryl group, or an alkyl group optionally substituted with one or more groups selected from the group consisting of aryl, halogen, heteroaryl, hydroxyl , -C (= O) NY ³ Y ⁴ , -C (= O) -OR ⁵ , -ΝΥ ³ Υ, -N (R ⁶ ) -C (= O) -R ⁷ , -N ^(R6) -C (= 0) -NY ³ Y ^4, -N (R ⁵⁾ -SO 2 R ^7, -N ^(R) -SO ₂ ~ NY ³ Y ⁴ and -OR ^7; or the group -NY ³ Y ² may form a cyclic amine;

Y ³ and Y ⁴ are independently hydrogen, alkenyl, alkyl, aryl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY ³ Y ⁴ may form a cyclic amine;

B

Z is O or S (O) _r ;

n is zero or an integer of 1 or 2;

and their corresponding N-oxides and their prodrugs, and their acidic bioisosteres; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N -oxides and prodrugs thereof, and acidic bioisomers thereof; together with one or more pharmaceutically acceptable carriers and excipients.

according to the present invention means the compound of the present invention and equivalent terms of the compound of formula I as described above, including prodrugs, pharmaceutically acceptable salts, solvates, for example hydrates, if the context so permits. Similarly, when they are intermediates, whether or not claimed, they also include salts and solvates when the context permits. For the sake of completeness, it is noted that specific examples are given several times in the text, but these examples are, if the context permits, merely illusory and do not preclude any other embodiment corresponding to the claimed compounds or other embodiments if the context permits.

The following terms used hereinbefore and again in the text of the present invention have the following meanings unless otherwise indicated:

The term patient includes both human and other mammals.

The term acidic bicisosteres refers to groups that are chemically and physically similar and provide similar biological properties to carboxyl groups (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 Bioiscsterism In Drug Design "; Yun, Hwahak Sekye, 1993, 33 To New Drug Design, Zhao, Huaxue Tongbao, 1995, pages 34-38 3-Isosteric Replacement And Development Of Lead Compounds In Drug Design, Graham, Theochem, 1995, 343, Pages 105-109 Threoreoical Studies Applied To Drug Design (ab initio Electronic Distributions In Bioisosteres). Examples of suitable bioisomers are: -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ SH, -C (= O) -NHCN, sulfo, phosphonio, alkylsulfonyloxycarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, hetercarylsulfonylcarbamoyl, N-methoxycarbamoyl-1,3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1, 2,4-oxadiazole or heterocyclic phenols such as a 3-hydroxyisoxazolyl group and a 3-hydroxy-1-methylpyrazolyl group.

The term acyl group means an H-CO- group or an alkyl-CO- group in which the alkyl group is described according to the present invention.

The term acylamino means acyi-ΝΗ-, wherein the acyl group is as defined herein.

The term alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched and contains 2 to 15 carbon atoms in the chain. Preferred alkenyl groups contain 2 to 12 carbon atoms in the chain; more preferably, they contain 2 to 6 carbon atoms (for example 2 to 4 carbon atoms) in the chain. Branched means according to the present invention that one or more lower alkyl groups, such as a methyl group, an ethyl group or a propyl group, are attached to the linear chain (in this case, the linear alkenyl chain). The lower alkenyl group contains 2 to 4 carbon atoms in the chain, which may be straight or branched. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and deceryl.

Alkenyloxy is an alkenyl-Ο- group wherein the alkenyl group is as previously defined. An example of an alkenyloxy group is an allyloxy group.

Alkoxy is an alkyl-Ο- group, wherein the alkyl group is as defined herein. Examples of the alkoxy group include difluoroethoxy, methoxy, trifluoromethoxy, etcxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.

An alkoxycarbonyl group is an alkyl-O-CO- group, wherein the alkyl group is as defined herein. Exemplary alkoxycarbonyl groups include methoxy and ethoxycarbonyl.

Unless otherwise stated, the term alkyl means an aliphatic hydrocarbon group which may be straight or branched and may contain from 1 to 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Preferred alkyl groups contain 1 to 6 carbon atoms. Lower alkyl * as a single group or as part of a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group; is an aliphatic hydrocarbon group, which may be straight or branched and contains 1 to 3 carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl group, n-propyl, isopropyl, n-butyl, s-butyl, tert-butyl, n-penoyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl.

Alkylene is an aliphatic bivalent radical derived directly; or a branched alkyl group, wherein the alkyl group is as defined above. Examples of alkylene groups include methylene, ethylene and trimethylene. O P A P PU E 3.

Alkylenedioxy is a -O-alkylene-O- group in which the alkylene group is as previously defined. Examples of alkylenedioxy groups include methylenedioxy and ethylenedioxy.

An alkylsulfinyl group is an alkyl-SO- group in which the alkylene group is as defined above. Preferred alkylsulfinyl groups are those wherein the alkyl group is a (1-4C) alkyl group.

An alkylsulfonyl group is an alkyl-SO ₂ - group in which the alkylene group is as defined above. Preferred alkylsulfonyl groups are those wherein the alkyl group is a (1-4C) alkyl group.

Alkylsulfonylcarbamoyl is an alkyl-SCp-NH-C (= O) - group in which the alkylene group is as previously defined. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is an alkyl group having from 1 to 4 carbon atoms.

Alkylthio is an alkyl-S- group in which the alkylene group is as previously defined. Preferred alkylthio groups are methylthio, ethylthio, isopropylthio and heptylthio.

An alkynyl group is an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched and may contain 2 to 15 carbon atoms in the chain. Preferred alkynyl groups contain 2 to 12 carbon atoms in the chain; and more preferably contain 2 to 6 carbon atoms in the chain (e.g., 2 to 4 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutinyl, 3-methylbut-2-ynyl and n-pentinyl.

An arovyl group is an aryl-CO- group wherein the aryl group is as defined in the present invention. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl groups.

Aroylamino group is an aroyl-ΝΗ- group, wherein the arcyl moiety is as defined above.

An aryl group as a single group or as part of a group is: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic group having 6 to 11 carbon atoms, such as a phenyl group or a naphthyl group; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic group in which an aryl group and a cycloalkyl group or a cycloalkenyl group are condensed to form a cyclic structure such as a retrahydronaphthyl group, an indenyl group or an indanyl group. Unless otherwise indicated, the aryl groups may be substituted with one; or a plurality of aryl substituents, which may be the same or different, wherein the aryl substituent is, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryloxy, aroyl, aroyl, aroyl, aroyl, aroyl, aroyl, aroyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxyl or acidic bioisoster), cyano, halogen, heteroaroyl, hydroxy, heteroaryl, heteroaryl, heteroaryl, heteroaryl, trifluoromethyl, -NY ^J Yp -CONY ³ Yp SO ² Y ³ Y ⁴ , -NY ^J C (= O) alkyl, -NY ^J SO 2 alkyl or alkyl optionally substituted aryl heteroaryl, hydroxyl

4 or -NY Y.

Arylalkyl is an aryl-alkyl- group in which the aryl group and the alkyl group are as defined above. Preferred arylalkyl groups are alkyl groups containing 1 to 4 carbon atoms. Examples of arylalkyl groups include benzyl, 2-phenethyl and naphthalenomethyl.

Arylalkyloxy is an arylalkyl-O- group wherein the arylalkyl group is cited earlier. Examples of arylalkyloxy include benzyloxy and 1- or 2-naphthalenemethoxy.

An arylalkyloxycarbonyl group is an arylalkyl-O-00- group in which the arylalkyl group is as defined above. An example of an arylalkyloxycarbonyl group is a benzyloxycarbonyl group.

Arylalkylthio is an arylalkyl-S- group wherein the arylalkyl group is as defined above. An example of arylalkylthio is benzylthio.

Aryloxy is an aryl-O- group, as defined above. Examples include phenoxy and naphthoxy, each substituted.

in which the aryl aryloxy group is one of them is optionally

Aryloxycarbonyl is aryl-G-C (= O) -,

in which it is aryl group defined more likely. Between examples aryloxycarbonyl groups include phenoxycarbonyl group and naphthoxycarbonyl group. arylsulfinyl group is a group aryl-SO-, wherein aryl group is defined more likely. arylsulfonyl group is a group aryl-SO 2 -, wherein aryl group is defined more likely.

Arylsulfonylcarbamoyl is an aryl-SO ₂ -NHC (== 0) - group, wherein the aryl group is as previously defined.

Arylthio is an aryl-S- group wherein the aryl group is as previously defined. Examples of arylthio groups include phenylthio and naphthylthio.

An azaheteroaryl group is an aromatic carbocyclic group containing 5 to 10 ring atoms wherein one of the ring members is a nitrogen atom and the other ring members are a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom. Examples of azahetercaryl groups include benzimidazolyl, imidazolyl, inazazolinyl, rnoolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, cninazcinyl and tetrahydroindolizinyl groups.

A cyclic amino group is a 3- to 8-membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by a nitrogen atom and which may contain another heteroatom-containing group selected from the group consisting of oxygen, sulfur, SO ₂ , or NY ³ (where Y ⁵ is H, alkyl, aryl, aralkyl, -C (= O) ^-R, -C (= G, -OR ', or -SO ₂ R), and ( ii) may be fused to another aryl group (e.g., ferryl), heteroaryl (e.g., pyridyl), heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic ring system Examples of cyclic amino groups include pyrrolidine, morpholine, piperidine piperazine, indol, pyrindoline, tetrahydroquinoline and the like.

A cycloalkenyl group is a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and containing 3 to 13 carbon atoms. Examples of monocyclic cycloaikenyl rings include a cyclopentenyl group, a cyclohexenyl group, and a cyclcheptenyl group.

Cycloalkyl is a saturated monocyclic or bicyclic ring system containing 3 to 13 carbon atoms, optionally substituted with an oxo group. Examples of monocyclic cycloalkyl rings include C 3 -C 8 cycloalkyl groups such as cyclopropyl, cyrlopentyl, cyclohexyl and cycloheptyl.

A cycloalkylalkyl group is a cycloalkyl-alkyl- group wherein the cycloalkyl group and the alkyl group are as defined above. Examples of monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

The halogen atom is a fluorine, chlorine, bromine or iodine atom. Fluorine and chlorine are preferred.

Heteroaroyl is a heteroaryl-C (= O) - group, wherein the heteroaryl group is as previously defined. Examples of heteroaryl groups include pyridylcarbonyl.

A heteroaroylamino group is a heteroaroyl-ΝΗ- group, wherein the heteroaryl group is as previously defined.

A heteroaryl group as a single group or as part of a group is: (i) an optionally substituted aromatic monocyclic or multicyclic organic group containing 5 to 10 ring members in which one or more ring members is other than a carbon atom, for example nitrogen, oxygen or sulfur such as benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazidyyl, pyrazidyyl pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl, optionally substituted with one or more aryl substituents which are d effected earlier (except where expressly stated otherwise); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic group wherein the heteroaryl group and the cycloalkyl group or the cycloalkenyl group are fused to form a cyclic structure (e.g., groups containing pyrindanyl groups optionally substituted with one or more aryl substituents Optional substituents include one or more aryl group substituents as defined herein, unless otherwise specifically indicated.

A heteroarylalkyl group is a heteroaryl-alkyl- group in which the heteroaryl group and the alkyl group are as previously defined. Preferred heteroarylalkyl groups include alkyl groups containing 1 to 4 carbon atoms. Examples of heteroarylalkyl groups include the pyridylmethyl group.

Heteroarylalkyloxy is a heteroarylalkyl-O- group in which the heteroarylalkyl group is as defined above. Examples include heteroaryioxysxupir. include optionally substituted pyrimidylmethoxy groups.

Heteroaryloxy is a heteroaryl-Ο- group in which the heteroaryl group is as previously defined. Examples of heteroaryloxy groups include the optionally substituted pyridyloxy group.

Heteroarylsulfonylcarbamoyl is a heteroaryl-SO 3 -NH-C (= O; -) group in which the heteroaryl group is as previously defined.

A heterocycloalkyl group is: (i; a cycloalkyl group containing 3 to 7 ring members which contains one or more heteroatoms or groups containing heteroatoms selected from oxygen, sulfur and MY ³ and may optionally be substituted by oxo; (ii) partially saturated multicyclic; a heterocarbocyclic group in which the aryl group (or heteroaryl group) is optionally substituted with one or more aryl group substituents, and the heterocycloalkyl group is fused to form a cyclic structure (examples include chromanyl, dihydroberofuranyl, indolinyl and pyrindolinyl).

Heterocycloalkylalkyl is a heterocycloalkyl-alkyl- group in which the heterocycloalkyl group is as defined above.

The term prodrug refers to a compound which can be converted in vivo metabolically (for example by hydrolysis) to a compound of formula I, including N-oxides thereof. For example, an ester of a compound of formula I containing a hydroxyl group can be converted in vivo to the parent molecule by hydrolysis. Alternatively, an ester of a compound of formula I containing a carboxyl group can be converted in vivo by hydrolysis to the parent molecule.

Suitable esters of the hydroxyl-containing compounds of the formula I are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-p-hydroxynaphthates, gentisates, isethionates, di-p-toluoyltartrates , methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

Suitable esters of the compounds of formula I containing a carboxyl group are, for example, those described in F.J. Leinweber, Drug Metab. Res., 1987, 18, p.

Suitable esters of the compounds of formula (I) containing both carboxyl and hydroxyl groups in the -L 1 -Y group include lactones formed by the elimination of water between the carboxyl group and the hydroxyl group. Examples of such lactones include caprolactones and butyrolactones.

A particularly suitable class of esters of compounds of formula I containing a hydroxyl group may be formed from acidic groups selected from those described by Bundgaard et al., J.

Oven. Chem., 1939, 32, pages 2503-2507, and includes substituted (arriving ethyl) benzoates, such as diazkylaminomethylbenzenes, in which two alkyl groups may be linked by Doropy and / or interrupted by an oxygen atom. or optionally substituted, nitrogen, e.g. alkylated nitrogen, especially (morpholinomethyl) benzoates, e.g. 3- or 4- (trifluoromethyl) benzoates, and (4-alkylipiperazin-1-yl) benzoates, e.g. 3- or 4- (4-aikylpiperazln-yl; benzoates.

If the compound of the present invention contains a carboxyl group or a sufficiently acidic bioisoster, basic addition salts may be formed and are a more convenient form for use; in practice, the corresponding amount of salt is formed as in the free form. Bases that can be used to prepare basic addition salts include, preferably, those which, in combination with the free acid, provide pharmaceutically acceptable salts, i.e., salts whose cations are non-toxic to patients using pharmaceutical doses of salt, so that the beneficial inhibitory effects inherent in the free base are not disturbed by side effects caused by cannons. Pharmaceutically acceptable salts, including those derived from the alkali metal and alkaline earth metal salts of the present invention include salts derived from the following bases: sodium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenedtamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzyiphenethylamine, diethylamine, hydroxymethylamine, tris (hydroxymethyl) amine;

Certain compounds of the present invention are basic and such compounds are useful in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts.

Acid addition salts are more suitable for use in the present invention; and in practice the salt forms the corresponding amount as in the free base form. Acids which can be used to prepare acid addition salts include preferably those which, in combination with the free base, produce pharmaceutically acceptable salts, i.e. salts whose anions are non-toxic to patients in pharmaceutical doses of salts, so that the beneficial inhibitory effects inherent in the free in principle, they are not adversely affected by side effects caused by anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base forms even when the respective salt itself is only required as an intermediate, for example, when the salt is formed solely for purification and identification purposes, or used as an intermediate in the preparation of a pharmaceutically acceptable salt using ion exchange procedures. Pharmaceutically acceptable salts of the present invention include those derived from inorganic and organic acids and include hydrogen halides such as hydrochlorides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates , fumarates, maleates, methylene-bis-p-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

As the salts of the compounds of the present invention are useful as active compounds, they are also suitable for the purification of the compounds, for example, by utilizing differences in solubility of salts and parent compounds, by-products and / or starting materials using techniques that are skilled in the art. known.

In the case of the compounds of formula I above, the following groups of compounds are preferred and more preferred:

R ¹ may in particular be:

(i) a hydrogen atom;

(ii) an alkyl group having 1 to 4 carbon atoms (e.g., sxupine -CH ₃ or -ΟΗ ₂ ΟΗ ₃ );

(iii) an alkyl group having 1 to 4 carbon atoms substituted with an aromatic halogen [e.g., -CH ₂ CF ₃ i;

(o) a C 1-4 alkyl substituted by a hydroxyl group [e.g., -CH ₂ OH, -CH ₂ CE ₂ OH, or -CH ₂ CH ₂ CH ₂ OHJ;

(v) an alkyl group having from 1 to 4 carbon atoms sulfonated with -N (R ^e ) C (= O) -R '[e.g., -CE ₂ CH ₂ CH ₂ NKC: = O) CH ₃ ];

(vi) an alkyl group of up to 4 carbon atoms substituted with -C (= O) -NY1 ^{; 2} [eg group

-CH — C (= O) ~ N \ _ O]:

(vii) a cycloalkylalkyl group substituted with a hydroxyl group [e.g.

ch ₂ oh

Compounds of formula I wherein R ¹ is hydrogen, -CH 3, -CH ₂ CH ₃ , -CH ₂ CF ₃ , or

-CH = C (= O) -N

are particularly preferred.

R ¹ is particularly preferably a hydrogen atom.

suitably a boxyl group or an acidic bioisoster (e.g.

N ·

N '

(ii) a hydroxyl group;

(iii) an allyl group substituted with a carboxyl group [e.g., -CH ₂ CH ₂ CO ₂ H];

v) a heteroaryl group [e.g., a pyridyl group];

N '

CH, or ivi) a -CR 'group wherein R ⁴ is an alkyl group [e.g., -OCH 3];

-OR ', where R ⁴ is an alkyl or cycloalkylalkyl group substituted with one or more hydroxyl groups [e.g., -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ CH ₂ OH, -OCH (CH ₃ ) CH ₂ OH, -OCH ₂ CH (OH) CH ₃ , group

Q_'QH ² | | ² or -OCH 2 CH (OH) CH ₂ OH];

-O-C-CH 2 CH ₂ OH (vii) -OR ⁴ wherein R 1 is an alkyl group substituted with one or more alkoxy groups [e.g., -OCH- (CH 3) CH ₂ OCH ₃ ];

(viii) -OR ⁴ where R ⁴ is an alkyl or cycloalkyl group substituted with one or more carboxyl groups [e.g., -OCH ₂ CO ₂ H,

-OCH (CH 3) CO ₂ H or i Y ** 2

II _O-C-CH2];

co ₂ h) ix) -OR ', where R ⁴ is cycloalkyl substituted or -C' = O) -NY ¹ Y ² [e.g.

-oh ₂ c — ch ₂

-ch ₂ ];

h ₂ c — ch ₂

-O-C-CH,

CON,

CONHCH, x) a -C (= O) -R group wherein R is an alkyl group [e.g., a-C 1 = O) -CH 3 group];

(xi) -C (= O) -NY'Y ² [e.g., -CONH ₂ , -CONHCH _3, -CONHCH ₁ CH ₂ OH) ₂ , -CONHCH ₂ CH ₂ OH, -CONHC (CK ₃ ) CH ₂ OH, -CONHCH ₂ CH ₂ OCH 3, -CONHCH ₂ CH ₂ CONH ₂ , -CCNHCH ₂ C (CH ₃ ) ₂ OH, or w

(xii) -N (R 0) -C (= O) -R '[e.g. -NHC (= C) CH ₃ ] group.

Compounds of formula I wherein R ² is -OCH ₃ or -CONHC (CK ₃ ) ₂ CH ₂ OH are particularly preferred. More preferably, R b is -OCH 3.

Pb may preferably be:

(i) hydrogen aroma;

(ii) cyano;

(iii1 an optionally substituted aryl group (e.g. phenyl group i;

(iv) an optionally substituted heteroaryl group (e.g. an optionally substituted pyridyl group or an optionally sub-substituted indlyl group, in particular z-x group)

//

N (v) an alkyl group (for example, a meuyl group or an ethyl group);

(vi) an alkyl group substituted with one or more halogen atoms (e.g., trifluoromethyl);

(vii; alkyl substituted with -C (= O) -NY ¹ Y ² , especially -CH ₂ -CH ₂ -C (= O) NHCH ₃ ;

(viii) an alkyl group substituted with -OR '(e.g., -ix ₂ -CH ₂ -CH ₂ -OCH ₃ );

(ix '-ZR ⁴ , especially -OCH ₃ , -OCH ₂ CH ₃ , -OC ₂ H, or -OCH ₂ -CH ₂ -OCH ₃ ;

(xi) -C (= O) -OR ⁵ , especially -C (= O) -OH;

(xi -C (= 0) ^ -NY ^2, in particular -C (= 0) _NHCH3 or -C (= 0) -NH-C (CH _{3) 2} CH ₂ OH, and

-N (xii; ^ -NY ² group, specifically

Compounds of formula (I) wherein R ³ is hydrogen, cyano, pyridyl, tri fluoromethyl, -CH ₂ CH ₂ -C (= O) NHCH ₃ , -OCF ₂ H, -C (= O) - NHC (CH ₃ ) ₂ are particularly preferred. More preferably,

-CH ₂ OH or -θ is -OCH ₃ . \

The ring is preferably bound at the 3-position of the indole

It should be noted that the present invention encompasses all convenient combinations of the particular and preferred groups mentioned above.

Particularly preferred compounds of the present invention are the following:

(ΙΠ)

(IN)

(VI) (VII)

(IX)

(X) (XI)

(XXD ()Π))

HO

(XXIV) 2 from CH ₂ OH

(XXV)

(XXVII) and the corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs.

Particularly preferred compounds of the present invention are the following:

-methoxy-6-; 5-methoxy-1H-inool-3-yl) -7X-pyrrolo [2,3-d] pyrimidine;

and the corresponding N-oxides and prodrugs thereof; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of these compounds and their N-oxides and prodrugs.

The compounds of the present invention possess advantageous pharmacological activity and are therefore formulated into pharmaceutical compositions and are used in the treatment of patients suffering from certain diseases. Accordingly, the present invention provides as a further aspect the compounds of the present invention and compositions comprising the compounds of the present invention for use in therapy. The compounds of the present invention block the catalytic kinase activity according to the tests described in the literature and the in vivo procedures described below, and the results of these restraints are believed to be consistent with the pharmacological activity in humans and other mammals. Thus, in another embodiment, the present invention relates to compounds of the present invention and compositions comprising compounds of the present invention for use in the treatment of patients suffering from diseases that are administered by protein kinase inhibitors

KDR or Aurora2), in particular a Syk kinase inhibitor. For example, the compounds of the present invention are useful in the treatment of inflammatory diseases; for example asthma;

(e.g., psoriasis, herpetiform necrosis and cutaneous vasculitis, bullous disease); allergic rhinitis and allergic conjunctivitis; joint inflammation, including arthritis, rheumatoid arthritis and other arthritic diseases such as rheumatoid spondylitis, gout arthritis, can be alleviated by, for example, Syk, FAK, inflammatory dermatitis, eczema dermatitis, traumatic arthritis and osteoarthritis psoriasis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis. The compounds are also useful in the treatment of chronic obstructive pulmonary disease (COPD), acute synovitis, autoimmune diabetes, acute encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, restenosis, myocarditis, lymphomas of the host cell lymphoma, lymphomas of the B cell, and other organ rejections in transplantation; cancer and tumors (such as colorectal cancer, prostate cancer, breast cancer, thyroid cancer, colon cancer, and lung cancer) and inflammatory bowel disease. Further, the compounds of the present invention are useful as tumor anti-angiogenic agents.

A particular embodiment of the treatment methods of the present invention is the treatment of asthma.

Another particular embodiment of the therapeutic methods of the present invention is the treatment of psoriasis.

Another particular embodiment of the therapeutic methods of the present invention is the treatment of inflammation of the joints.

Another particular embodiment of the therapeutic methods of the present invention is the treatment of inflammatory bowel disease.

Another particular embodiment of the therapeutic methods of the present invention is the treatment of cancer and tumors.

According to another aspect, the present invention provides a method of treating a human or animal suffering from or at risk of a disease which may be alleviated by administration of a protein kinase inhibitor (e.g. Syk, FAK, KDR or Auroraf), for example a disease described above wherein the method comprises administering an effective amount of the compound. according to the present invention or a composition comprising a compound of the present invention to a patient. An effective amount means an amount of a compound of the present invention effective in inhibiting the catalytic activity of a protein kinase such as Syk, FAK, KDR or Auroraf to achieve the desired therapeutic effect.

It is understood that references to treatment include prophylactic treatment as well as treatment of pre-existing diseases.

The present invention also encompasses pharmaceutical compositions comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention may be administered by any suitable route. In practice, the compounds of the present invention may be administered parenterally, topically, rectally, orally, or by inhalation, in particular by the oral route.

The compositions of the present invention may be prepared by conventional procedures using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be prepared in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of sweetening, flavoring, coloring or stabilizing agents to obtain a pharmaceutical. acceptable compositions. The choice of vehicle and the active compound content of the vehicle will usually be determined by the solubility and chemical properties of the active compound, the particular mode of administration and the conditions common in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrant such as starch, alginic acid and some complex silicates associated with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used to prepare the tablets. Lactose and high molecular weight polyethylene glycols are preferred for the preparation of capsules. If aqueous suspensions are used, they may contain emulsifying agents or agents which promote suspension stability. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products of the present invention in vegetable oils, such as sesame oil, peanut oil or olive oil, or voco-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, and also sterile aqueous solutions of pharmaceutically acceptable salts. Salts of the products of the present invention are particularly suitable for administration by intramuscular or subcutaneous injection. Aqueous solutions, including also salt solutions in pure distilled water, may be used for intravenous

administration with provided that their pH is appropriately adjusted, they are flocons buffered isotonic with sufficient glucose aleoo chlorine: and are sterilized by heating, irradiation aleoo mikrco filtration. On oop For administration, gels may be used (for science or alkcr. ol; creams or ointments containing the compounds of p e o i o g e h; and the invention. The compounds of the present invention are can also r : to gel or base for application in form plasters, k This may allow controlled release of the compound. niny over tre nsdermal barrier. For min For administration by administration, the compounds of the present invention may be administered invention rco lowered or suspended in a suitable carrier for use. those vc jorm e nebulizer or aerosol suspension or solution, or me- they can be absorbed or adsorbed onto a suitable solid support for use in dry powder inhalers. Fixed / compositions for rectal administration include suppositories pravené pom according to known methods and comprising at least one

a poodle compound of the present invention.

The percentage of active ingredient in the composition of the present invention may be varied, and the ratio,

which would ur allowing a suitable dosage of the compound. Of course, e possible feeders at several unit dosage forms; at the same time. Appropriate dose and will be determined by the physician and will depend upon the therapeutic desired

effect, route of administration and duration of treatment, and from the condition being treated

patient. 'J matures The patient's dose will generally vary v r o z s and h u 0, 301 to 50, preferably 0.001 to 5 mg / kg body weight

nostr per day by inhalation, in the range of 0.01 to 100, preferably 0.1 to 70, more preferably 0.5 to 10 mg / kg of body weight per day for oral administration, and in the range of 0.001 to 10, preferably 0.01 to 1 mg / kg body weight per day for intramuscular administration. In each particular case, the dosage will be determined according to factors relevant to the patient to be treated, such as age, weight, general condition and medical condition, and other characteristics that may affect the efficacy of the medicinal product.

The compounds of the present invention may be administered as often as necessary to achieve the desired therapeutic effect. Some patients may have a faster response to a higher or lower dose, and may be much less likely to maintain an appropriate dose, while other patients may need longer-term treatment at 1 to 4 doses per day, depending on the physiological requirements of each particular patient. In general, the active product may be administered orally one to four times a day. Of course, some patients may need not to prescribe more than one or two doses per day.

The compounds of the present invention are heated by application or modification of known procedures, such as those described in the present invention, for example those described in R.C. Larock, Organic Transformatons, VCH Publishers, 1989.

they can prepare by laying or in the letter Comprehensive

In the reactions described below, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl, if these are required in the final products to prevent their controlled participation in the reactions. Conventional protecting groups may be used according to conventional procedures described, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, 1991.

Compounds of formula I wherein R ¹ , R ² and R ³ are as described above are prepared by reaction of compounds of formula

XXVIII:

(XXVff1) wherein R ^J is as defined above, X ¹ is a halogen atom, preferably an iodine atom, or a triflate group, with a compound of formula XXIX:

(XXIX) wherein R and R are ^the oefinované above. The condensation reaction may conveniently be carried out, for example, in the presence of a metal catalyst complex such as tetrakis (triphenylphosphine) palladium (0) and sodium hydrogen carbonate in aqueous oimethyiform.amide at a temperature until the reaction mixture boils. This reaction is usually carried out with a pyrrole NH in a compound XXVIII protected for example with a tosyl group and an indole NH in a compound XXIX protected for example with a tert-butyloxycarbonyl group.

The compounds of formula I wherein R ² and R ³ are as defined above and ^{R, is} an optionally substituted alkyl group, are prepared by reacting the corresponding compounds of formula I, wherein R ^x and R ³ are as defined above and R is H, with an appropriate alylhalidom R ² -X ² , wherein R ² is an optionally substituted alkyl group and X ² is a halogen atom. This reaction is particularly suitable for the preparation of compounds of the general formula wherein R ¹ is a morpholinoacetyl group.

The compounds of the present invention may also be prepared by interconversion of other compounds of the present invention.

Thus, for example, compounds of formula I containing a carboxyl group can be prepared by hydrolysis of the corresponding esters. Hydrolysis is usually carried out by alkaline hydrolysis using a base such as an alkali metal hydroxide such as lithium hydroxide or an alkali metal carbonate such as potassium carbonate in the presence of an aqueous / organic solvent mixture using organic solvents such as dioxane, tetrahydrofuran or methanol at room temperature to the boiling point of the reaction mixture. Hydrolysis of the esters can also be carried out by acid hydrolysis using an inorganic acid such as hydrochloric acid in the presence of an aqueous / organic solvent mixture, using organic solvents such as dioxane or tetrahydrofuran at a temperature of 50 ° C to 80 ° C.

Another example of compounds of formula I containing a carboxyl group can be prepared by acid-catalyzed removal of the tert-butyl group from the corresponding tert-butyl esters using standard reaction conditions, for example by reaction with trifluoroacetic acid at about room temperature.

Another example of compounds of formula I containing a carboxyl group can be prepared by hydrogenation of the corresponding benzyl esters. The reaction may be carried out in the presence of an ammonium formate and a suitable metal catalyst, for example palladium deposited on an inert support such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature around the boiling point of the reaction mixture. Alternatively, the reaction may be carried out in the presence of a suitable metal catalyst, for example platinum or palladium, supported on an inert support such as carbon, preferably in a solvent such as methanol.

As a further example of the conversion salt, compounds may be used

-C (= O) N1 -;

of formula 1 comprising the coupling of compounds of formula 1 containing a carboxyl group with an amine of formula HNY'Y 'to give an amide bond using standard peptide coupling, for example, coupling in the presence of O- (7-azabenzetriazol-1-yl) - 1,1,3,3-tetramethylurexhexafluorosulfate with triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature. This process is particularly suitable for the preparation of (i) compounds of formula 1 wherein P 1 is -C (= O) -NY * Y ^Z or (ii) compounds of formula I wherein P 1 is -C (= O) - ^ NY. The condensation may also be carried out by rearrangement of compounds of formula Z containing a carboxyl group with N-oxide of N- ((dimethylamino) (1H-1,2,3-triazolo [4,5-b] pyridin-1-yl) methylene} - N-methylmethanaminium hexafluorophosphate in the presence of a suitable base, such as diisopropylethylamine, in an inert solvent such as dimethylformamide and at room temperature, and then reaction with an amine of formula HNY4 (to prepare compounds of formula I containing -C (= CH 2 -NH ₂₎ The condensation can also be carried out by reacting compounds of formula I containing a carboxyl group with 2- (1H-benzetriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, in dry dimethylformamide, followed by reaction with an amine of formula HNY4 in the presence of diisopropylethylamine.

As a further example of the interconversion process, compounds of formula I containing a -CH ₂ OH group can be prepared by reduction of the corresponding compounds of formula I containing -CHO or -CO ₂ R '(where Ph is a lower alkyl group). For example, the reduction can be carried out by assisting the reaction with lithium aniline hydride, in an inert solvent such as tetrahydrofuran, and at a temperature between room temperature and the boiling point of the reaction mixture.

As another example of the interconversion process, compounds of formula I wherein R ² is hydroxyl may be prepared by reaction of the corresponding compounds of formula I wherein R ¹ is methoxy with a Lewis acid such as boron tribromide in an inert solvent such as dichloromethane and for a temperature in the range of 0 ° C to room temperature.

As another example of the interconversion process, compounds of formula 5 wherein R ² is -OR ⁴ (where R ⁴ is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycioalkyl or heterocycloalkylalkyl) may be prepared by alkylation of the corresponding compounds of formula I wherein R ² is a hydroxyl group, a compound of formula XXX:

R ⁴ -X ³ (XXX) wherein R ⁴ is as defined above and X ³ is a halogen atom, preferably a bromine atom, or a tosyl group, using standard alkylation conditions. For example, the alkylation may be carried out in the presence of a base such as an alkali metal carbonate (e.g. potassium or cesium carbonate), an alkali metal alkoxide (e.g. potassium tert-butoxide) or an alkali metal hydride (e.g. sodium hydride), dimethylformamide, or dimethylsulfoxide. temperature in the range of 0 ° C to 100 ° C.

As another example of an interconversion process, compounds of formula I wherein R ¹ is alkyl, alkenyl, cycloalkyl, heterocycioalkyl, or alkyl substituted with -C (= O) NY ¹ Y ² , -OR ³ , may be -C (= O) -OR ^7, -NY ^{I 'groups} Y ² may be prepared by alkylation of the corresponding compound of formula Ia, wherein ^{R, is} a hydrogen atom, an appropriate halide of formula XXXI:

R ¹ -Yc (XXXI) wherein d is alkyl, alkenyl, cycloalkyl, heterocyrloalkyl, or alkyl substituted with -C (= O) NY'Y ² , -OFo ', -C (= C) , -CR ', -NY'YS, and X * is a halogen atom, preferably a bromine atom, using standard alkylation conditions such as those described above.

As a further example of the interconversion process, compounds of formula (T) containing a sulfoxide bridge can be prepared by oxidizing the corresponding compounds containing a -S- bridge. For example, the oxidation may be carried out by reaction with a peroxyacid, for example 3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably at near room temperature, or alternatively with potassium hydrogen peroxide monosulfate in a medium such as aqueous methanol buffered to pH about 5. at 0 ° C and room temperature. This method is advantageous for compounds containing an acid labile group.

As a further example of the interconversion process, compounds of formula I containing a sulfone bridge can be prepared by oxidizing the corresponding compounds containing a bridge -Salebc sulfoxide bridge. For example, the oxidation may conveniently be carried out by reaction with peroxyacids, for example 3-chloroperbenzoic acid, preferably in an inert solvent, for example dichloromethane, preferably at a temperature close to room temperature.

As another example of the interconversion process, compounds of formula I containing a cyano group can be prepared by reacting the corresponding compound of formula I containing a group -C (= O) -NH ₂ with phosphorus pentachloride in the presence of trietvlamine. The reaction may conveniently be carried out in an inert solvent such as tetrahydrofuran and at a temperature around the boiling point of the reaction mixture.

As another example of the interconversion process, compounds of formula I containing a -C (= O) -NH _{2 group can be} prepared by reacting the corresponding compound of formula I containing a cyano group with hydrogen peroxide in the presence of sodium hydroxide. The reaction may conveniently be carried out in methanol at room temperature.

As another example of the interconversion process, compounds of formula I wherein R ³ is -NY ¹ Y ² (where Y ¹ and Y ² are as defined above) can be prepared by reaction of the corresponding compound of formula I wherein R ³ is halogen ( chlorine atom) with an amine of the formula vzorca ^Ί * Υ ² (where Y ¹ and Y ² are as defined above).

As another example of an interconversion process, compounds of formula I wherein R ³ is cyano can be prepared by reacting a compound of formula I wherein X ¹ is halogen, preferably chlorine, with zinc cyanide in the presence of zinc powder, complex [1, 1 '- bis (diphenylphosphino) ferrocene] dichloropalladium (11) and dichloromethane (catalytic amount) and N, N-dimethylacetamide at a temperature of up to about 150 ° C.

As another example of the interconversion process, compounds of formula I containing -C (= O) -OR ³ (where R ⁵ is as defined above) can be prepared by reacting the corresponding compounds of formula I containing -C (= O) -OH with alcohols R ⁵ -OH. For example, when R ^{5 is a} tert-butyl group, the reaction is conveniently carried out in the presence of 1,1'-carbonyldiimidazole and 1,8-diazabicyclo [5.4.0] undec-7-ene at room temperature.

It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently have the R or S configuration. Those skilled in the art will recognize that some of the compounds of the present invention may also exhibit geometric isomerism. It is to be understood that the present invention encompasses the individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures, of the compounds of Formula I above. These isomers may be isolated from the mixtures by known methods, for example, by chromatographic techniques and recrystallization techniques, or may be prepared separately from the corresponding isomers of their m. Zipers.

In another aspect of the present invention, addition salts of the compounds of the present invention can be prepared by reacting the free base with the appropriate acid, using known procedures. For example, acid addition salts of the compounds of the present invention may be prepared either by dissolving the free base in bulk or in an aqueous alcoholic solution or other solvent-containing solvent and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent. directly or can be obtained by evaporation of the solution.

The acid addition salts of the compounds of the present invention can be regenerated from the salts by known methods. For example, the parent compound of the present invention can be regenerated from the acid addition salt by reaction with a base, for example an aqueous sodium bicarbonate solution or an aqueous ammonia solution.

The compounds of the present invention can be regenerated from basic addition salts by known methods. For example, the parent compound of the present invention can be regenerated from a base addition salt by reaction with an acid, for example hydrochloric acid.

The compounds of the present invention may conveniently be prepared or isolated in the methods of the present invention in the form of solvates (e.g. hydrates). Hydrates of the compounds of the present invention may conveniently be prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxane, tetrahydrofuran or methane.

According to another aspect of the present invention, the base addition salts of the compounds of the present invention can be prepared by reacting the free acid with a suitable base using known procedures. For example, the base addition salts of the compounds of the present invention can be prepared either by dissolving the free acid in water or aqueous alcoholic solution or another suitable solvent containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent. can be obtained by evaporating the solution.

The starting materials and intermediates can be prepared by known methods, for example by the methods given in the Reference Examples or by their apparent chemical equivalents.

Intermediates of formula XXVIII, wherein R ³ is as defined above, X ¹ is an iodine atom and the pyrrole NH group is protected with a tosyl group, can be prepared by the procedure outlined in Scheme 1.

Scheme 1

(XXXII)

(xxxm)

Thus, for example, compounds of formula XXXIV may be prepared as follows:

(i) reacting compounds of formula XXXII with para-toluenesulfonyl chloride in the presence of aqueous sodium hydroxide and cetrabutylammonium sulfate in an inert solvent such as toluene and at room temperature;

(ii) subsequently reacting the obtained compound of formula (I)

XXXIII with butyl lithium in tetrahydrofuran, at a temperature of about

- 78 ° C;

(iii) reacting the obtained anion with iodine.

The intermediates of formula XXXIII, roe is heteroaryl, can be prepared by reacting a compound of formula XXXIII, where Pr is a halogen, for example chlorine, with a borane of formula R ^J EEt _2, RDC R "is a heteroaryl group. The reaction is conveniently carried out in the presence of tetrakis (triphenylphosphine) palladium (0) and potassium carbonate, in tetrahydrofuran at the boiling point of the reaction mixture. This reaction is particularly suitable for the preparation of compounds of formula (XXXIII), a ring (P ³ -pyridyl).

Intermediates of formula XXXI11 wherein Pr is a heteroaryl group can also be prepared by reacting compounds of formula XXXIII wherein R ³ is an atom. halogen, for example chlorine, with a heteroarylboronic acid of the formula R ³ S (CH) ₂ in the presence of tetrakis (triphenylphosphine) palladium (0) and an aqueous solution of sodium bicarbonate, in dimethylformamide, at the boiling point of the reaction mixture. This reaction is particularly suitable for the preparation of compounds of formula XXXIII, wherein R ^J is an optionally substituted indolyl srupina.

Intermediates of formula XXXIIi, where Pr is an OR ⁴ group, where R ⁴ is as defined above, can be prepared by reacting compounds of formula XXXIII wherein R ³ is a halogen atom such as chlorine with compounds of formula R ⁴ ONa (prepared by reaction of alcohols of formula R ⁴ OH with sodium) at a temperature of up to about 65 ° C. This reaction is particularly useful for the preparation of compounds of formula XXXIII wherein R ³ is OMe.

The present invention is further illustrated by the following examples and reference examples, which are not to be construed as limiting the scope thereof.

DETAILED DESCRIPTION OF THE INVENTION

The conditions of high pressure liquid chromatography-mass spectrometry (LC-MS) for determining retention times (R _T ) are as follows:

Method A: Hypersil BDS C-18 reverse phase column (4.6 mm x 50 nm) operating under elution gradient conditions with a mixture of (A) water containing 0.05% trifluoroacetic acid and (E, acetonitrile containing 0.05% acid) Trifluoroacetate as mobile phase: 0.00 min 100% A: 0% B; linear gradient up to 100% B over 2 min; then held for 3.5 min); flow rate i mi / minute at a mass spectrometer flow rate of about 0.25 ml / minute; Injection volume 10 μΐ; Hewlett Packard Model HPI 100 You cover a W detector with a wavelength of 200 nm; Evaporative light scattering (ELS) detection - temperature 46 ° C, nitrogen pressure 400 kPa (4 bar).

Method B: Gilson 215 5 µ column (4.6 mm gradient with Hypersil HyPURzTY C-18 x 50 mm spray mixture) operating under elution (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0, 05% trifluoroacetic acid as mobile phase: (0.00 min 95% A: 5% 3; linear gradient to 95% B in 4 minutes; then 5% B in 4.5 minutes, then held for 6 minutes); volume, injection of 5 μΐ and flow rate of 1 ml / min to UV (DAD) detector, afterwards flow of 0.1 ml / min to mass spectrometer (positive electrosp.), rest to ELS detector.

Method C: Elemental analysis device model LCT connected to device H? 1100. Representation of compound was detected using a model HP G1315A photodiode detector with a wavelength of 200-600 nm and an evaporative light derector model Sedex 65. The mass spectrum was recorded in the range of 180-800. The data were analyzed using Micromass MassLynx software. Separation is carried out on a Hypersil BDS C18 column, with a particle size of 3 μτη (50 x 4.60 mol, eluting with a linear gradient of 5 to 90% acetonitrile containing 0.051 vol% of influenzaic acid in water containing 0.05 vol% of trifluoroacetic acid over 3.5 minutes at a flow rate of 1 ml / minute The total time, including column re-equilibration, is 7 minutes.

Example 13. d 1

2- [5-Methoxy-3- (4-trifluoromethyl-2 H -pyrrolo [2,3-b] pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-one; - 4 - y 1 e t ar. Or.

General compound

R ² is -OMe, R ^{3 is} r ^1, R ¹ is -C 1j,

is bound at the 3-position of the indole ring and the group R ² is bound at the 5-position of the indole ring of formula II:

is prepared according to the procedure illustrated in the following scheme:

(i) reacting 7H-pyrrolo [2,3-b] pyrimidine (1) with 3-chloroperbenzoic acid in dichloromethane at 0 ° C to give 7H-pyrrolo [2,3-b] pyrimidine-N-oxide (2);

(ii) reacting the compound of formula (2) with phosphorus oxybromide at 50 ° C to give 4-bromo-7H-pyrrolo [2,3-b] pyrimidine (3);

(iii) reacting the compound of formula (3) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulphate and aqueous sodium hydroxide in toluene to give 4-bromo-7H-pyrrolo [2,3-b] pyrimidine (4);

(iv) reacting the compound of formula (4) with trifluoromethyltrimethylsulfonate in the presence of potassium fluoride and copper iodide in dimethylformamide at 60 ° C to give 7- (trifluoro-4-sulfonyl; -4-trifluoromethyl-7 H -pyrrolo 2-2); 3-b] pyrimidine (5);

(v) reacting the compound of formula (5) with lithium diisopropylaminone, in the presence of tetrahydrofuran, at -78 ° C, and then reacting the obtained anion with iodine to give 6-iodo-7- (thieno-4-sulfonyl) -4-trifluoromethyl-7.d-pyrrolo [2,3-h] pyrimidine (6i.

(vi) condensation of a compound of formula (6) with 1- tert -butyloxycarbonyl-o-methoxy-1H-indci-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) sodium bicarbonate, in dimethylformamide, boiling and removal of the tert-butyloxyxycarbonyl protecting group in the presence of secular hydric, followed by treatment with methyl iodide in the nature of sodium hydride, in tetrahydrofuran to give 6- (5-methoxyethoxy-indol-3-yl) -7- ( toluene-4-sulfonyl-4-trifluoromethyl-β-pyrrolo [2,3-d] pyrimidine (7);

(viii) deprotection of the tesyl protecting group of (f) by treatment with potassium hydroxide in methanol to give 6- (5-methoxy-1H-indol-3-yl) -4-trifluoromethyl-7H-pyrrolo [2, 3-h [pyrimidine (3 [a] (ix) alkylation of a compound of formula (8) with 4- (2-chloroacetyl) morpholine in the presence of sodium hydride in dimethylformamide to afford 2- [5-methoxy-3- (4-tri Fluoromethyl-7β-pyrrolo [2,3-b] pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-yl-ethanone (II j.

Example 2 1-Methyl-3- (7H-pyrrolo [2,3-d] pyrimidin-6-yl-1H-indole-5-carboxylic acid 2-hydroxy-1,1-dimethylethyl) -amide

Compound of Formula I wherein R ¹ is -CH ₃ , R 1 is

About Me Me

N CH OH H ²

R ³ is a hydrogen atom

R ² is bound III:

is bound at position 5 at position 3 of the indole indole ring and the ring, generally with the purchase of the formula

prepare the steps of the procedure illustrated in the following scheme:

(JU) reacting the compound of formula (9) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulphate and aqueous sodium hydroxide in toluene to give the compound of formula iii by reacting the compound of formula (10) with lithium diisopropylamide in tetrahydrofuran at -73 ° C, then reacting the obtained an iodine anion to give a compound of formula (11);

iii) condensation of the compound of formula (11) with i-tert-butyloxycarbonyl-5-methoxy-11-indole-3-boronic acid (12) in the presence of tetrakis triphenylphosphine) palladium (0) and hydrogen carbonate, in aqueous dimethylformamide at boiling point and removing tert-butyloxycarbonyl; protection; groups in the presence of sodium hydride, in tetrahydrofuran to give 6-1 '(1-methyl-5-carbomethoxyindol) -3-yl (-7H-pyrrolo [2,3-pyrimidine (13));

(iv) reacting the compound of formula (13) with aqueous methanolic potassium hydroxide solution at boiling point to give 6 - [(1-methyl-5-carboxyindol) -3-yl] -7H-pyrrolo [2,3-b] and (v) condensing compound (14) with 2-hydroxy-1,1-dimethylethylamine in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give (2-hydroxy-1,1-dimethylethyl) amide

1-methyl-3- (7H-pyrrolo [2,3-b] pyrimidin-6-yl) -1H-indole-5-carboxylic acid of formula (III).

Example 3

2 - {[5-Methoxy-3- (7H-pyrrolo [2,3-b) pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-yl} -ethanone

A compound of formula I wherein R ¹ is -ch

R '

R ^Z is -OMe, R ^J is hydrogen, R is bonded in the 3-position of the indole ring and the group R to a 5-position of the indole ring of formula IV:

is bound

(IV)

(i) condensation of 6-iodo-7-toluene-4-sulfonyl) -7 N-pyrrolo [2,3-b] pyrimidine of formula (11) and 1-tert-butyloxycarbonyl-5-methoxyindole Of 3-boronic acid of formula (15) in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate, in aqueous dimethylformamide at boiling and removal of the tert-butyloxycarbonyl protecting group to give 6-) (5-methoxyindole) -3- yl] -7- (toluene-4-sulfonyl) -7 H -pyrrolo [2,3- b] pyrimidine of formula (16);

(ii) reacting the compound of formula (16) with an aqueous methanolic potassium hydroxide solution at boiling to give 6 - [(5-methoxyindol) -3-yl] -7H-pyrrolo [2,3-b] pyrimidine of formula (17) ; and (iii) reacting the compound of formula (13) with sodium hydride in dimethylformamide, followed by treatment with a morpholinamide 2-iorómoctove acid hydrochloride to give 2- {[5-methoxy-3- (7L ^T-pyrrolo [2, 3- b] pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-yl} ethanone of formula (IV).

Example 4

Compound of Formula I wherein R ¹ is -CH ₂ CF ₃ , R ² is -OMe, R ³ is -CN,

is bound at the 3-position of the indole ring and the R ² group is bound at the 5-position of the indole ring of formula VII:

is prepared according to the procedure illustrated in the following scheme:

(i) reacting a compound of formula (18) and (19) in the presence of potassium carbonate and sodium iodide to give a compound of formula (20);

(ii) reacting a compound of formula (20) with thiourea in the presence of sodium ethoxide in ethanol to give a compound of formula

21) (iii) cyclizing the compound of formula (21) by heating in toluene at boiling point to thereby afford the title compound. to obtain a compound of formula (22);

(iv) reacting the compound of formula (22) with phosphorus oxybromide to give 4-bromo-7b-pyrrolo [2,3b] pyrimidine of formula (23);

(v) reacting a compound of formula (23) with 4-toluenesulfonyl chloride in the -OMe group, R ³ is the presence of tetrabutylammonium sulfar in aqueous sodium hydroxide solution in toluene to give a compound of formula (24);

(vi) reacting the compound of formula (24) with lithium diisopropylamide in tetrahydrofuran, at -78 ° C, then reacting the obtained anion with iodine to give the compound of formula (25);

(vii) condensing a compound of formula (25) with 1-tert-butyloxycarbonyl-5-methoxyindole-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate, in aqueous dimethylformamide solution at boiling point and removing tert-butyloxycarbonyl protecting group to give 4-bromo-6 - [(5-methoxyindol) -3-yl] -7- (toluene-4-sulfonyl) -4-pyrrolo [2,3-b] pyrimidine (26);

(viii) reacting a compound of formula (26) with sodium hydride in tetrahydrofuran and then reacting with 2-trifluoroiodoethane to give a compound of formula (27);

(ix) reacting a compound of formula (27) with zinc cyanide in the presence of paradium in N, N-dimethylaniline at 140 ° C to give a compound of formula (28); and (x) reacting a compound of formula (28) with an aqueous methanolic potassium hydroxide solution at boiling to give a compound of formula VII.

Example 5

A compound of formula I, wherein R ¹ is -CH _3, R ² is 9 Me Me, CH ₂ ^OH?

is bound at the position of the incicl group Ph is bound at the position o of the indole ring of formula IX:

prepared according to the procedure illustrated in the following scheme:

of formula (26) with a hydride

(i) reaction with sodium in tetrahydrofuran and then reaction with methyl iodide to give a compound of formula (29);

i) reacting the compound of formula (29) with palladium in methanol at boiling, with an carbon monoxide to give a carbon monoxide compound in the presence of a compound;

(30);

(iii) reacting the compound of formula (30) with aqueous methanolic potassium hydroxide solution at boiling to give a compound of formula (31); and (iv) coupling a compound of formula (31) with 2-hydroxy-1,1-dimethylethylamine in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, thereby to give a compound of formula (IX).

ABOUT

OH

Fc is -OMe, R ³ is the group X ² = _CH '' NHMe 'group

R '

is bound at the 3-position of the indole ring and the R group is bound at the 5-position of the indole ring of formula V:

CONHMe _MeO

N '(V) was prepared according to the procedure illustrated in the following scheme:

(i) reacting the compound of formula (26) with methyl acrylate in the presence of palladium acetate, triphenylphosphine and triethylamine at a temperature of about 11 ° C to give the compound of formula (32);

(ii) hydrogenating the compound of formula (32) in the presence of palladium n carbon to give a compound of formula (33);

(iii) reacting the compound of formula (33) with aqueous methanolic potassium hydroxide at boiling to give the acid of formula (34);

(iv) condensing the compound of formula (34) with methylmorphine. in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give a compound of formula (35); and (v) alkylating the compound of formula (35) with 4- (2-chloroacetyl) morphelin in the presence of sodium hydride, in dimethylformamide, to give the compound of formula (V).

Annex 7

-ch ₂ ^ n

A compound of formula I wherein R ¹ is a group

R ² is a group -Obe, R ³ is a group

//

N, groups;

is bound at the 3-position of the indole ring and the group

R 'is attached at the 5-position of the indole ring of formula VI:

(i

(25)

HO 'OH

'36)

KOH 5N, MeOH

DMF, reflux aq. NajCO ₃ PdtPPhJ

(VI)

Condensation of a compound of formula (26i) with pynoin-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate, in fragrant dimethylformamide under ara to afford 4- (pyridin-3-yl)

5-Methoxy-indol-3-yl] -7- (toluene-4-sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine of formula

(Ii) reacting a compound of formula (36) with an aqueous methanolic potassium hydroxide solution at boiling to give a compound of formula

37, Example 9); and (iii) alkylating the compound of formula (37, Example 9) with 4- (2-chloroacetyl) morpholine in the presence of aqueous sodium in dimethylformamide to give 2- [5-methoxy-3- (4- (pyridin-3-yl)) N-pyrrolo [2,1-b] pyrimidin-6-yl-indol-1-yl (-1-morpholin-4-yl-ethanol) of formula (VI).

Example 8 A compound of formula I wherein

-m -CH ₂ CH ₃ , P. ²

Group -Obe, is a group

group

r.a is bound is bound at position 3 of the indole ring at position 5 of the indole ring of formula VII and

(i) alkylating the compound of formula (26) with ethyl iodide in the presence of sodium hydride, in dimethylformamide to give the compound of formula (38);

(ir) reacting a compound of formula (38) with morpholine in a microwave at about 200 ° C in α, α, α-trifluorotoluene to give a compound of formula (39); and (iii) reacting the compound of formula (39) with aqueous methanolic potassium hydroxide solution at boiling to give the compound of formula (VIII).

Example 1 and 9

6- (5-Methoxy-1H-indol-3-yl) -4-pyrrolidin-3-yl-7H-pyrrole (2,3-a '] pyrimidine

A solution of 260 mg of 6-iodo-4-n-methylphenylpsulfonyp-4-pyridin-1-yl-7H-pyrrolo [2,3-c] pyrimidine (Reference Example 1) and 178 mg of 1-tert-butyloxycarbonyl-5-methoxy-1H of indole-3-boronic acid (Reference Example 12) in 10 ml of dimethylformamide, is treated with 13 mg of palladium tetrakistriphenylphosphine and 8 mg of sodium bicarbonate. The reaction mixture was stirred at reflux for 2 hours and allowed to cool to room temperature. The solvents were evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate and methanol (95: 5), v / v) to give 20 mg of 6- (5-methoxy-1H-indol-3-yl) -4-pyridin-3-yl N-pyrrolo [2,3-a] pyrimidine as an amorphous solid.

MS: 342 [MH] +, LC-MS (Method A) R _t = 2.57 minutes.

Example 10

-Methoxy-6- (5-methoxy-1-methyl-1H-indol-3-yl) -7H-pyrrolo [2,3-d] pyrimidine

A solution of 361 mg of 4-methoxy-6- (5-methoxy-1-methyl-1H-indol-3-yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine ( Reference Example 4) in 20 ml of methanol is treated with 1.53 g of potassium hydroxide. The reaction mixture was stirred at room temperature for 16 hours and heated at reflux for 1 hour. The solution was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated with diethyl ether to give 155 mg of 4-methoxy-6- (5-methoxy-1-methyl-1H-indol-3-yl) -7H-pyrrolo) 2,3-d] pyrimidine as a solid.

Mp = 184 ³ C. MS: 309 [MH] Item

Example 11

4-Methoxy-6- (5-methoxy-lH-indol-3-yl) -7 H -pyrrolo [2,3-d] pyrimidine

MeO

A solution of 448 mg of 4-methoxy-6- (5-methoxy-1H-indol-3-yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example) 5) in 15 ml of methanol is treated with 1.96 g of potassium hydroxide. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The rest

clean by flash column chromatography on silica gel over e 1 u c i e mixture ethyl acetate and cyclohexane (60:20, v / v) ka the 32 mg 4-methoxy-6- (5-methoxy-IM-indole-3-yl) -7 H-pyrrolo [2,3- -d] pyr imidínu in the form of a yellow solid, m.p. h e w as 2 6u ^c C. MS: 2 9 5 [MH] ’.

Example 12

- (5-Methoxy-1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl-1H-pyrrolo [2,3-d] pyrimidine

Solution S3 mg of 4- (5-methoxy-1-] (4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) - 7 - [(4-methylphenyl) sulfonyl] -7 H -pyrrolo [2,3- d] pyrimidine (Reference Example 9) in 5 ml of methanol is treated with 249 mg of potassium hydroxide. The reaction mixture was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by HPLC to give 9 mg of 4- (5-methoxy-1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-a '] pyrimidine as a gum.

MS: 424 [MH] +. LC-MS (Method B) R _t = 3.15 min.

Reference example 1

6-Iodo-7 - [(1-methylphenyl) sulfonyl] -4-pyridin-3-yl-7 H -pyrrolo [2,31]

d] pyrimidine

To a solution of 1 g of 7 - [(4-methylphenyl) sulfonyl] -4-pyridin-3-yl-7d-pyrrolo [2,3-d] pyrimidine (Reference Example 2) in 20 ml of tetrahydrofuran at -78 ° C. 2 ml of a 1.6 M solution of butyllithium in hexane was added dropwise under an inert atmosphere. The solution was stirred at this temperature for 1.5 hours and 796 mg of iodine was added. The reaction mixture was stirred for an additional hour at -78 ° C and allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase is separated, then dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with a gradient of ethyl acetate: cyclohexane (50:50 to 100, v / v) to give the title compound as an amorphous solid (260 mg).

MS: 477 [MH] &lt; ^{+ &gt};. LCMS (Method B) R _t = 3.26 min.

Reference example 2

- [(4-Methylphenyl) sulfonyl] -4-methyl-3-yl-7'-methyl-2,3-d: pyrimidine

A solution of 4 g of 4-chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 3) and 2.1 g of diethyl 3-pyridylborane in 150 ml of tetrahydrofuran is treated with 0.65 g of palladium tetrakistriphenylphosphine and 3.59 g of potassium carbonate. The solution was stirred at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified twice by column flash chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (90/1, v / v) and a mixture of ethyl acetate and cyclohexane (50:50, v / v) to give 2.5 g of the title compound as amorphous, solid.

MS: 351 [MH] +. LCMS (Method B1 R _T = 3.05 min.

Reference example 3

- Chloro-7- [1,4-methylphenyl) sulfonyl] - 1H-pyrrolo [2,3-d] pyrimidine

A solution of 20 g of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (ref .: Ger ster, John F .; Hinshaw, Barbara C.; Robins, Roland F.; Rounseno Leroy B. Probes of elecrrophylic substitution in ohe) pyrrolo [2,3-d] pyrimidine ring, J. Heterocycl. Chem. (1969;, (2;, 207-213)

28.6 g of para-toluenesulfonyl chloride in 1 toluene were treated with a solution of 50 g of sodium hydroxide in 800 ml of water and 462 mg of tetrabutyl ammonium sulfate. The solution was stirred vigorously for 2 hours at room temperature and partitioned between ethyl acetate and brine. The Crganic phase is separated, then dried over magnesium sulphate and then evaporated under reduced pressure. The residue is purified by fiash column chromatography on silica gel eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v / v) to give 2.5 g of the title compound as a solid, m.p. Melting point = 143 DEG.

LCMS (Method Bi R _T = 2.78 min.

Reference example 4

4-Methoxy-6- (5-methoxy-1-methyl-1H-indol-3-yl) -7- ((4-methylphenyl) sulfonyl) -7H-pyrrolo [2,3-d] pyrimidine

To a solution of 448 mg of 4-methoxy-6- (5-methoxy-1H-indol-3-yl) -7-f (4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 5) 156 mg of methyl hydride are added in 20 ml of dimethylformamide under an inert atmosphere at 44 ng (60% dispersion in mineral oil) of sodium hydride. The solution was stirred at room temperature for 1 hour and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (30/70, v / v) to give 260 mg of the title compound as an amorphous solid.

MS: 464 [MH] ⁺ . LC-MS (Method B) R _t = 4.39 min.

Reference example 5

4-Methoxy-6- (5-methoxy-1H-indol-3-yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-c] pyrimidine

A solution of 1.98 g of 6-iodo-4-methoxy-7 - ((4-methylphenyl) sulfonyl] -7H-pyrrole-2,3-d] pyrimidine (Reference Example 6) and 1.26 g of 1-tert-butylcarboxy- Of 5-methoxy-1H-indole-3-boronic acid (Reference Example 12) was sequentially treated with 10 ml of saturated aqueous sodium bicarbonate solution and 165 mg of palladium tetrakistriphenylphosphine, and the reaction mixture was stirred at reflux for 3 hours and the solvent was evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water, the organic phase is separated, dried over magnesium sulphate and then evaporated under reduced pressure, and the residue is purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (50/50 by volume). to give 1.8 g of the title compound as a gray solid, m.p. 131 ° C.

MS: 450 [MH] &lt; ^{+ &} gt ; ^.

Reference example 6

6-Iodo-4-methoxy-7 - [(4-methylphenyl) sulfonyl] -7 H -pyrrolo [2,3- d] pyrrolidine

To a solution of 2.23 g of 4-methoxy-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 7) in 35 ml of theorohydrofuran at -78 ° C in 5 ml of a 1.6 M solution of butyllithium in hexane was added dropwise to the inert atmosphere. The solution was stirred for 1 hour at -7 ° C and 2.05 g of iodine was added. The reaction mixture was stirred for an additional hour at -70 ° C, allowed to warm to room temperature, and partitioned between ethyl acetate and water solution. The phase is separated, then dried over magnesium sulphate. and evaporated under reduced pressure to give 2.64 g of the title compound as an amorphous solid.

MS: 430 [. LC-MS (Method B) R _t = 4.15 min.

Reference example 7

4-Methoxy-7- ((4-methylphenyl) sulfonyl) 77-oyrolo [2,1-d] pyrimidine

A solution of 1.2 g of 4-methoxy-7d-pyrrolo [2,3-d] pyrimidine (Reference Example 6) and 1.77 g of para-toluenesulfonyl chloride in 60 ml of toluene is treated with a solution of 3.2 g of sodium hydroxide in 30 ml. of water and 27 mg of tetrabutylammonium sulfate. The solution was stirred vigorously for 4 hours at room temperature and partitioned between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate. and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate: cyclohexane (50:50 to 80:20, v / v) to give 2.23 g of the title compound as an amorphous solid.

MS: 304 [MH] R LC-MS (Method B) R _t = 3.83 minutes.

Reference example 8

4-methoxy-7H-pyrrolo] 2,3-d] pyrimidine

To a solution of sodium methoxide prepared by the sequential addition of 2 g of sodium to 100 ml of methanol under an inert atmosphere is added 3.5 g of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (reference: Gerster, John F .; Hinshaw, Barbara C .; Robins, Rclanc K .; Tovnsend, Lercy 3.

Study of electrophylic substitution in pyrrolo [2,3-ch pyrtmidine ring. J. Heterocycl. Chem. (1969), (2), 207-13. The solution was stirred at 65 ° C for hours and partitioned between ethyl acetate and brine. The organic phase is separated, dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to give 1.2 g of the title compound as an amorphous solid.

MS: 150 [MH] &lt; ^{+ &gt};. LC-MS (Method B) R _t = 2.39 min.

Reference example 9

4- (5-Methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) -7- [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine

To a solution of 270 mg of 4- (5-methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1H-indol-3-yl) -7- ( (4-Methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine (Reference Example 10) in 10 ml of DMF was added in an inert atmosphere 10 mg of sodium hydride as a 60% dispersion in mineral oil and 0.025 ml of methyl iodide. The solution was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate, the organic phase separated, then dried over magnesium sulphate and evaporated under reduced pressure. Silica gel eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) gave 93 mg of the title compound as an amorphous solid.

MS: 732 [MH] &lt; ^{+ &gt};. LC-MS (Method B) R _t = 4.68 min.

Reference example 10

4- (5-Methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1H-indol-3-yl) -7-) (4-methylphenyl) sulfonyl) - 1 H -pyrrolo [2,6- d] pyrimidine

A solution of 1.72 g of 4-methyl-6-methyl-7- (4-methyl-6-methyl) -3-methyl-7'-pyrrole-2,3-d] pyrimidine (Reference Example 11) and 1.26 g

tert-Butylaarboxy-1-methoxy-1'-indole-3-boronic acid (Reference Example 12) in 36.5 ml of dimethylformamide is successively treated with 9 ml of saturated aqueous sodium hydrogen carbonate solution and 0.3 g of palladium tetrakistriphenylphosphine. The reaction mixture was stirred at reflux for 1 hour and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (3C: 70, v / v) to give 270 mg of the title compound as a gum.

MS: 718 [MH] &lt; ^{+ &gt};. LC-MS (Method B) R _t = 4.44 min.

Reference example 11

4-Chloro-6-iodo-7 - [(i-methylphenyl) sulfonyl) -7b-yl py _{ro o} \ 2, 3-d) pyrimidine

To a solution of 5.4 g of 4-chloro-7- (1-non-phenylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 3) in 96 ml of tetrahydrefuran at -78 ° C under inert atmosphere ± 2.1 ml of a 1.6 M solution of butyllithium in hexane is added dropwise. The solution was stirred at -78 ° C for 3 hours, then 8.9 g of iodine was added. The reaction mixture was stirred at -78 ° C for 2 hours and allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium cyanate, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash-column chromatography on silica gel eluting with a patient mixture of ethyl acetate and cyclohexane (50:50 to 100, v / v) to give 1.5 g of the title compound as an amorphous solid.

MS: 434 [MH] &lt; ^{+ &gt};. LC-MS (Method B) R _t = 4.25 min.

Reference example 12

1-tert-Butylcarboxyl-5-methoxy-1H-indole-3-boronic acid

A stirred solution of 50 g of 3-bromo-5-methoxyindole-1-carboxylic acid tert -butyl ester (Reference Example 13) in 800 mL of tetrahydrofuran under nitrogen was treated with 49.5 mL of tributyl borate, then cooled to -100 ° C and it is then treated with 94 ml of a 2.5 M solution of n-butyllithium in hexane, maintaining the temperature at -90 ° C. Once the addition is complete, the mixture is allowed to warm slowly to room temperature over 1 hour and quenched by the addition of 10 g of ice. The organic solvents were evaporated under reduced pressure and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The organic layer was dried over magnesium sulfate and then evaporated to give 28 g of the title compound as a cream colored solid.

MS: 314 (MH &lt; ^{+ &gt};). LC-MS (Method C) R _t = 4.07 min.

Reference example 13

3-Bromo-5-methoxyindole-1-xarboxylic acid tert-butyl ester

A solution of 10 g of 5-methoxyindole in 150 ml of dry dimethylformamide at room temperature is treated with 4 ml of bromine (dropwise), maintaining the temperature below 30 ° C. The mixture is immediately reacted with 28 ml of triethylamine and 0.5 g of 4-dimethylaminopyridine and then with a solution of 18 g of di-tert-butyl dicarbonate with 80 ml of dry dimethylformamide and stirred for a further 4 hours. The reaction mixture was evaporated and the residue was partitioned between 250 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic phases are washed with 100 ml of water, then 100 ml of brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (19/1 by volume) to give 23.4 g of the title compound as a colorless solid of melting point 111-112 ^C. C.

Procedure of in vitro SYK tests

1. Engaging activity: compounds with respect to Syk kinases Catalytic domains; Syk kinase (A340-N635) is expanded. is like a fusion protein of t  yeast and purified and of homogeneity. If- The activity of Kínase is determined in 50 mM Tris-HCl at pH 7, com 50 mM NaCl, 5 mM M 5Cl 2, 5 mM MnCl 2, µm adenosine triphosphate a

μΜ Synthetic peptide Biotin- (β-Alanine) 3-DEEDYEIPP-NH ₂ The enzyme reaction is terminated by adding a buffer containing 0.4M KP

133 mM EDTA, pH 7.0, containing the streptavidin-XL665 conjugate and monoclonaline conjugate = j phosphospecific antibody with europium- meryptatom (Eu-K). parts of both fluorotors, XL-665 and Eu-K are shown G. Mathis et al., Anticancer Research, 1957, 17, pages 3011- -3014. Specific long-term signal XL-665,

produced only when synthetic peptide phosph is Syylated, is measured on a LJL microtiter plate reader

Biosystems Analyst AD. Inhibition of Syk Activity by Compounds of the Invention of the present invention is expressed as percent inhibition control artivity you) collected in the absence of tested valuables. Especially preferred compounds of the present invention in- hibi Syk activity t IC 50 in the range of 100 μπιοί to 100 nmol. A particularly preferred compound: The flax of the present invention inhibits Syk activity at ICm: v ranging from 1 pmol to 10 nmol. 2. Antigen induced decranulation of basophilic leukemia cells in rat (R3L)

2.1 Cell culture, no RBL-2H3 cell bleeding and assay run Bu n x in RBL -1H 3 with u store in flasks? 75 at 37 ° C; and 5% CCp, and passage L every 3 to 4 days. Cells are isolated, flask was washed with 5 ml of trypsin η-EDTA, add 5 ml of trypsin to each

flasks and incubate for 2 minutes at room temperature. Cells are transferred to a tube of 14 ml medium, centrifuged at HOC rpm at room temperature for 5 minutes, and resuspended at 2 x 10 ³ / ml. Cells are sensitized by adding 1 μΐ DNP specific IgE for every 10 ml of cells. Add 200 μΐ cells to each well of a 96 well flat bottom microtiter plate (40,000 cells / well) and incubate overnight at 37 ° C and 5% CO ₂ . The next day compounds were prepared in 100% dimethylsulfoxide at 10 mM. Each compound is then diluted 1: 100 with assay buffer and then further diluted with 1% DMSC assay buffer to give a final concentration of 0.03 to 30 μΜ. Add SO μΐ of assay buffer to each well, then. 10 μΐ of diluted compound. Incubation is performed for 5 minutes. Add 10 μΐ DNP-HSA (100 ng / ml) to each well and incubate for 30 minutes at 307 ° C (no CO ₂ ). As one control, 1% dimethylsulfoxide (without compound) alone is added to a series of wells to determine complete release. As a further control, buffer is added instead of DNP-HSA to another series of wells to determine the background of the assay. After 30 minutes of incubation, the supernatants are transferred to a 96 well microtiter plate. Add 50 μΐ of the supernatant to each well of the assay plate. Add 100 μ subst of substrate solution to each well and incubate for 90 minutes at 37 ° C. 50 μΐ of a 0.4 M glycine solution is added to terminate the reaction and the plate is read at 405 nm on a Molecular Devices SpectraMax 250 microplate reader.

2.2. Calculation of results (i) Calculate ± SD of each series of wells in triplicate.

(ii) Maximum response was provided by positive control wells containing antigen (100 ng / ml), not containing compound.

(iii) Minimum response was provided by control wells containing buffer (no antigen) and no compound.

(iv) Using these data as the maximum value of '1001' and the minimum (C *), respectively, the experimental data were calculated as a percentage relative to the maximum response (indicated as 0% control).

(v) Using Prism GraphPad software and non-linear; regresue; analysis of the smallest squares, a dose-response curve was plotted and the IC53 value was calculated.

The compounds of the present invention inhibit antigens induced by degranulation of basophilic leukemia cells in rats (RBL; at ZC =; in the range of 100 pmol to 1 pmol).

Claims (23)

A compound of formula I (I) wherein R ¹ is hydrogen, -C (= O)-) ⁴ Υ ² , -C (O) -OR ⁵ , -SO2-NY'Y ² , -SO2-R ⁷ , -C (= O) R ⁷ , or R ^{1 is} alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more groups selected from: the group consisting of aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO or a five, six or seven-membered cyclic acetal derivative of -CHO, -C (= 0) ^ -NY ² Y, -C (= C ^-OR group -NY ^ ^2, -N (R ^e) -C (= 0) R ^7, -N (R ⁶ -C (= 0} -NY ³ Y ^4, N (R ⁶⁾ -SO 2 R ^7, -N (R ⁶⁾ -SO 2 NY ³ Y ^4, -OR ', -C (O) ^-R7, hydroxy, alkoxy, and carboxyl ová group; R ² is one or more selected from the group consisting of hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halogen, hydroxy, heteroaryl, heterocycloalkyl, nitro, R 2 ⁴ , -C; = O) -ΝΥ ⁷ Υ ² , -C (= O) -OR ⁵ , -NY * Y ² , H (R ⁶⁾ -C (= 0) R ^7, -N (R ^e) -C (= 0) - \ "Y ³ Y ^4, -N R ⁶⁾ C (--- O, -CR ^7, -N (R ⁶⁾ -SO 2 R ^7, -N (R ⁶⁾ -SO 2 NY ³ Y O group ^and -SO 2 NY ¹ Y ^'s and the group -ZR ^4; R 6 is hydrogen, cyano, halogen, hydroxyl, nitro, R ' ⁵ , NY'Y ^Z , -ZR ", -C (= O) -OR ³ , -O (= 0) - R ', -C (= O) -NY ¹ Y', -N (R ⁸ ) -C (= O) -R ', -N (R ⁸ ) -C (= O) -HY'YŔ -N R d) -C (= C) -CR ⁵ group, -SO 2 NY ³ Y ⁴ a_ebo -N (R ^fc) -SO 2 R ', or R ' ⁵ is an aryl, heteroaryl, alkenyl or alkynyl group, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cyano, atom. halogen, hydroxyl, heteroaryl, heterocycloalkyl, nitro, -C (= O) -NY-Y ³ , -C (= O) -OR ³ , -N ' ³ Y ² , -N (R ^C) ) = 0) -PC group -n (R ^b ) -c (= o; - YY, -N (R) -C (= O) -OR ', -NR ^(c ) -SO 2 -R, -N (R ⁶ ) -SO ₂ -NY ³ Y ⁴ , -SO ₂ -NY ¹ Y ³ or -ZR '; R 10 is an allyl, cycloalkyl or cycloalkylalkyl group, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cyclcalkyl, cyano, halogen, heteroaryl, heterocycloalkyl, hydroxyl, a -CHO group or a five-membered, six-membered or seven-membered acetal derivative of such a -CHO group, -C (= O) -HY ³ group, -C (= O) -OR ⁵ group, -NY ¹ Y ² group, -N ( F (-C) = O) -R ', -N (R ° -C 1 = O) -NY ³ Yy -N (R ⁶ ) -SO 2 -R', -N (R ^e ) -SCp -NY'Y ⁴ , -OR ^7, and C (= O) -FO; R ⁴ may also contain a group selected from the group consisting of oxygen, S (G) r, -NR ^C ; R ⁵ is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R c is hydrogen or lower alkyl; R ^; is alkyl, aryl, aryialkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R 7 is a hydrogen atom or a lower alkyl group; Y and Y ² are each independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted with one or more of aryl, halogen, heteroaryl, hydroxyl, -C (= O) NY ³ Y ⁴ , -C (= O) -OR ⁵ , -NY ³ Y ⁴ , -N (R ⁶ ) -C (= O) -R ⁷ , -N ( R ⁶ ) -C (= O) -NY ³ Y ⁴ , -N (R ⁶ ) -SO 2 -R ⁷ , -N (R ⁶ ) -SO 2 -NY ³ Y ^4, and -OR ⁷ ; or the group -NY ³ Y ² may form a cyclic amine; Y ³ and Y ⁴ are, independently of one another, a hydrogen atom, an alkenyl group, an alkyl group, an aryl group, an aryialkyl group, a cycloalkyl group, a heteroaryl group or a heteroarylalkyl group; or the group -NY ³ Y ⁴ may form a cyclic amine; Z is O or S (O) _n ; n is zero or an integer of 1 or 2; or An N-oxide, prodrug, acid bioisoster, pharmaceutically acceptable salt or solvate thereof; or an N-oxide, prodrug, or acidic bioisoster of such a salt or solvate. A compound according to claim 1, wherein R 'is hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted with halogen, C 1-4 alkyl substituted with hydroxyl, C 1-4 alkyl substituted -N (R °) C (= O) -R, C 1-4 alkyl substituted by -C (= O) -NY'Y ² , or hydroxyl substituted cycloalkylalkyl group. A compound according to claim 1, wherein R ¹ is an atom. of -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , or / -CH - C (= O) -N \ - Q. The compound of claim 1, wherein R ^x is hydrogen. A compound according to any one of claims 1 to 4, wherein R ² is a carboxyl group or an acidic bioisoster, a hydroxyl group, an alkyl group substituted with a carboxyl group, a heteroaryl group or is a Po group -OR ⁴ wherein R is an alkyl group with a -OR group. '', wherein R ⁴ is alkyl with to buy or cycloalkylalkyl substituted by one or more hydroxy radicals ·, -OR ^4, coe ^R4 is alkyl substituted by one or more alkoxyskuomami, -CR ^4, wherein R ⁴ is an alkyl group or a cycloalkyl group substituted with one or more carboxyl groups, -OR ⁴ , wherein R ⁴ is a cycloalkyl group substituted with -C (= O) -NYV or -C (= C; -R) where R j e alkyl group or is a group -C (= O) -NY ^: Y ² or stupina -h R p -C (= O) -R ⁷ . 6. A compound according to any of of claims 1 to 4, wherein R ^z is -OCH ₃ or -CONHC (CH 3) ₂ ch ₂ oh. i. Compound of any of them of claims 1 to 4, wherein R ² is -OCH ₃ group. A compound according to any one of claims 1 to 7, wherein R ³ is a hydrogen atom, a cyano group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an alkyl group, an alkyl group substituted with one or more halogen atoms, an alkyl group substituted with -C (= 0) -NYT, alkyl substituted with -OR ³ or R ³ is a group -ZR ^4, -C (= O) -OR ^5, -C (= O) -NY ^{1 Y} or a group -nyV. A compound according to any one of claims 1 to 7, wherein R ³ is hydrogen, cyano, pyridyl, trifluoromethyl, -CH 2 -CH 2 -C (= O) NHCH 3, -OCF 2 H, -C (= O) -NH-C (CH 3) ₂ -CH ₂ OH or a group (1) -N O. A compound of any one of claims 1 to 7, wherein R ³ is -OCH 3. A compound according to any one of claims 1 to 10, wherein R ² is bonded at the 5-position of the indium ring. A compound according to any one of claims 1 to 11, wherein the group is attached at the 3-position of the indium ring. The compound of claim 1 which is OMe or an N-oxide, prodrug, pharmaceutically acceptable salt or salt thereof; or an N-oxide or prodrug of this salt or solvate. The compound of claim 1 which is or an N-ox: d, prodrug, pharmaceutically acceptable salt or solvate thereof; or an N-oxide or prodrug of this salt or solvate. 15. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 together with one or more pharmaceutically acceptable carriers or excipients. A method of treating a patient suffering from or susceptible to a disease that can be alleviated by administering an inhibitor of Syk catalytic activity, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of a composition according to claim 15. 17. A method of treating an inflammatory disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of the composition of claim 15. A method of treating a patient suffering from or susceptible to a disease which may be alleviated by administering an inhibitor of FAK catalytic activity, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of a composition according to claim 15. A method of treating a patient suffering from or susceptible to a disease that may be alleviated by administering an inhibitor of catalytic KDR activity, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of a composition according to claim 15. A method of treating a patient suffering from or susceptible to a disease that can be alleviated by administering an inhibitor of catalytic activity of Aurora2, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. The method of claim 17, wherein the inflammatory disease is asthma, inflammatory aermatosis, allergic rhinitis, allergic conjunctivitis or inflammation of the joints. The method of claim 17, wherein the inflammatory disease is asthma, psoriasis, herpetiform dermatitis, eczema, necrosis vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis. arthritis or osteoarthritis. 24. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of the composition of claim 15. 25. The method of claim 21, wherein the cancer being treated is colorectal cancer, prostate cancer, breast cancer, thyroid cancer, skin cancer, colon cancer, or lung cancer.