RS51698B - Pyrrolopyrimidines as Protein Kinase Inhibitors - Google Patents

Abstract

The compound of the formula R1 represents hydrogen, -C (= O) -NY1Y2, -C (= O) -OR5, -SO2-NY1Y2, -SO2-R7, -C (= O) R7, or R1 represents alkenyl, alkenyloxy, alkyl, alkynyl , aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each optionally substituted by one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO, -C (= O) -NY1Y2, -C (= O ) -OR5, -NY1Y2, -N (R6) -C (= O) -R7, -N (R6) -C (= O) -NY3Y4, -N (R6) -SO2-R7, -N (R6) -SO2-NY3Y4, -OR7, -C (= O) -R7, hydroxy, alkoxy and carboxy; R2 represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy , heteroaryl, heterocycloalkyl, nitro, R4, -C (= O) -NY1Y2, -C (= O) -OR5, -NY1Y2, -N (R6) -C (= O) -R7, N (R6) -C (= O) -NY3Y4, -N (R6) -C (= O) -OR7, -N (R6) -SO2-R7, -N (R6) -SO2-NY3Y4, -SO2-NY1Y2 and -ZR4; R3 represents H, cyano, halo, hydroxy, nitro, R4, NY1Y2, -ZR4, -C (= O) -OR5, C (= O) -R7, -C (= O) -NY1Y2, -N (R8) - C (= O) -R4, -N (R8) -C (= O) NY1Y2; -N (R8) -C (= O) -OR5, -SO2-NY3Y4 or -N (R8) -SO2-R7, or R3 represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted by one or more groups selected from aryl , cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C (= O) -NY1Y2, -C (= O) -OR5, -NY1Y2, -N (R6) -C (= O) -R7, -N (R6) -C (= O) -NY3Y4, -N (R6) -C (= O) -OR7, -N (R6) -SO2-R7, -N (R6) -SO2-NY3Y4, -SO2-NY1Y2 and -ZR4; R4 represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted by one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO, -C (= O) -NY1Y2, -C ( = O) -OR5, -NY1Y2, -N (R6) -C (= O) -R7, -N (R6) -C (= O) -NY3Y4, -N (R6) -SO2-R7, -N ( R6) -SO2-NY3Y4, -OR7 and -C (= O) -R7 wherein R4 is an optionally inserted group selected from O, S (O) n, and NR6R5 represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R6 represents hydrogen or lower alkyl; R7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R8 represents hydrogen or lower alkyl; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C (= O) - NY3Y4, -C (= O) -OR5, -NY3Y4, -N (R6) -C (= O) - R7, -N (R6) -C (= O) -NY3Y4, -N (R6) -SO2- R7, -N (R6) -SO2-NY3Y4 and -OR7; or the group - NY1Y2 may form a cyclic amine; Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or a -NY3Y4 group may form a cyclic amine; Z represents O or S (O) n; n is zero or number 1 or 2; or N-oxide, an acid bioisoster, a pharmaceutically acceptable salt or solvate of a given compound; or N-oxide, or an acidic bioisomer of a given salt or solvate, wherein the alkenyl is an aliphatic hydrocarbon group containing a carbon-carbon double bond and a straight or branched chain of 2 to 15 carbon atoms, wherein

Description

This invention relates to substituted pyrrolopyrimidines, their preparation, pharmaceutical preparations containing these compounds, and their pharmaceutical use in the treatment of disease states that can be regulated by inhibiting protein kinases.

Protein kinases participate in signaling events that control cell activation, growth, and differentiation in response to extracellular mediators and changes in the environment. In general, these kinases fall into several groups; those that predominantly phosphorylate serine and/or threonine residues and those that predominantly phosphorylate tyrosine residues [S. K. Hanks and T. Hunter, FASEB. J. r1995, 9, p. 576-596]. Serine/threonine kinases include e.g. C isoforms of protein kinase [A. C. Newton, J. Biol. Chem., 1995, 270, p. 28495-28498] and a group of cyclin-dependent kinases such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, p. 195-197]. Tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S. Ivvashita and M. Kobazashi, Cellular Signaling, 1992, 4, p. 123-132], and non-receptor cytosolic kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan et. al., Ann. Rev. Immunol., 1994, 12, p. 555-592].

Inappropriately high activity of protein kinases is involved in many diseases resulting from abnormal cellular function. This can occur either directly or indirectly, e.g. by canceling the appropriate control mechanisms for kinases, related e.g. for mutation, overexpression or inappropriate activation of enzymes; or by excessive or insufficient production of cytokines or growth factors that also participate in signal transduction to or from the kinases. In all these cases, selective inhibition of kinase activity can be expected to produce a beneficial effect.

Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is secreted by various hematopoietic cells and is an essential element in several antigen receptor-binding cascades in cell responses. Thus, Syk plays a central role in signaling the high-affinity IgE receptor, FceR1, in mastoid cells and in antigen receptor signaling in T and B lymphocytes. Signal transduction pathways in mastoid, T, and B cells share common features. The ligand-binding domain of the receptor omits (misses) its own tyrosine kinase activity. However, they interact with transduction subunits that have immunoreceptor tyrosine-based activation motifs (ITAMs) [M. Reth, Nature, 1989, 338, p. 383-384]. These motifs are present in both the 6 and y subunits of FceR1, in the ^-subunit of the T cell receptor (TCR), and in the IgGa and IgGS subunits of the B cell receptor (BCR).

[N. S. van Oers and A. Weiss, Seminars in Immunology, 1995, 7, p. 227-236]. After antigen binding and multimerization, ITAM residues are phosphorylated by protein tyrosine kinases of the Src family. Syk belongs to a unique class of tyrosine kinases that have two paired Src homolog 2 (SH2) domains and a C-terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs, and this SH2-mediated association of Syk with a single activated receptor stimulates Syk kinase activity and localizes Syk to the plasma membrane.

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

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

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in the integrin-mediated signal transduction pathway. FAK co-localizes with integrins at focal contact sites, and FAK activation and its tyrosine phosphorylation in many cell types have been shown to depend on the binding of integrins to their extracellular ligands. The results of several studies support the hypothesis that FAK inhibitors may be useful in the treatment of cancer. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and overexpression of the C-terminal domain of FAK blocks cell spreading 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 oligonucleotides lost their attachment and underwent apoptosis (Xu et al., Cell Growth Differ., 1996, 4, 413-418). There are reports of increased FAK expression in prostate, breast, thyroid, colon, and lung cancers. The level of FAK expression is directly related to tumors showing the most aggressive phenotype.

Angiogenesis, or the formation of new blood vessels by developing from existing vasculature, is central to embryonic development and organogenesis. Abnormally increased neovascularization is observed in rheumatoid arthritis, diabetic retinopathy and during tumor development vi-.">lkman, Nat. Med., 1995, 1, 27-31.). Angiogenesis is a complex multistep process involving the activation, migration, proliferation and survival of endothelial cells. Extensive studies in the field of tumor angiogenesis in the last two decades have identified a number of therapeutic targets including kinases, proteases and integrin, which has resulted in the discovery of many antiangiogenic agents, including KDR inhibitors, some of which are currently under clinical evaluation (Jekunen, et al., Cancer Treatment Rev., 1997, 23, 263-286).Angiogenesis inhibitors can be used as the main, adjunctive or even preventive in the occurrence or regrowth of malignancy.

Several proteins involved in chromosome segregation and spindle structure emergence have been identified in the yeast idrosophila. Degradation of these proteins leads to chromosome de-segregation and monopolar or degraded spindles. Among these kinases are Ipl1 and aurora kinases from S. cerevisiaeidrosophila, respectively, which are required for centrosome separation and chromosome segregation. Recently, a human homologue of yeast Ipl1 has been cloned and characterized in various laboratories. This kinase, called Aurora2, STK15 or BTAK, belongs to the serine/thronine family of kinases. Bischoff et al. have shown that Aurora2 is oncogenic and amplified in human colorectal cancer {EMBO J., 1998, 17, 3052-3065). It is also indicated in cancers involving epithelial tumors such as breast cancer.

This invention deals with substituted pyrrolipyrimidines of formula (I), which have the ability to inhibit one or more protein kinases, more specifically, FAK, KDR, Syk kinase or Aurora2, especially Syk kinase.

where

R<1>represents hydrogen, -C(=0)-NY1Y2 -C(=0)-OR5 -S02-NY1Y2 -S02-R<7>, - C(=0)R7 or R<1>can be alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each optionally substituted with one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl,

-CHO (or their 5-, 6- or 7-membered cyclic acetal derivative), -C(=0)-NY<1>Y<2>, -C(=0)-OR5 -NY<1>Y<2>, -N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NY<3>Y<4>, -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4>, -OR7, -C(=0)-R<7>, hydroxy, alkoxy and carboxy; R<2>represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkylenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R4 -C(=0)-NY<1>Y<2>, -C(=0)-OR<5>, -NY<1>Y<2>, -N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NY<3>Y<4>, -N(R<6>)-C(=0)-R<7>,-N(R<6>)-S02-R<7>,-N(R<6>)-S02-NY<3>Y<4>,-S02-NY<1>Y<2>, and -ZR<4>;R<3> represents H, cyano, halo, hydroxy, nitro, R<4>, -NY<1>Y<2>,-ZR<4>, -C(=0)-OR<5>, - C(=0)-R<7>, -C(=0)-NY<1>Y<2>, -N(R<8>)-C(=0)- R<4>, -N(R<đ>)-C(=0)-NY<1>Y<2>, -N(R<8>)-C(=0)-OR<5>, -SO2-NY<3>Y<4>or -N(R<8>)- SO2-R<7>, or R<3>represents aryl, heteroaryl, alkenyl, or alkynyl, each optionally substituted with one or more groups selected from aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C(=0)-NY<1>Y<2>, -C(=0)-OR<5>, -N<Y1>Y<2>, -N(R6)-C(=0)-R7 -N(R<6>)-C(=0)-NY<3>Y<4>, -N(R<6>)-C(=0)-OR<7>, - N(R<6>)-S02-R<7>, -N(R<6>)-S02-NY<3>Y<4>, -S02-NY<1>Y<2>or -ZR<4>;

R<4>represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted with one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO (or their 5-, 6- or 7-membered cyclic acetal derivative), - C(=0)-NY<1>Y<2>, -C(=0)-OR<5>, -NY<1>Y<2>, -N(R6)-C(= 0)-R7, -N(R<6>)-C(=0)-NY<3>Y<4>, - N(R<6>)-S02-R<7>, -N(R<6>)-S02-NY3Y<4>, -OR<7> or -C(=0)-R<7>; R<4> can also be with an optionally inserted group selected from O, S(0)n, NR<6>;

R<5> represents hydrogen, alkyl, allenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,

R<6> represents hydrogen or lower alkyl;

R<7> represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R8 represents hydrogen or lower alkyl;

Y<1> and Y<2> are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted with one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C(=0)-NY<3>Y<4>, -C(=0)-OR<5>, -NY3Y4 -N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NY3Y4 -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4> and -OR<7>; or the -NY1Y<2> group may be a cyclic amine;

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

Z represents O or S(O)n;

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 (eg, hydrates) of such compounds and their N-oxides and their prodrugs, and their acidic bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients.

In this specification, the term "compound of the present invention", and equivalent terms, are meant to include compounds of general formula (I) as described hereinabove, which term also includes prodrugs, pharmaceutically acceptable salts, solvates, e.g. hydrate, where the context allows. Similarly, references to intermediates, whether or not they are themselves claimed, are meant to include salts and solvates thereof, where the context permits. For clarity, specific cases are cited in the text when the context permits, but these cases are purely illustrative and are not intended to exclude other cases where the context permits.

When used above, and throughout the description of the invention, the following terms, unless otherwise specified, are considered to have the following meanings:-

"Patient" includes humans and other mammals.

"Acid bioisoster" means a group having chemical and physical similarities that confer broadly similar biological characteristics to the carboxyl group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 "Bioisosterism In Drug Design"; Yun,

Hwahak Sekye, 1993, 33, p. 576-579 "Application Of Bioisosterism And Development Of Lead Compounds In Drug Design"; Granham, Theochem, 1995, 343, p. 105-109 "Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acidic bioisosteres include: -C(=0)-NHOH, -C(=0)-CH2OH, -C(=0)-CH2SH, -C(=0)-NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonyl carbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione. 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

"Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.

"Acylamino" is an acyl-NH- group where acyl is as defined herein.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched and may have 2 to about 12 carbon atoms in the chain; and more preferably 2 to 6 carbon atoms (eg 2 to 4 carbon atoms) in the chain. "Branched", as used herein and throughout, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight chain; here a straight alkenyl chain. "Lower alkenyl" means 2 to 4 carbon atoms in the chain, which may be straight or branched. Examples of alkenyl groups are ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and dekenyl.

"Alkenyloxy" is an alkenyl-O- group where alkenyl is as defined herein. Examples of alkenyloxy groups include allyloxy.

"Alkoxy" means one alkyl-O- group wherein the alkyl group is as defined herein. Examples of alcohol groups are difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

"Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein. Examples of oxycarbonyl groups are methoxy- and ethoxycarbonyl.

"Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having from about 1 to about 15 carbon atoms in the chain, optionally substituted with one or more halogen atoms. Special alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or as part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl, or lower alkylsulfonyl group, unless otherwise specified, means an aliphatic hydrocarbon group which may be straight or branched chain having from 1 to about 4 carbon atoms in the chain. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl.

"Alkylene" means an aliphatic bivalent radical derived from a straight or branched alkyl group, wherein the alkyl group is as defined herein. Examples of alkylene radicals include methylene, ethylene, and trimethylene.

"Alkylenedioxy" means one -O-alkylene-O- group wherein alkylene is as defined above. Examples of alkylenedioxy groups include methylenedioxy and ethylenedioxy.

"Alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those wherein the alkyl group is C1-4 alkyl.

"Alkylsulfonyl" means an alkyl-SO2- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those wherein the alkyl group is C1-4 alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-SO 2 -NH-C(=O)- group wherein the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is C 1-6 alkyl.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Examples of alkylthio groups are methylthio, ethylthio, isopropylthio, and heptylthio.

"Alkynyl" means an aliphatic hydrocarbon group having a carbon-carbon triple bond and which hole may be straight or branched chain having about 2 to about 15 atoms

of carbon in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (eg 2 to 4 carbon atoms) in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl and n-pentynyl.

"Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl.

"Aroylamino" is an aroyl-NH- group where aroyl is as previously defined.

"Aryl" as a group or part of a group means: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic radical of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic radical in which one aryl and one cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Unless otherwise defined, aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes e.g. acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylaulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid bioisoster), cyano, halo, heteroaroyl, heteroaryl, heteroarylalkoxy, heteroaroylamino, heteroaroyloxy, hydroxy, nitro, trifluoromethyl, -NY<3>Y<4>, - CONY3Y<4>, -SO2NY3Y<4>, -NY<3->C(=0)alkyl, -NY<3>SO2alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy or -NY<3>Y<4>

"Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1-6 alkyl residue. Examples of arylalkyl groups are benzyl, 2-phenethyl and naphthalenemethyl.

"Arylalkyloxy" means an arylalkyl-O- group in which the arylalkyl groups are as previously described. Examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

"Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl groups are as previously described. One example of an arylalkyloxycarbonyl group is benzyloxycarbonyl.

"Arylalkylthio" means an arylalkyl-S- group wherein the arylalkyl group is as previously described. One example of an arylalkyloxycarbonyl group is benzylthio.

"Aryloxy" means an aryl-O- group wherein the aryl group is as previously described. Examples of aryloxy groups are phenoxy and naphthoxy, each optionally substituted.

"Aryloxycarbonyl" means an aryl-O-C(=O)- group wherein the aryl group is as previously described. Examples of aryloxycarbonyl groups are phenoxycarbonyl and naphthoxycarbonyl.

"Arylsulfinyl" means an aryl-SO- group wherein the aryl group is as previously described.

"Arylsulfonyl" means an aryl-SCV group wherein the aryl group is as previously described.

"Arylsulfonylcarbamoyl" means an aryl-SO 2 -NH-C(=O)- group wherein the aryl group is as previously described.

"Arylthio" means an aryl-S- group wherein the aryl group is as previously described. The primers of the arylthio group are phenylthio and naphthylthio.

"Azaheteroaryl" means an aromatic carboxylic acid residue of about 5 to about 5 ring members wherein one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, and nitrogen. Examples of azoheteroaryl groups are benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl, and tetrahydroindolizinyl.

"Cyclic amine" means a 3- to 8-membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may also contain further groups containing hetero atoms selected from O, S, SO2 or HV<5> (wherein Y<5> is hydrogen, alkyl, aryl, arylalkyl, -C(=0)-R<7>, -C(=0)-OR<7>, or -SO2R<7>); and (ii) may be fused with additional aryl (eg, phenyl), heteroaryl (eg, pyridyl), heterocycloalkyl, or alkyl rings to form a bicyclic or tricyclic ring

system. Examples of cyclic amines are pyrrolidine, piperginine, morpholine, piperazine, indoline, pyroindoline, tetrahydroquinoline and similar groups.

"Cycoalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings are cyclopentenyl, cyclohexenyl and cycloheptenyl.

"Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted with oxo. Examples of monocyclic cycloalkyl rings are C 3-6 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

"Cycloalkylalkyl" means a cycloalkyl-alkyl group wherein the cycloalkyl and alkyl moieties are as previously described. Examples of monocyclic cycloalkylalkyl groups are cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

"Halo" or "Halogen" means fluoro, chloro, bromo or iodo. Fluoro and chloro are preferred.

"Heteroaroyl" means a heteroaryl-C(=O)- group wherein the heteroaryl group is as described herein. An example of a heteroaroic group is pyridylcarbonyl.

"Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaroyl residue is as previously described.

"Heteroaryl" as a group or part of a group means: (i) one optionally substituted aromatic monocyclic or multicyclic residue of about 5 to about 10 ring members of which one or more members is/are element(s) other than carbon, e.g. nitrogen, oxygen or sulfur (examples of such groups are benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted with one or more substituents aryl groups as defined above, unless otherwise defined); (ii) one optional

a substituted partially saturated multicyclic heterocarbocyclic radical in which one heteroaryl and one cycloalkyl or cycloalkenyl group are fused to give a cyclic structure (examples of such groups are pyrindanyl groups, optionally substituted with one or more "aryl group substituents" as defined above, except where otherwise defined). Optional substituents are one or more "aryl substituents" as defined above, except where otherwise defined.

"Heteroarylalkyl" means a heteroarylalkyl group wherein the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C 1-4 alkyl residue. An example of a heteroarylalkyl group is pyridylmethyl.

"Heteroarylalkyloxy" means a heteroarylalkyl-O- group wherein the heteroarylalkyl group is as previously described. Examples of heteroallyloxy groups include optionally substituted pyridylmethoxy.

"Heteroaryloxy" means a heteroaryl-O- group wherein the heteroaryl group is as previously described. An example of a heteroaryloxy group is optionally substituted pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a heteroaryl-SO 2 -NH-C(=O)- group wherein the heteroaryl group is as previously described.

"Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members containing one or more heteroatoms or heteroatom-containing groups selected from 0, S and NY<5> and may be optionally substituted with oxo; (ii) a partially saturated multicyclic heterocarbocyclic residue in which one aryl (or heteroaryl) ring, each optionally substituted with one or more "aryl group substituents", and one heterocycloalkyl group are fused together to form a cyclic structure.

(Examples of such groups are chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

"Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.

"Prodrug" means a compound that can be converted in vivo by metabolism (eg, hydrolysis) to a compound of formula (I), including their N-oxides. NA rpimer an ester of a compound of formula (I) containing a hydroxy group can be converted by hydrolysis to the parent molecule in vivo. Alternatively, an ester of a compound of formula (I) containing a carboxyl group can be hydrolyzed in vivo to the parent molecule.

Suitable esters of compounds of formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, tumarates, maleates, methylene-ib/s-3-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates.

Suitable esters of compounds of formula (I) containing a carboxy group are e.g. those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, p. 379.

Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the -|J-Y residue are lactones formed by the loss of water between said carboxy and hydroxy groups. Examples of such lactones are caprolactones and butyrolactones.

One particularly useful class of esters of compounds of formula (I), which contain a hydroxy group, can be obtained from acidic residues selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, p. 2503-2507 and include substituted (aminomethyl)-benzoates, e.g. dialkylamino-methylbenzoates in which two alkyl groups can be united and/or separated by an oxygen atom or an optionally substituted nitrogen atom, e.g. with one alkylated nitrogen atom, more specifically (morpholino-methyl)benzoate, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

When the compound of the present invention contains a carboxyl group, or a bioisoster of sufficiently acidic character, base addition salts can be obtained and are simply suitable form for use; in practice, the use in the form of a salt by coil is of course the same as the use in the form of the free acid. Base kcjc; can be used to obtain base addition salts are preferably those which give, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the patient in pharmaceutical doses of the salt, so that the beneficial inhibitory effects inherent to the free base are not impaired by side effects attributable to the cations. Pharmaceutically acceptable salts, including those derived from salts of alkali and alkaline earth metals, within the scope of this invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine. lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammoniumhydroxide, and si.

Some of the compounds of this invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

Acidic addition salts are the more convenient form to use; in practice, use in the form of a salt per coil is of course the same as use in the form of a free base. Acids that can be used to obtain acid addition salts are preferably those which, when combined with free bases, give pharmaceutically acceptable salts, i.e., salts whose anions are not toxic to the patient in pharmaceutical doses of the salt, so that the beneficial inhibitory effect inherent in the free base is not impaired by the side effects attributed to the anions. Although pharmaceutically acceptable salts of the above base compounds are preferred, all acid addition salts are useful as sources of the free base even when the particular salt, per se, is only desired as an intermediate such as e.g. when the salt is formed only for the purpose of purification, identification, or when it is used as an intermediate in obtaining a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of this invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-beta-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates.

In addition to being useful per se as active compounds, the salts of the compounds of the present invention are useful for the purpose of purifying the compounds, e.g. using the difference in solubility between the salt and the parent compounds, side products and/or starting materials by techniques known to the person skilled in the art.

Starting from the above formula (I), the following groups are special and desirable:

R<1> may specifically represent:

(i) hydrogen

(ii) C 1-4 alkyl [e.g. -CH3 or -CH2CH3]; (iii) C 1-6 alkyl substituted with halo [e.g. -CH2CF3]; (iv) C 1-4 alkyl substituted with hydroxy [e.g. -CH2OH, -CH2CH2OH, or - (v) C1-6 alkyl substituted with -N(R<6>)C(=0)-R<7> [e.g. CH2CH2CH2NHC(=0)CH3 ]; (vi) C1-4 alkyl substituted : (vii) cycloalkyl substituted with hydrogen [eg. Compounds of formula (I) where R<1> represents hydrogen, -CH3, -CH2CH3, -CH2CF3 or

are particularly desirable. R<1> even more specifically represents hydrogen.

R<2> can specifically represent:

(i) carboxy or bioisosteric acids (ii) hydroxy; (iii) alkyl substituted with carboxy -CH2CH2CO2H]; (iv) heteroaryl (eg or pyridyl); (v) -OR<4> where R<4> is alkyl [eg -OCH3]; (vi) -OR<4> where R<4> is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups

[eg -OCH2CH2OH, -OCH2CH2CH2OH, -OCH(CH3)CH2OH]

-OCH2CH(OH)CH3, or -OCH2CH(OH)CH2OH]; (vii) -OR<4> where R<4> is alkyl substituted with one or more alkoxy groups [e.g. -OCH(CH3)CH2OCH3]; (viii) -OR<4>where R<4>is alkyl or cycloalkyl substituted with one or more carboxy groups [eg -OCH2CO2H , -OCH(CH3)CO2H or (ix) -OR<4>where R<4>is cycloalkyl substituted with (x) -C(=0)-R where R is alkyl [eg -C(=O)-CH3]; (xi) -C(=0)-NY<1>Y<2>[e.g. -CONH2 , -CONHCH3, -CONHCH(CH2OH) 2 , -CONHChhCr-feOH, -CONHC(CH3)2CH20H, -CONHChbChfeOCHs , -CONHCH2CH2CONH2, -C0NHCH2C(CH3)20H or

Compounds of formula (I) where R<2> represents -OCH3 or -CONHC(CH3)2CH2OH are particularly preferred. More specifically, R<2> represents -OCH3

R<3> may specifically represent:

(i) hydrogen; (ii) cyano; (iii) optionally substituted aryl (eg, phenyl); (iv) optionally substituted heteroaryl (eg, optionally substituted pyridyl or optionally substituted indolyl, especially (v) alkyl (eg methyl iii ethyl); (vi) alkyl substituted with one or more halogen atoms (eg trifluoromethyl); (vii) alkyl substituted with -C(=O)-NY<1>Y<2>, especially -CH2-CH2-C(=0)NHCH3; (viii) alkyl substituted with -OR<7> (eg -CH2-CH2-OCH3); (ix) -ZR<4>, especially -OCH3, -OCH2CH3, -OCF2H or -OCH2-CH2-OCH3; (x) -C(=0)-OR<5>, especially -C(=0)-OH; (xi) -C(=0)-NY<1>Y<2>, especially -C(=0)NHCH3 or -C(=O)-NH-C(CH3)2-CH2OH; and (xii)-NY1Y<2>, especially compounds of formula (I) where R<3> represents hydrogen, cyano, pyridyl, trifluoromethyl,

are particularly desirable. R<3> preferably represents -OCH3.

R<2> is preferably attached at position 5 on the indole ring.

It is desirable that the group

be attached in position 3 on the indole ring.

It is to be understood that this invention covers all suitable combinations of the specific and preferred groups set forth herein.

Particularly preferred compounds of this invention are:

and corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (eg, hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of this invention are:

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

and corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (eg, hydrates) of such compounds and their N-oxygens and prodrugs.

The compounds of the present invention exhibit beneficial pharmacological activity and are accordingly incorporated into pharmaceutical preparations and used in the treatment of patients suffering from certain medical disorders. The present invention thus, in accordance with a further aspect, provides compounds of the present invention and compositions containing compounds of the present invention for use in therapy.

The compounds of the present invention block the catalytic action of kinases according to assays described in the literature and in vitro procedures described herein, and which assay results are believed to correlate with pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the present invention and compositions comprising compounds of the present invention for use in treating patients suffering from, or affected by, conditions that may be ameliorated by the administration of protein kinase inhibitors (eg, Syk, FAK, KDR, or Aurora2), particularly Syk kinase inhibitors. For example, the compounds of the present invention are useful in the treatment of inflammatory compounds, e.g. asthma: inflammatory dermatoses (eg psoriasis, dermatitis herpetiformis, eczema, necrotization and skin vasculitis, bullous disease); allergic rhinitis and allergic conjunctivitis; joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis. The compounds are also useful in the treatment of Chronic Obstructive Pulmonary Disease (COPD), acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, myocarditis, B-cell lymphoma, systemic lupus erythematosus, graft-versus-host disease, and other events related to transplant rejection, cancers and tumors (such as colorectal, prostate, breast, thyroid, colon and lungs) and inflammatory bowel disease. Additionally, these compounds are useful as tumor anti-angiogenic agents.

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

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

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

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

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

According to further features of the present invention there is provided a method for treating a human or animal patient suffering from, or subject to, conditions that can be ameliorated by the administration of protein kinase inhibitors (eg Syk, FAK, KDR or Aurora2) eg. conditions as described hereinabove, which consists in administering to the patient an effective amount of a compound of the present invention or a preparation containing a compound of the present invention. "Effective amount" is used to describe that amount of a compound of the present invention that is effective in inhibiting the catalytic action of a protein kinase, such as Syk, FAK, KDR, or Aurora2, thereby producing the desired therapeutic effect.

Reference to treatment here should be understood to include prophylactic therapy as well as treatment of already established conditions.

The present invention also encompasses pharmaceutical preparations containing at least one of the compounds of the present invention in association with a pharmaceutically acceptable carrier or excipient.

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

Preparations according to this invention can be obtained according to usual procedures, using one or more pharmaceutically acceptable auxiliary ingredients or excipients. Auxiliary ingredients are, among others, diluents, sterile aqueous media and various non-toxic organic solvents. Preparations can be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injection solutions, elixirs or syrups, and can contain one or more agents selected from the group consisting of sweeteners, flavors, colors, or stabilizers in order to obtain pharmaceutical acceptable preparations. The choice of the carrier and the content of the active substance in the carrier is generally determined according to the solubility and chemical properties of the active compound, the specific method of administration and the conditions that must be ensured in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrants such as starch, alginic acids, and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate, and talc can be used to form tablets. In obtaining capsules, it is preferable to use lactose and polyethylene glycols of higher molecular weight. When aqueous suspensions are used, they may contain emulsifying agents or suspending agents. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol, and chloroform or mixtures thereof may also be used.

Emulsions, suspensions or solutions of the product according to this invention in vegetable oil are used for parenteral administration, e.g. sesame oil, peanut oil, or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, and sterile aqueous solutions of pharmaceutically acceptable salts. Salt solutions of the products of this invention are particularly useful for administration by intramuscular or subcutaneous injection. Aqueous solutions, which also include solutions consisting of salt solutions in pure distilled water, may be used for intravenous administration provided that they are appropriately pH adjusted, confirmed buffered and made isotonic with sufficient glucose or sodium chloride, and sterilized by heat, radiation, or microfiltration.

Gels (based on water or alcohol), creams or pomades containing the compounds of this invention are used for topical administration. The compounds of the present invention may also be incorporated into a gel or matrix base for administration with binders that will allow controlled penetration of the compound through the transdermal barrier.

For administration by inhalation, the compounds of this invention may be dissolved or suspended in a suitable carrier for use in a nebulizer, or in an aerosol for suspensions or solutions, or may be absorbed or adsorbed on a suitable solid carrier for use in a dry powder inhaler.

Solid preparations for rectal administration include suppositories formulated according to known methods and containing at least one compound of the present invention.

The percentage of active ingredient in the preparations of this invention may vary, as it is necessary to represent such a proportion to obtain a suitable dosage. Of course, multiple unit doses can be prescribed simultaneously. The dose to be used will be determined by the doctor, and depends on the desired therapeutic effect, by which the duration of the treatment is prescribed, and the patient's condition.

In adults, doses generally range from about 0.001 to about 50, preferably about 0.001 to about 5 mg/kg of body weight per day for inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more particularly 0.5 to 10 mg/kg of body weight per day for oral administration, and from about 0.001 to about 10, preferably 0.01 to 1 mg/kg of body weight per day for intravenous administration. In each individual case, doses will be determined according to the characteristic factors of the subject being treated, such as age, weight, general health, and other characteristics that may affect the effectiveness of the medicinal product.

The compounds of this invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to higher or lower doses and may find that a much lower maintenance dose is adequate. Other patients may require long-term treatment with 1 to 4 doses per day, according to the physiological requirements of each individual patient. In general, the active product can be administered orally 1 to 4 times a day. Of course, for some patients it will be necessary to exceed no more than one or two doses per day.

The compounds of the present invention can be obtained by applying or adapting known procedures, referring to the procedures used herein or described in the literature, e.g. those described by R. C. Larck in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described later here it may be necessary to protect functional groups, e.g. hydroxy, amino, imino, thio or carboxy group, where they are desired in the final product, to avoid their unwanted participation in the reactions. Common protective groups may be used in accordance with standard practice, e.g. see T. VV. Greene and P. G. M. Woods in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Compounds of formula (I), where R1, R2 and R3 are as previously defined herein, are obtained by reacting a compound of formula (XXVIII): where R<3>as defined hereinbefore and X<1>is a halogen atom, preferably iodine, or a triflate group, with a compound of formula (XXIX):

where R<1> and R<2> are as defined above. The coupling reaction can be carried out in a conventional manner, e.g. in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in an aqueous solution of dimethylformamide at a temperature up to the reflux temperature. This reaction is usually carried out with pyrrole NH in compound (XXVIII) protected by e.g. with tosyl group and indole NH in compound (XXIX) protected e.g. with a tert-butyloxycarbonyl group. Compounds of formula (1) where R<2> and R<3> are as described above and R<1> is optionally substituted alkyl are obtained by reacting the corresponding compound of formula (I) where R<2> and R<3> are as defined above and R<1> is hydrogen with the corresponding alkyl halide R<2>->X<2>where R<2> is optionally substituted alkyl and X<2> is halo. This reaction is particularly suitable for obtaining compounds of formula (I) where R<1> is morpholinoacetyl.

The compounds of this invention can also be obtained by interconversion of other compounds of this invention.

Thus, for example compounds of formula (1) containing a carboxy group can be obtained by hydrolysis of the corresponding esters. The hydrolysis can be carried out conventionally by alkaline hydrolysis using a base, such as alkali metal hydroxides, e.g. lithium hydroxide, or alkali metal carbonates, e.g. potassium carbonate, in the presence of a water/organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol, at a temperature from ambient to about reflux. Hydrolysis of esters can also be carried out by acid hydrolysis using inorganic acids, such as hydrochloric acid, in the presence of a water/inert organic solvent mixture, using organic solvents such as dioxane or tetrahydrofuran, at a temperature of about 50°C to about 80°C.

As another example, compounds of formula (I) having a carboxy group can be obtained by removal of the tert-butyl group with the appropriate tert-butyl esters using standard reaction conditions, e.g. by reaction with trifluoroacetic acid at room temperature

As another example, compounds of formula (I) containing a carboxy group can be obtained by hydrogenation of the corresponding benzyl esters. The reaction can be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, on an inert support such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature around the reflux temperature. The reaction can alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol.

As another example of the interconversion procedure, compounds of formula (I) containing

-C(=0)-NY<1>Y<2> group can be obtained by coupling a compound of formula (I) containing a carboxy group with an amine of formula HNY<1>Y<2> to form an amide bond using standard peptide coupling procedures, e.g. by coupling in the presence of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropyl ethyl amine) in tetrahydrofuran (or dimethylformamide) at room temperature. This process is particularly useful for obtaining (i) a compound of formula (I) wherein R<3>-C(=0)-NY<1>Y<2>Hi (ii) a compound of formula (I) wherein R<2>-C(=0)-NY<1>Y<2>. Coupling can also be effected by reacting a compound of formula (I) containing a carboxy group with N-{(dimethylamino)(1H-1,2,3-triazaolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide in the presence of a suitable base, such as diisopropylethylamine, in an inert solvent, such as dimethylformamide, and at about room temperature, followed by reaction with the same formula HNY<1>Y<2> (ammonium chloride can be used to obtain compounds of formula (I) containing a -C(=0)-NH2 group.) Coupling can also be carried out by reacting a compound of formula (I) containing a carboxy group with 2-(1 H -benzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate, in dry dimethylformamide, followed by reaction with an amine of the formula HNY<1>Y<2> in the presence of diisopropylethylamine. As another example of an interconversion procedure, compounds of formula (I) containing a -CH 2 OH group can be obtained by reduction of the corresponding compound of formula (I) containing a -CHO or -CO 2 R<7> (where R<7> is lower alkyl) group. For example, the reduction can be conventionally carried out via a lithium-aluminum-hydride reaction, in an inert solvent, such as tetrahydrofuran, and at a temperature from about room temperature to about reflux temperature.

As another example of an interconversion procedure, a compound of formula (I) wherein R<2> is hydroxy can be prepared by reacting the corresponding compound of formula (I) wherein R<1> is methoxy with a Lewis acid, such as boron tribromide, in an inert solvent such as dichloromethane and at a temperature of from about 0°C to about room temperature.

As another example of an interconversion procedure, compounds of formula (I) where R<2> is OR<4> (where R<4> is optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl) can be obtained by alkylating the corresponding compound of formula (I) where R<2> is hydroxy, with a compound of formula (XXX):

where R<4> is as defined immediately above and X<3> is a halogen atom, preferably bromine, or a tosyl group, using standard alkylation conditions. Alkylation is e.g. can be carried out in the presence of a base, such as an alkali metal carbonate (eg, calcium carbonate or cesium carbonate), an alkali metal alkoxide (eg, potassium tertiary butoxide), or an alkali metal hydride (eg, sodium hydride), in dimethylformamide, or diethylsulfoxide, at a temperature of about 0°C to about 100°C.

As another example of an interconversion procedure, compounds of formula (1) where R<1> is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted with -C(=0)NY<1>Y<2>, -OR<7>, -C(=0)-OR<7>, -NY<1>Y<2> can be obtained by alkylating the corresponding compound of formula (la) where R1 is hydrogen, with the appropriate halide of formula (XXXI):

R<1->X<4>(XXXI)

where R<1> is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted with - C(=0)NY<1>Y<2>, -OR<7>, -C(=0)-OR7, -NY<1>Y<2> and X<4> is a halogen atom, preferably bromine, using standard alkylation conditions, e.g. those described above.

As another example of an interconversion procedure, compounds of formula (I) containing sulfoxy bonds can be obtained by oxidation of the corresponding compounds containing -S-bonds. For example oxidation can be carried out by the usual procedure with a peroxy acid, e.g. with 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or around room temperature, or alternatively using potassium hydrogen proxomonosulfate in a medium such as aqueous methanol buffered to about pH 5, at temperatures between OC and room temperature. This latter procedure is preferred for compounds containing some acid-labile group.

As another example of the interconversion procedure, compounds of formula (I) containing sulfonic bonds can be obtained by oxidation of the corresponding compounds containing -S- or sulfoxide bonds. For example the oxidation can be carried out in a conventional way by reaction with a peroxy acid, e.g. with 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.

As another example of an interconversion procedure, compounds of formula (1) containing a cyano group can be obtained by reacting the corresponding compound of formula (I) containing a -C(=O)-NH2 group with phosphorus pentachloride in the presence of triethylamine. The reaction can usually be carried out in an inert solvent such as tetrahydrofuran and at a temperature around the reflux temperature.

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

As another example of an interconversion procedure, compounds of formula (I) wherein R 3 is -NY<1>Y<2> (wherein Y<1> and Y<2> are as defined herein above), may be obtained by reacting the corresponding compound of formula (I) wherein R<A> is halo (eg, chloro) with an amine of formula HNY<1>Y<2> (wherein Y<1> and Y<2> are as defined immediately above).

As another example of an interconversion procedure, compounds of formula (I) where R<3> is cyano can be obtained by reacting the corresponding compound of formula (I) where X<1> is halo, preferably chloro, with zinc cyanide in the presence of zinc powder, [1'1-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex and dichloromethane (catalytic amount) and N,N-dimethylacetamide at a temperature of up to about 150°C.

As another example of an interconversion procedure, compounds of formula (I) containing a -C(=0)-OR<5> group (wherein R<5> is as defined above) can be obtained by reacting a corresponding compound of formula (I) containing a -C(=0)-OH group with an alcohol of formula R<5>OH. For example if R<5> is tert-butyl the reaction can be conventionally carried out in the presence of 1-1'-carbonyldiimidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene at a temperature around room temperature.

It is particularly appreciated that the compounds of the present invention may contain centers of asymmetry. These asymmetric centers can optionally be R or S configuration. It will be apparent to one skilled in the art that certain compounds of the present invention may exhibit geometric isomerism. It is understood that the present invention encompasses the individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures, of the compounds of formula (I) listed above. Such isomers can be separated from their mixtures by applying or adapting known procedures, e.g. chromatographic technique and recrystallization technique, or they are obtained separately from the corresponding isomers of their intermediates.

According to a further feature of this invention, acid addition salts of compounds of this invention can be obtained by reacting a free base with a suitable acid, using or adapting known procedures. For example acid addition salts of the compounds of this invention can be obtained either by dissolving the free base in water or an aqueous solution of alcohol or other suitable solvent containing a suitable acid and isolating the salt by evaporating the solution, or by reacting the free base with the acid in an organic solvent, in which case the salt is either isolated directly or can be obtained by concentrating the solution.

The acid addition salts of this invention can be regenerated from the salt by applying or adapting known procedures. For example parent compounds of this invention can be regenerated from their acid addition salts by treatment with, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

The compounds of this invention can be regenerated from their base addition salts by applying or adapting known procedures. For example parent compounds of this invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.

The compounds of the present invention may conveniently be obtained, or formed during the process of the present invention, as solvates (eg hydrates). The hydrates of the compounds of the present invention can conveniently be obtained by recrystallization from a water/organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol.

According to a further feature of this invention, base addition salts of compounds of this invention can be obtained by reacting a free acid with a suitable base, using or adapting known procedures. For example base addition salts of this invention can be obtained either by dissolving the free acid in water or an aqueous solution of alcohol or other suitable solvents containing a suitable base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt is isolated directly or can be obtained by concentrating the solution.

Starting materials and intermediates can be obtained by applying or adapting known procedures, e.g. procedures described in the Reference Examples or their obvious chemical equivalents.

Intermediates of formula (XXVIII), where R<3>as previously defined herein, X<1>is iodo and the NH on the pyrrole is protected by a tosyl group, can be obtained as shown in Scheme 1.

SCHEME1

For example, compounds of formula (XXXIV) can be obtained:

(i) by reacting a compound of formula (XXXII) with para-toluenesulfonyl chloride in the presence of an aqueous solution of sodium hydroxide and tetrabutylammonium sulfate in an inert solvent, such as toluene, at room temperature; (ii) then by treating the resulting compound of formula (XXXIII) with butyl lithium in tetrahydrofuran, at a temperature of about -78 C;

(iii) reaction of the formed anion with iodine.

Intermediates of formula (XXXIII) where R<3> is heteroaryl can be obtained by reacting compounds of formula (XXXIII) where R<3> is halo, e.g. chloro, with a borane of formula R<3>BEt2where R<3>heteroaryl. The reaction can conveniently be carried out in the presence of tetrakis(triphenylphosphine)palladium(O) and potassium carbonate, in tetrahydrofuran at a temperature up to the reflux temperature. This reaction is particularly suitable for obtaining compounds of formula (XXXIII) where R<3> is pyridyl.

Intermediates of formula (XXXIII) where R<3> is heteroaryl can also be obtained by reacting compounds of formula (XXXIII) where R<3> is halo, e.g. chloro, with a heteroarylboronic acid of the formula R<3>B(OH)2 in the presence of tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution, in dimethylformamide at a temperature up to the reflux temperature. This reaction is particularly suitable for obtaining compounds of formula (XXXIII) where R<3> is optionally substituted indolyl.

Intermediates of formula (XXXIII) where R<3>represents OR<4>, where R<4> is as defined hereinabove, can be obtained by reacting compounds of formula (XXXIII) where R<3>is halo, e.g. chloro, with the compound of the formula R<4>0Na (obtained by the reaction of the alcohol of the formula R<4>OH with sodium) at a temperature of up to about 65°C. This reaction is particularly suitable for obtaining compounds of formula (XXXIII) where R<3> represents OMe.

This invention is further described in more detail but not limited in the illustrative Examples 1 Reference Examples which follow.

The conditions of Mass Spectrometry - High Pressure Liquid Chromatography (LC-MS) for determination of retention time (Rt) were as follows:-

Procedure A. Hvpersil BDS C-18 reverse-phase column (4.6 mm x 50 mm) run under stepwise elution conditions with mixtures of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05% trifluoroacetic acid as mobile phase gradient: (0.00 min 100%A:0%B; linear gradient to 100% B on 2 minutes; then hold for up to 3.5 minutes); flow rate 1 mL/min with a split of approximately 0.25 mL/min in the Mass Spectrometer; injection volume 10 uL; Hewlett Packard Model HP 1100 Series UV detector wavelength 200 nm; Evaporative light scattering detector (ELS) - temperature 46°C, nitrogen pressure 4 bar.

Procedure B: Gilson 215 injector model using Hvpersil HyPURITY C-18-5u column (4.6 mm x 50 mm) run under step-elution conditions with mixtures of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05% trifluoroacetic acid as mobile phase gradient: (0.00 minute 95%A:5%B; linear gradient to 95% B for 4 min; then to 5% B for 4.5 min; then hold for 6 min); injection volume 5 µL and flow rate 1 mL/min into the UV (DAD) detector after which approximately 0.100 mL/min was sprayed into the Mass Spectrometer (positive electrospray) with the remainder into the ELS detector.

Procedure C: Micromass instrument model LCT attached to model HP 1100 instrument. The proportion of compounds was determined using an HP model Gl 315A photodiode array detector in the wavelength range 200-600 nm and a Sedex model 65 evaporative light scattering detector. Mass spectra were obtained in the range 180 to 800. Data were analyzed using Micromass MassLynx software. Separation was performed on a Hypersil BDS C18 column (50 x 4.6 mm), particle size 3 µm eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v/v) trifluoroacetic acid in water containing 0.05% (v/v) trifluoroacetic acid over 3.5 min at a flow rate of 1 mL/min. Total run time including column re-equilibration was 7 minutes.

EXAMPLE 1

2- r5-Methoxy-3-(4- trifluoromethyl^

4-yl-ethanone

Compound of formula (1), where R<1>

, R 2 is -OMe, R 3 is -CF 3 , the group is attached to the 3-position of the indole ring, and the R<2> group is attached to the 5-position of the indole ring, represented by formula (II): is obtained in the manner shown in the following scheme: (i) treating 7H-pyrrolo[2,3-b]pyrimidine (1) with 3-chloroperbenzoic acid in dichloromethane at a temperature of about 0°C to give 7H-pyrrolo[2,3-b]pyrimidine-N-oxide (2); (ii) reaction of (2) with phosphorus oxybromide at about 50°C to give 4-bromo-7H-pyrrolo[2,3-b]pyrimidine (3); (iii) reaction of (3) with 4-toluene sulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide solution in toluene to give 4-bromo-7H-pyrrolo[2,3-b]pyrimidine (4); (iv) reaction of (4) with trifluoromethyltrimethylsilane in the presence of potassium fluoride and copper(l)-iodide in dimethylformamide at about 60°C to give 7-(toluene-4-sulfonyl)-4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidine (5); (v) treating (5) with lithium diisopropylamide in tetrahydrofuran, at about -78°C, followed by reaction of the resulting anion with iodine to give 6-iodo-7-(toluene-4-sulfonyl)-4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidine (6). (vi) coupling (6) with 1-tert-butyloxycarbonyl-5-methoxy-1H-indole-3-boronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux temperature and removal of the tert-butyloxycarbonyl protecting group followed by treatment with methyl iodide in the presence of sodium hydride in tetrahydrofuran to give 6-(5-methoxy-1H-indol-3-yl)-7-(toluene-4-sulfonyl)-4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidine (7); (viii) removal of the tosyl protecting group in (7), by treatment with sodium hydroxide in methanol to give 6-(5-methoxy-1H-indol-3-yl)-4-trifluoromethyl-7H-pyrrolo[2,3-bpyrimidine (8); and

(ix) alkylation of (8) with 4-(2-chloroacetyl)morpholine in the presence of sodium hydride in dimethylformamide to give 2-[5-methoxy-3-(4-trifluoromethyl-7H-pyrrolo[2,3-b]pyrimidin-6yl)-indol-1-yl]-1-morpholin-4-yl-ethanone (II).

EXAMPLE 2

(2-hydroxy-1,1-dimethylethyl)-amide 1-Methyl-3-(7H-pyrrolor2,3-blpyrimidin-6-yl)-1H-indol-5-

carboxylic acids

A compound of formula (I), where R<1> is -CH3, R<2> is

,R3 is -H

group

is attached to position 3 of the indole ring and the group R<2> is attached to position 5 of the indole ring, represented by formula (III): is obtained as shown in the following scheme: (i) reaction of (9) with 4-toluene sulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide solution in toluene to obtain (10); (ii) treating (10) with lithium diisopropylamide in tetrahydrofuran, at about -78 C, followed by reaction of the resulting anion with iodine to give (11); (iii) coupling (11) with 1-tert-butyloxycarbonyl-5-methoxy-1H-indole-3-boronic acid (12) in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux temperature and removal of the tert-butyloxycarbonyl protecting group followed by treatment with methyl iodide in the presence of sodium hydride in tetrahydrofuran to give 6-[(1-methyl-5-carbomethoxyindole)3-yl-[H-pyrrolo[2,3-b]pyrimidine (13); (iv) treating (13) with a solution of potassium hydroxide in water and methanol at reflux temperature to give 6-[(1methyl-5-carboxyindol)3-yl]-7H-pyrrolo[2,3-b]pyrimidine (14); and (v) coupling (14) with 2-hydroxy-1,1-dimethylethylamine in the presence of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give (2-hydroxy-1,1-dimethyl-ethyl)-amide. 1-Methyl-3-(7H-pyrrolo[2,3b]pyrimidin-6-yl)-1H-1-indole-5-carboxylic acids (III).

EXAMPLE 3

24r5- methoxy- 3^ 7H- pyrrolo2. 3- blpyrimidine- 6- in- indole- 1- in- 1- morpholine- 4- yl>- ethanone

A compound of formula (I), where R<1>

, R2 is -OMe, R3 is -H, the group is attached in position 3 of the indole ring and the group R<2> is attached in position 5 of the indole ring, represented by formula (IV): is obtained in the manner shown in the following scheme: (i) coupling of 6-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (11) 1-tert-butyloxycarbonyl-5-methoxyindole-3-boronic acid (15) in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux temperature and removal of the tert-butyloxycarbonyl protecting group to give 6-[(5-methoxyindole)-3-yl]-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (16); (ii) treating (16) with a solution of potassium hydroxide in water and methanol at reflux to give 6-[(5-methoxyindole)3-yl]-7H-pyrrolo[2,3-b]pyrimidine (17); and (iii) reaction of (17) with sodium hydride in dimethylformamide followed by reaction with 2-bromoacetic acid morpholinamide to give 2-{[5-methoxy-3-(7H-pyrrolo[2,3-b]pyrimidin-6yl)-indol-1 -yl]-1 -morpholin-4-yl}-ethanone (IV).

EXAMPLE 4

A compound of formula (I), where R<1> is -CH2CF3, R2 is -OMe, R3 is -CN,

group

is attached at the 3-position of the indole ring and the R<2> group is attached at the 5-position of the indole ring, represented by formula (VII): is obtained as shown in the following scheme: (i) reaction of (18) and (19) in the presence of potassium carbonate and sodium iodide to give (20); (ii) reaction of (20) with thiourea in the presence of sodium ethoxide in ethanol to give (21); (iii) cyclization of (21) by heating in toluene at about reflux temperature to give (22); (iv) reaction of (22) with phosphorus oxybromide to give 4-bromo-7H-pyrrolo[2,3 b]pyrimidine (23); (v) reacting (23) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide in toluene to give (24); (vi) treating (24) with lithium diisopropylamide in tetrahydrofuran, at about -78°C, followed by reaction of the resulting anion with iodine to give (25); (vii) coupling (25) with 1-tert-butyloxycarbonyl-5-methoxyindole-3-boronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at about reflux temperature and removal of the tert-butyloxycarbonyl protecting group, to give 4-bromo-6-[(5-methoxyindole)3-yl]-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (26); (viii) reaction of (26) with sodium hydride in tetrahydrofuran followed by reaction with 2-trifluoroiodoethane to give (27); (ix) reacting (27) with zinc cyanide in the presence of oaladium in N'N-dimethylaniline at about 140°C to give (28), and (x) treating (28) with a solution of potassium hydroxide in water and methanol at reflux temperature to give (VII). ddim<pp>c; Compound of formula (1), where R<1> is -CH3, R2 is -OMe, R3 is group is attached in position 3 of the indole ring and the group R<2> is attached in position 5 of the indole ring, represented by formula (IX): is obtained as shown in the following scheme: (ii) reaction of (26) with sodium hydride in tetrahydrofuran followed by reaction with methyl iodide to give (29); (ii) reacting (29) with carbon monoxide in the presence of palladium in methanol at reflux temperature to give (30); (iii) treating (30) with a solution of potassium hydroxide in water and methanol at reflux temperature to give (31); and (iv) coupling (31) with 2-hydroxy-1,1-dimethylethylamine in the presence of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give (IX).

EXAMPLE 6

A compound of formula (I), where

group is attached at position 3 of the indole ring and the group R<2> is attached at position 5 of the indole ring, represented by formula (V): is obtained as shown in the following scheme: (i) reaction of (26) with methyl acrylate in the presence of palladium acetate, triphenyl phosphine and triethylamine at about 110°C to give (32); (ii) hydrogenating (32) in the presence of palladium on carbon to give (33); (iii) treating (33) with a solution of potassium hydroxide in water and methanol at reflux temperature to give acid (34); (iv) coupling (34) with methylamine in the presence of 0-(7-azabenzotriazol-1-ii)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to give (35); and (v) alkylating (35) with 4-(2-chloroacetyl)morpholine in the presence of sodium hydride, in dimethylformamide to give (V).

EXAMPLE 7

A compound of formula (I), where

group is attached in the 3-position of the indole ring and the R<2> group is attached in the 5-position of the indole ring, represented by formula (VI): is obtained in the manner shown in the following scheme: (i) coupling (26) with pyridine-3-boronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in an aqueous solution of dimethylformamide at a temperature around the reflux temperature to give 4-(pyridin-3-yl)-6-[(5-methoxyindole)3H1]-7-(toluene 3 -sulfonyl)-7H-pyrrolo[2,3-b]pyrimidine (36); (ii) treating (36) with a solution of potassium hydroxide in water and methanol at reflux temperature to give (37, Example 9); and (iii) alkylation of (37, Example 9) with 4-(2-chloroacetyl)morpholine in the presence of sodium hydride, in dimethylformamide to give 2-[5-methoxy-3-(4-(pyridin-3-yl)-7H-pyrrolo[2,3-b]pyrimidin-6-yl)-indol-1-yl]-1-morpholin-4-yl-ethanone (VI).

EXAMPLE 8

Compound of formula (1), where R<1> is -CH2CH3, R2 is -OMe, R<3> is

group is attached at position 3 of the indole ring and the group R<2> is attached at position 5 of the indole ring, represented by formula (VIII): is obtained as shown in the following scheme: (i) alkylating (26) with ethyl iodide in the presence of sodium hydride, in dimethylformamide to give (38); (ii) reacting (38) with morpholine in a microwave oven at about 200°C in α,α,α-trifluorotoluene to give (39); and (iii) treating (39) with a solution of potassium hydroxide in water and methanol at reflux temperature to give (VIII). EXAMPLE 9 6-(5-Methoxy-1H-indol-3-yl)-4-pyridin-3-yl-7H-pyrroloph2. 3- dlpyrimidine

A solution of 6-iodo-7-[(4-methylphenyl)sulfonyl]-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine [260 mg, Reference Example 1] and 1-tert-butyl4<arboxyl-5-methoxy-1H-indole-3-boronic acid [178 mg, Reference Example 12] in dimethylformamide (10 mL) was treated with palladium. tetrakis triphenyl phosphine (13 mg) and sodium bicarbonate (8 mg). The reaction mixture was stirred at reflux temperature for 2 h and allowed to cool to room temperature. The solution was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to flash silica gel column chromatography eluting with a mixture of ethyl acetate and methanol (95:5, v/v) to give 6-(5-Methoxy-1H-indol-3-yl)-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine (20 mg) as an amorphous solid. MS: 342 [MH]<+>, LCMS (Procedure A) Rt=2.57 minutes.

EXAMPLE 10

4-Methoxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7H-pyrroloph2. 3- dlpyrimidine

A solution of 4-methoxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [361 mg, Reference Example 4] in methanol (20 mL) was treated with potassium hydroxide (1.53 g). The reaction mixture was stirred for 16 h at room temperature and refluxed for 1 h. The solution was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diethyl ether to give 4-methoxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3~d]pyrimidine (155 mg) as a solid, m.p. warmer = 184°C. MS: 309 [MH]+.

EXAMPLE 11

4- methoxy- 6-( 5- methoxy- 1H- indol- 3- yl)- 7H- pyrrolo2, 3- dlpyrimidine

A solution of 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7-[(4methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [448 mg, Reference Example 5] in methanol (15 mL) was treated with potassium hydroxide (1.96 g). The reaction mixture was stirred for 2 h at room temperature and the solvent was evaporated under reduced pressure. The residue is separated between water and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is subjected to flash silica column chromatography eluting with a mixture of et lacetate and cyclohexane (80:20, v/v) to give 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (320 mg) as a yellow solid, m.p. warmer > 260°C. MS: 295 [MH]+.

EXAMPLE 12

4-(5-Methoxy-1H-indol-3-yn-6-(5-methoxy-1-methyl-1H-indol-3-yl V7H-pyrroloph2.3-d| pyrimidine)

A solution 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]-7H-pyrrolo[2 3 d]pyrimidine [93 mg, Reference Example 9] in methanol (5 mL) was treated with potassium hydroxide (249 mg). The mixture was stirred for 16 h at room temperature. The solution was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was purified by HPLC to give 4-(5-methoxy-1H-indol-3-yl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (9 mg) as a gum. MS: 424 [MH]<+>. LCMS (Procedure B) RT= 3.15 minutes.

REFERENCE EXAMPLE 1

6-iodo-7-f(4-methylphenyl)sulfonin-4-pyridin-3-yl-7H-pyrrolo[2,3-dlpyrimidine

To a solution of 7-[(4-methylphenyl)sulfonyl]-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine [1 g, Reference Example 2] in tetrahydrofuran (20 mL) at -78°C was added dropwise a solution of butyl lithium in hexane (2 mL, 1.6 M) under an inert atmosphere. The solution was stirred at this temperature for 1.5 h and iodine (796 mg) was added. The reaction mixture was stirred at -78°C for an additional 1 h and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to afford the title compound (260 mg) as an amorphous solid. MS: 477 [MH]<+.>LCMS (Procedure B) RT= 3.26 minutes.

REFERENCE EXAMPLE 2

7- r( 4- Methylpheninesulfonin- 4- pyridin- 3- yl- 7H- pyrrolo[ 2, 3- dlpyrimidine

A solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [4 g, Reference Example 3] and diethyl-3-pyridyl-borane (2.1 g) in tetrahydrofuran (180 mL) was treated with palladium tetrakis triphenylphosphine (0.65 g) and potassium carbonate (3.59 g). The solution was stirred at reflux for 24 h and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated brine. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to flash silica column chromatography twice eluting with ethyl acetate/methanol (90:10, v/v) and ethyl acetate/cyclohexane (50:50, v/v) to give the title compound (2.5 g) as an amorphous solid. MS: 351 [MHf. LCMS (Procedure B) RT= 3.05 minutes.

REFERENCE EXAMPLE 3

4-Chloro-7-f(4-methylphenyl)sulfonine-7H-pyrrolor2,3-dloirimidine

Solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (References: Gerster, John F.; Hinshav, Barbara C; Robins, Roland K; Tovnsend, Leroy B. Study of electrophilic substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem.

(1969), -(2), 207-213) (20 g) of para-toluenesulfonyl chloride (28.6 g) in toluene (1 L) was treated with a solution of sodium hydroxide (50 g) in water (800 mL), and tetrabutyl ammonium sulfate (462 mg). The solution was stirred vigorously at room temperature for 2 h and partitioned between ethyl acetate and saturated brine. The organic phase is separated, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash silica chromatography eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v/v) to give the title compound (2.5 g) as a solid, m.p. = 143°C. LCMS (Procedure B) RT= 2.78 minutes.

REFERENCE EXAMPLE 4

4-Methoxy- 6-(5- methoxy- 1- methyl- 1H- indole- 3- yn- 7- f( 4- methylphenyl) sulfonyl- 7H- pyrrolo

2. 3- dpyrimidine

To a solution of 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo [2,3-d]pyrimidine [448 mg, Reference Example 5] in dimethylformamide (20 mL) was added sodium hydride (44 mg, 60% dispersion in oil) and methyl iodide (156 mg) under inert atmosphere. The solution was stirred for 1 h at room temperature 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 sulfate and then evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a mixture of ethyl acetate and cyclohexane (30:70, v/v) to give the title compound (260 mg) as an amorphous solid. MS: 464 [MH]+. LCMS (Procedure B) RT= 4.39 minutes.

REFERENCE EXAMPLE 5

4-Methoxy-6-(5-Methoxy-1H-indol-3-yl)-74(4-meth:lphenyl)sulfonin-7H

d lpyrimidine

A solution of 6-iodo-4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [1.98 g, Reference Example 6] and 1-tert-butyl-carboxyl-5-methoxy-1H-indole-3-boronic acid [1.26 g, Reference Example 12] in dimethylformamide (40 mL) was treated sequentially with saturated aq. sodium bicarbonate (10 mL) and palladium tetrakis triphenylphosphine (165 mg). The reaction mixture was stirred at reflux for 3 h 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 sulfate and then evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (1.8 g) as a gray solid, m.p. = 131°C. MS: 450 [MH]+.

REFERENCE EXAMPLE 6

6- iodo- 4- methoxy- 7- f(;4- methylphenyl) sulfonyl1- 7H- pyrrolo2, 3- d1pyrimidine

To a solution of 4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [2.23 g, Reference Example 7] in tetrahydrofuran (35 mL) at -78°C was added dropwise a solution of butyl lithium in hexane (5 mL, 1.6 M) under an inert atmosphere. The solution was stirred at -70°C for 1 h and iodine (2.05 g) was added. The reaction mixture was stirred at -70°C for an additional 1 h, then allowed to reach room temperature and partitioned between ethyl acetate and aqueous sodium sulfite. The organic phase was separated, dried over magnesium sulfate and then evaporated under reduced pressure to give the title compound (2.64 g) as an amorphous solid. MS: 430 [MHf. LCMS (Procedure B) RT= 4.15 minutes.

REFERENCE EXAMPLE 7

4-Methoxy-7-f(4-methylphenyl)sulfonine-7H-pyrrolo[2,3-d]pyrimidine

A solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine [1.2 g, Reference Example 8] and para-toluene sulfonyl chloride (1.77 g) in toluene (60 mL) was treated with a solution of sodium hydroxide (3.2 g) in water (30 mL), and tetrabutyl ammonium sulfate (27 mg). The solution was stirred vigorously at room temperature for 4 h and partitioned between ethyl acetate and saturated brine. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v/v) to give the title compound (2.23 g) as an amorphous solid. MS: 304 [MHf. LCMS (Procedure B) RT= 3.88 minutes.

REFERENCE EXAMPLE 8

4-Methoxy-7H-pyrroloph2, 3-d] pyrimidine

To a solution of sodium methoxide prepared by adding sodium (2 g) to methanol (100 mL) in portions under an inert atmosphere, is added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (References: Gerster, John F. ; Hinshaw, Barbara C_; Robins, Roland K.; Tovnsend, Leroy B. Study of electrophilic substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem. (1969), -(2), 207-13.) (3.5g). The solution was stirred at 65 C for 16 h and then partitioned between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (1.2 g) as an amorphous solid. MS: 150 [MH]+. LCMS (Procedure B) RT= 2.39 minutes.

REFERENCE EXAMPLE 9

4-(5-Methoxy-1-r(4-methylphenyl)sulfonin-1H-indol-3-yl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7-f(4-methylphenyl)sulfonyl-7H-pyrrolor2. 3- dlpyrimidine

Sodium hydride (10 mg, 60% dispersion) was added to a solution of 4-(5-methoxy-1-[(4-methylphenyl)sulfonyl]-1 H-indol-3-yl)-6-(5-methoxy-1 H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [270 mg, Reference Example 10] in dimethylformamide (10 mL). in oil) and methyl iodide (0.025 mL) under an inert atmosphere. The solution was stirred for 16 h at room temperature 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 sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (93 mg) as an amorphous solid. MS: 732 [MH]<+>. LCMS (Procedure B) RT= 4.68 minutes

REFERENCE EXAMPLE 10

4-(5-Methoxy-1-f(4-methylphenyl)sulfonyl1-1H-indol-3-yl)-6-(5-methoxy-1H-indol-3-yl)-7-f(4-

methylphenyl) sulfonine- 7H- pyrrolo2, 3- dlpyrimidine

A solution of 4-chloro-6-iodo-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [1.72 g, Reference Example 11] and 1-tert-butyl4<arboxyl-5-methoxy-1H-indole-3-boronic acid [1.26 g, Reference Example 12] in dimethylformamide (36.5 mL) was treated sequentially with saturated aqueous sodium bicarbonate solution (9.1 mL) and palladium tetrakis triphenylphosphine (0.3 g). The reaction mixture was stirred at reflux for 12 h 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 sulfate and then evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a mixture of ethyl acetate and cyclohexane (30:70, v/v) to give the title compound (270 mg) as a gum. MS: 718 [MH]<+>. LCMS (Procedure B) RT= 4.44 minutes.

REFERENCE EXAMPLE 11

4-Chloro-6-iodo-7-[(4-methylphenyl)sulfonyl1-7H-pyrroloph2. 3-d] pyrimidine

To a solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [5.4 g, Reference Example 3], in tetrahydrofuran (96 mL) at -78°C was added dropwise a solution of butyl lithium in hexane (12.1 mL, 1.6 M) under an inert atmosphere. The solution was stirred at -78°C for 3 h and iodine (8.9 g) was added. The reaction mixture was stirred at -78°C for 2 h and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to flash silica column chromatography eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to afford the title compound (1.52 g) as an amorphous solid.

MS: 434 [MH]<+.>LCMS (Procedure B) RT= 4.26 minutes.

REFERENCE EXAMPLE 12

1 - tert - butyl - carboxyl - 5 - methoxy - 1 H - indole - 3 - boric acid

A mixed solution of 3-bromo-5-methoxy-indole-1-carboxylic acid, tert-butyl ester [50 g, Reference Example 13)] in tetrahydrofuran (800 mL), under a nitrogen atmosphere, is treated with tributylborate (49.5 mL), then cooled to -100°C and then treated with a solution of n-butyllithium in hexane (94 mL, 2.5 M) while maintaining the temperature below -90°C. When the addition is complete, the mixture is allowed to slowly warm to room temperature over 1 h and quenched by the addition of ice (10 g). The organic layers were removed under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (400 mL). The organic layer was dried over magnesium sulfate and evaporated to give the title compound as a cream solid (28 g). MS: 314 [M+Na]<+>LCMS (Procedure C) RT= 4.07 minutes.

REFERENCE EXAMPLE 13

3-Bromo-5-methoxy-indole-1-carboxylic acid tert-butyl ester

A solution of 5-methoxyindole (10 g) in dry dimethylformamide (150 mL) at ambient temperature was treated with bromine (4 mL) dropwise ensuring that the temperature was raised above 30°C. The mixture was immediately treated with triethylamine (28 mL) and 4-dimethylaminopyridine (0.5 g), followed by a solution of di-tert-butyldicarbonate (18 g) in dry dimethylformamide (80 mL) and stirring was continued for another 4 h. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate (250 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (100 mL), then brine (100 mL), then dried over magnesium sulfate and evaporated. The residue was subjected to flash silica column chromatography eluting with a mixture of pentane and ethyl acetate (19/1, v/v) to give the title compound (23.4 g) as a colorless solid, m.p. 111-112°C.

IN VITRO test procedures for SYK

1. Inhibitory effects of compounds on SYK kinase

The inhibitory effects of compounds on Syk kinase were determined using a time-resolved fluorescence assay.

The catalytic domain of Syk kinase (residues A340-N635) is secreted as a fusion protein in yeast cells and purified to homogeneity. Kinase activity is determined in 50 mM Tris-HCl buffer pH 7.0 containing 50 mM NaCl, 5 mM MgCl2, 5 mM MnCl2, 1 µM adenosine triphosphate and 10 µM synthetic peptide Biotin-(j3-Alanine)3-DEEDYEIPP-NH2. The enzymatic reaction is stopped by adding a buffer containing 0.4 M KF, 133 mM EDTA, pH 7.0, containing a streptavidin-XL665 conjugate and a monoclonal phosphospecific antibody conjugated to europium cryptate (Eu-K). The properties of two fluorophores, XL-665 and Eu-K are described in G. Mathis et al., Anticancer Research, 1997, 17, pp. 3011-3014. The specific long-lasting signal of XL-665, which is produced only when the synthetic peptide is phosphorylated with Syk, was measured on an LJL Biosystems Analyst AD microplate reader. Inhibition of syk activity by compounds of the present invention is expressed as a percentage of the inhibition of activity shown by the control in the absence of the test compound. Particularly preferred compounds of the present invention inhibit syk activity with an IC50u range of 100 micromolar to 100 nanomolar. Particularly preferred compounds of the present invention inhibit syk activity with an IC50u range of 1 micromolar to 100 nanomolar. 2. Antigen-induced degranulation of basophilic leukemia in rat cells

(RBL)

2.1 Culturing cells, labeling RBL-2H3 cells and performing the assay.

RBL-2H3 cells were grown in T75 flasks at 37°C and 5% CO 2 , and monitored every 3-4 days. To harvest the cells, use 5 mL of trypsin-EDTA to wash the flasks once, then add 5 mL of trypsin to each flask, and incubate at room temperature for 2 min. Cells are transferred to a tube with 14 mL medium, centrifuged at 1100 min"<1>RT for 5 min and resuspended at 2x10<5>/mL. Cells are sensitized by adding 1 uL of DNP-specific IgE for every 10 mL of cells. 200 uL of cells are added to each well of a 96-well flat-bottom plate (40,000 cell/well), and the plate incubated overnight at 37 C and 5% CO 2 .

The following day, compounds were prepared in 100% DMSO at 10 mM. Each compound is then diluted 1:100 in assay buffer and further diluted to 1%

DMSO-assay buffer to obtain final concentrations of 0.03-30 µM. 80 µL of assay buffer is added to each well, followed by 10 µL of diluted compound. Followed by incubation for 5 min. Add 10 µL DNP-HSA (100 ng/mL) to each well and incubate at 37°C (no CO2) for 30 min. As a control, 1% DMSO alone (no compound) was added to a group of wells to determine total release. As a second control, buffer was added instead of DNP-HSA to another group of wells to determine the assay as baseline. After 30 min of incubation, the supernatants are transferred to a new plate with 96 wells. Add 50 µl of supernatant to each well of the test plate. Add 100 µL of substrate solution to each well and incubate at 37°C for 90 min. 50 µL of 0.4 M glycine solution was added to stop the reaction and the plate was read at 405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculating the results

(i) Mean ± SD of each triplicate set of wells is calculated.

(ii) Maximum response was in positive control wells containing antigen (100 ng/mL) but no compound. (iii) Minimal response was observed in control wells containing buffer (no antigen) without compound. (iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the experimental data were calculated to obtain a percentage of the maximum response (denoted as % of control). (v) A dose-response curve was plotted and the IC50 for the compound was calculated using Prism GrapliPad software and non-linear least-squares regression analysis.

The compounds of the present invention inhibit antigen-induced degranulation of rat Basophilic Leukemia (RBL) cells with EG^ou ranges from 100 micromolar to 1 micromolar.

Claims (18)

1. Compound of the formula where R<1>represents hydrogen, -C(=0)-NY'<y2>, -C(=0)-OR<s>, -SOa-NV'V<2>, -S02-R<7>, -C(=0)R<7>, or R<1>represents alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each optionally substituted with one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO, -C(=0)-NY'Y<2>, -C(=0)-OR<5>, -NY'Y<2>, -N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NYV, -N(R<6>)-S02-R<7>, -N(R<6>)-SO2-NY<3>Y<4>, -OR<7>, -C(-0)-R<7>, hydroxy, alkoxy and carboxy; R<2>represents one or more groups selected from hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R<4>, -C(=0)-NY'Y<2>, -C(=0)-OR5, -NY'Y2, -N(R<6>)-C(=0)-R<7>,N(R<6>)-C(=0)-NY<3>Y<4>, -N(R<6>)-C(=0)-0R<7>, -N(R<6>)-S02-R<7>, -N(R<6>)-S02-NY<3>Y<4>, -S02-NY 1Y2 and -ZR<4>; R<3>represents H, cyano, halo, hydroxy, nitro, R<4>, NV'V<2>, -ZR<4>, -C(=0)-OR<5>, C(=0)-R<7>, -C(=0)-NY'Y<2>, -N(R<8>)-C(=0)-R<4>, -N(rVc(=0)NY'Y2>, -N(R<8>)-C(=0)-OR<5>, -S02-NY<3>Y<4>or-N(R<8>)-S02-R<7>, or R<3>represents aryl, heteroaryl, alkenyl or alkynyl, each optionally substituted with one or more groups selected from aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, -C(=0)-NY'Y<2>, -C(=0)-OR<5>, -NY'Y2,-N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NY<3>Y<4>, -N(R<6>)-C(=0)-OR<7>, -N(R<6>)-S02-R<7>, -N(R<6>)-S02-NY<3>Y<4>, -SOs-NV<V>2i -ZR<4>; R<4>represents alkyl, cycloalkyl or cycloalkalalkyl each optionally substituted with one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO, -C(=0)-NY'Y<2>, -C(=0)-OR<s>, - NYlY2, -N(R<6>)-C(=0)-R<7>, -N(R<6>)-C(=0)-NY<3>Y<4>,-N(R<6>)-S02-R<7>, -N(R6)-S02-NYV, -OR<7>and -C(=0)-R<7>wherein R4 is optionally inserted a group selected from O, S(0)n, and NR<6>R<5>represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R<6> represents hydrogen or lower alkyl; R<7> represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R<8> represents hydrogen or lower alkyl; Y' and Y<2> are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted with one or more groups selected from aryl, chloro, heteroaryl, hydroxy, -C(=0)-NY<3>Y<4>, -C(=0)-OR<5>, -NY<3>Y4,-N(R<6>)-C(=0)- R<7>, -N(R<6>)-C(=0)-NY3Y<4>, -N(R<6>)-S02-R<7>, -N(R<6>)-SO2-NY<3>Y<4> and -OR<7>; or the group - NY<*>Y<2> can form a cyclic amine; Y<3> and Y<4> are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the -NY3Y4 group can form a cyclic amine; Z represents O or S(0)n; its zero or number 1 or 2; or N-oxide, acid bioisoster, pharmaceutically acceptable salt or solvate of the given compound; or the N-oxide, or the acid bioisostar of the given salt or solvate, wherein alkenyl is an aliphatic hydrocarbon group containing a carbon-carbon double bond and a straight or branched chain of 2 to 15 carbon atoms, wherein alkenyloxy is an alkenyl-O- group, wherein alkenyl is as previously defined, wherein e alkyl is an aliphatic hydrocarbon group which is straight or branched with 1 to 15 carbon atoms in the chain, wherein alkynyl is an aliphatic hydrocarbon group containing a carbon-carbon triple bond and a straight or branched chain with 2 to 15 carbon atoms in the chain, wherein aryl is selected from the group consisting of phenyl, naphthyl; tetrahydronaphthyl, indenyl and indanyl, wherein the heteroaryl is selected from the group consisting of benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl and pyrindanyl, wherein heterocycloalkyl is selected from the group consisting of chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl, wherein cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein cycloalkylalkyl is a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl residues are as previously defined, wherein alkoxy is an alkyl-O- group in which the alkyl group is >As defined above where acyl is H-CO- or an alkyl-CO- group in which the alkyl group is as defined above, where alkylene is an aliphatic divalent radical derived from a linear or branched alkyl group wherein the alkyl group is as previously defined, wherein alkylenedioxy is an -O-alkylene-O- group wherein alkylene is as previously defined, where lower alkyl is a straight or branched chain aliphatic hydrocarbon group with 1 to 4 carbon atoms in the chain, wherein the cyclic amine is selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, and tetrahydroquinoline, and wherein the acid bioisoster is a group possessing chemical and physical similarities that produce similar biological properties as the carboxyl group and wherein the corresponding acid bioisoster is selected from the group consisting of -C(=0)-NHOH, -C(=0)-CH2OH.-C(=0)-CH2SH, -C(-0)-NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl. tetrazolyl, arylsulfonylcarbamoyl. heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, 3-hydroxyisoxazolyl and 3-hydroxy-1 -methylpyrazolyl. 2. The compound according to claim 1, characterized in that R<1> is hydrogen, C1-4 alkyl, C1-4 alkyl substituted with halo. C 1 -C alkyl substituted with hydroxy, C 1 -C alkyl substituted with -N(R<6>)C(=0)-R<7>, C 1-6 alkyl substituted with -C(=O)-NY 'Y<2>, or cycloalkylalkyl substituted with hydroxy. 3. A compound according to claim 1, characterized in that R<1> is hydrogen -CH?, -CH2CH^, -Cl 4. A compound according to claim 1, characterized in that R1 is hydrogen. 5. A compound according to one of claims 1 to 4 characterized in that R<2>is carboxy or acidic bioisoster, hydroxy, alkyl substituted with carboxy, heteroaryl, or R2 is -OR4 where R4 is alkyl, -OR4 where R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups, -OR<4>where R4 is alkyl substituted by one or more alkoxy groups, -OR4 where R4 is alkyl or cycloalkyl substituted with one or more carboxy groups, -OR<4> where R4 is cycloalkyl substituted with -C(=0)-NY'Y<2> or R2 is -C(-0)-R where R is alkyl, or R2 is -C(=0)-NY'Y2 , or -N(R<6>)-C(=0)-R<7>. 6. A compound according to one of claims 1 to 4, characterized in that R2 is -OCH3 or -CONHC(CH3)2CH2OH. 7. A compound according to one of claims 1 to 4, characterized in that R<2> is -OCH3 8. A compound according to one of the claims, 1 to 7 characterized in that R<3> is hydrogen, cyano, aryl, heteroaryl, alkyl, alkyl substituted by one or more halogen atoms, alkyl substituted by -C(=0)-NY' Y2, alkyl substituted by -OR<7>, or R<3> is -ZR<4>, - C(=0)-OR<5>, -C(=0)-NY 'Y2, or -NY<!>Y<2.> 9. A compound according to one of claims 1 to 7, characterized in that RJ is hydrogen, cyano, pyridyl, trifluoromethyl, -CH2-CH2-C(=0)NHCH,. -OCF3H, -C(=0)-NH-C(CH,)2- CH2OH or 10. A compound according to one of claims 1 to 7, characterized in that R3 is -OCH3. 11. A compound according to one of claims 1 to 10, characterized in that R 2 is attached to position 5 of the indole ring. 12. A compound according to one of claims 1 to 11, characterized in that the group bound in position 3 of the indole ring. 13. A compound according to claim 1, characterized in that it is an N-oxide, a pharmaceutically acceptable salt or a solvate of the given compound; or the N-oxide of a given salt or solvate. 14. A compound according to claim 1, which is N-oxide, a pharmaceutically acceptable salt or solvate of said compound; or the N-oxide of a given salt or solvate. 15. A pharmaceutical composition containing a pharmaceutically effective amount of a compound according to one of claims 1 to 14, together with one or more pharmaceutically acceptable carriers or excipients. 16. Use of a compound according to one of claims 1 dto 14 for obtaining a drug for the treatment of an inflammatory disease, chronic obstructive pulmonary disease or cancer. 17. Use according to claim 16, characterized by the fact that the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis, joint inflammation, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis. arthritis, rheumatoid arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis. 18. Use according to claim 16, characterized in that the cancer being treated is colorectal cancer, prostate cancer, breast cancer, thyroid cancer, skin cancer, colon cancer or lung cancer.