CZ20033443A3 - Pyrrolopyrimidines as protein kinase inhibitors - Google Patents

Abstract

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

Description

Technical field

The present invention relates to substituted pyrrolopyrimidines, to a process for their preparation, to pharmaceutical compositions containing these compounds, and to their pharmaceutical use in the treatment of diseases that can be affected by the inhibition of protein kinase.

BACKGROUND OF THE INVENTION

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

Disproportionately high protein kinase activity is implicated in many diseases resulting from abnormal cellular function. This can occur either directly or indirectly, for example

failure of proper kinase control mechanisms, related, for example, to mutation, overexpression or inappropriate activation of the enzyme, or over- or under-production of cytokines or growth factors also involved in signal transduction upstream or downstream of the kinase. In all these examples, it can be expected that selective inhibition of the kinase effect could have a beneficial effect.

Syk is a 72 kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hemopoietic cells and is an essential element in several (signaling) cascades that link antigen receptors to cellular responses. Thus, Syk has a critical role in signaling the high affinity IgE receptor, FcεR1, in mast cells, and in signaling the antigen receptor in T and B cells. The signal transduction pathways present in mast cells, T and B lymphocytes, have common features. The ligand receptor binding domain lacks intrinsic (intrinsic) tyrosine kinase activity. However, they interact with transducing subunits that contain immunoreceptor tyrosine based activation motifs (ITAM) [M. Reth, Nature, 1989, 338, pages 383-384]. These motifs are present in both the FcsR1 β and γ subunits, the T-cell receptor ξ-subunit (TCR) and the IgG α and IgG β B-cell receptor (BCR) subunits. [N.S. Van Oers and A. Weiss, Seminars in Immunology, 1995, 7, pp. 227-236]. In antigen binding and multimerization, ITAM residues are phosphorylated by Src family protein tyrosine kinases. Syk belongs to a unique class of tyrosine kinases having two tandem domains with Src homology 2 (SH2) and a C terminal catalytic domain. These SH2 domains bind with high affinity for ITAM, and this SH2-mediated association of Syk with an activated receptor stimulates Syk kinase activity and Localizes Syk to the plasma membrane.

Syk deficient mice inhibit mast cell degranulation, suggesting that this is an important target for the development of mast cell stabilizing agents [P. S. Costello, Oncogene, 1996, 13, pp. 2595-2605]. Similar studies have demonstrated a critical role of Syk in BCR and TCR signaling. [AND. M. Cheng, Nature, 1995, 378, pp. 303-306, 1995, and D.H. Chu et al., Immunological

Reviews, 1998, 165, pp. 167-180]. Syk also appears to be involved in eosinophil survival in response to IL-5 and GM-CSF [S. Yousefi et al., J. Exp. Med., 1996, 183, pages 1407-1414].

Despite the key role of Syk in signaling mast cells, BCR and T lymphocytes, little is known about the mechanism by which Syk transmits the signal downstream to effectors. Two adapter proteins, BLNK (B-cell protein linker, SLP-65) and SLP-76, have been shown to be substrates of Syk in B cells and mast cells, respectively, and are thought to link Syk downstream of the signaling pathway with effectors [M. Ishiai et al., Immunity, 1999, 10, pages 117-125 and L. R. Hendricks-Taylor et al., J. Biol. Chem, 1997, 272, 1363-1367]. In addition, Syk appears to play an important role in the CD40 signaling pathway, which has an important role in B cell proliferation [M. Faris et al., J.Exp. Med., 1994, 179, pp. 1923-1931].

Syk is further involved in platelet activation stimulated by low affinity IgG receptors (Fc gamma-RIIA) or stimulated by collagen [F. Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471478].

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

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

Several proteins involved in chromosome segregation and

Mitotic spindle disease has been identified in yeast and drosophila. Failure of these proteins results in poor chromosome segregation and formation of a monopolar or broken spindle. Of these kinases, Ipl1 and S. cerevisiae aurorakinases and Drosophila are respectively necessary for centrosome separation and chromosome segregation. One human yeast Ipll homolog was recently cloned and characterized by various laboratories. This kinase called Aurora2, STK15 or BTAK belongs to the serine / threonine kinase family. Bischoff et al. have shown that Aurora2 is oncogenic and is amplified in human colorectal carcinoma cells (EMBO J, 1998, 17, 30523065). It has also been shown in cancers involving epithelial tumors, such as breast cancer.

SUMMARY OF THE INVENTION

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

(I) where

R ¹ is hydrogen, -C (= O) -NY ¹ Y ² , -C (O) -OR ⁵ , -SO ² -NY ¹ Y ² , -SO 2 -R ⁷ , -C (= O) R ⁷ , or R ¹ may be alkenyl, alkenyloxy, alkyl,

alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cycloalkyl, cyano, halogen, heteroaryl, heterocycloalkyl, -CHO (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), -C (= O) NY ¹ Y ² , -C (= O) -0R ⁵ , -ΝΥ ^ Ύ ² , -N (R ⁶ ) -C (= O) R ⁷ , -N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , -N (R ⁶ ) -SO 2 -R ⁷ , N ( R ⁶ ) -SO 2 -NY ³ Y ⁴ , -OR ⁷ , -C (O) -R ⁷ , hydroxyl, alkoxy, and carboxyl;

R ² is one or more selected from the group consisting of hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halogen, hydroxyl, heteroaryl, heterocycloalkyl, nitro, R 2 ⁴ , -C (= O) -ΝΥ ⁴ Υ ² , -C (= O) -OR ⁵ , -NY ¹ Y ² , -N (R ⁶ ) -C (= O) -R ⁷ , -N (R ⁶ ) -C (= O) NY ³ Y ⁴ , -N (R ⁶ ) -C (= O) -OR ⁷ , -N (R ⁶ ) -SO 2 -R ⁷ , N (R ⁶ ) -SO ₂ -NY ³ Y ⁴ , -SO ₂ -NY ¹ Y ^2, and -ZR ⁴ ;

R ³ is hydrogen, cyano, halogen, hydroxyl, nitro, R ⁴ , ΝΥ ⁷ Υ ² , -ZR ⁴ , -C (= O) -OR ⁵ , -C (= O) - R ⁷ , -C (= O) -NY ² Y ² , -N (R ⁸ ) -C (= O) -R ⁴ , -N (R ⁸ ) -C (= O) -ΝΥΝΥΎΎ ^2, N (R ⁸⁾ -C (= 0) -OR ⁵ group, -S02-NY ³ Y ^4, or -N (R ⁸⁾ -SO 2 R ^7, or R ³ is aryl, heteroaryl, , alkenyl or alkynyl, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cyano, halogen, hydroxyl, heteroaryl, heterocycloalkyl-

nitro, -C (= O) -NY ¹ Y ² , -C (= O) -OR ⁵ , -NY ^X Y ² , -N (R ⁶ ) -C (= O) - R ⁷ , -N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , N (R ⁶ ) -C (= O) -OR ⁷ , -N (R ⁶ ) -SO 2 -R ⁷ , -N (R ⁶⁾ -SO 2 NY ³ Y ^4, -SO ₂ NY ¹ Y ^2, or -zr ^4;

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

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

R ⁶ is hydrogen or lower alkyl;

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

R ⁸ is hydrogen or lower alkyl;

Y ¹ and Y ² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted with one or more groups selected from the group consisting of aryl,

halogen, heteroaryl, hydroxyl, -C (= O) NY ³ Y ⁴ , -C (= O) -OR ⁵ , -NY ³ Y ⁴ , -N (R ⁶ ) -C (= 0) ^-R7, -N (R ⁶⁾ -C (= 0) -NY ³ Y ^4, -N (R ⁶⁾ -SO 2 R ^7, -N (R ⁶⁾ -SO 2 NY ³ Y ⁴ and -OR ⁷ ; or the group -ΝΥΝΥ ΝΥ ² may form a cyclic amine;

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

Z is O or S (O) _n ;

n is zero or an integer of 1 or 2;

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

As used herein, the term "compound of the present invention and equivalent terms of a compound of formula I as described above, including prodrugs, pharmaceutically acceptable salts and solvates, for example hydrates, if the context permits. Similarly, with respect to intermediates, whether or not claimed, they also include salts and solvates when the context permits. For the sake of completeness, the following examples are given several times in the text, but these examples are illustrative only when the context permits and do not preclude any further embodiment.

corresponding to the claimed compounds or other embodiments, if the context permits.

The following terms used above and elsewhere in the text of the present invention have the following meanings, unless otherwise indicated:

The term "patient" encompasses both human and other mammals.

The term "acidic bioisosteres" refers to groups that are chemically and physically similar and provide similar biological properties to carboxyl groups (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 Bioisosterism In Drug Design; Yun, Hwahak Sekye, 1993, 33, pages 576579 Application Of Bioisosterism To New Drug Design; Zhao, Huaxue Tongbao, 1995, pages 34-38 Bioisosteric Replacement And Development Of Lead Compounds In Drug Design; Graham, Theochem, 1995, 343, Pages 105-109 Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions (Bioisosteres). Examples of suitable bioisosteres include: -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C (= O) CH ₂ SH, -C (= O) -NHCN, sulfo , phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoy-1,3-hydroxy-3-cyclobuten-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

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

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

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

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

"Alkoxy" is an alkyl-O- group, wherein the alkyl group is as defined herein. Examples of alkoxy include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy and heptoxy.

"Alkoxycarbonyl" is an alkyl-O-CO- group wherein the alkyl group is as defined herein.

Examples of alkoxycarbonyl groups include methoxy and ethoxycarbonyl.

Unless otherwise indicated, the term "alkyl" means an aliphatic hydrocarbon group which may be straight or branched and may contain 1 to 15 carbon atoms in the chain, optionally substituted with one or more halogen atoms. Preferred alkyl groups contain 1 to 6 carbon atoms. "A lower alkyl group as a single group or as part of a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, unless otherwise specified, is an aliphatic hydrocarbon group which may be straight or branched and contains 1 to 4 carbon atoms in the chain . Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl , a decyl group and a dodecyl group. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl.

An alkylene group is an aliphatic divalent group derived from a straight or branched alkyl group wherein the alkyl group is as defined above. Examples of alkylene groups include methylene, ethylene and trimethylene.

"Alkylenedioxy is an -O-alkylene-O- group in which the alkylene group is as defined above. Examples of alkylenedioxy include methylenedioxy and ethylenedioxy.

"Alkylsulfinyl is an alkyl-SO- group in which the alkylene group is as defined above. Preferred alkylsulphinyl • · «fcfc · ·· ·· * · fc • • • ···· fcfc fcfcfc · · · · fcfcfc fcfcfc • ···· ·· ·« • fcfc fcfcfcfc fcfc fcfc fcfcfc fcfcfcfc · »fcfc a nylon groups are groups wherein the alkyl group is an alkyl group having 1 to 4 carbon atoms.

"An alkylsulfonyl group is an alkyl-SO 2 - z group in which the alkylene group is as defined above. Preferred alkylsulfonyl groups are those wherein the alkyl group is an alkyl group having from 1 to 4 carbon atoms.

"Alkylsulfonylcarbamoyl is an alkyl-SO ₂ -NHC (= O) - group in which the alkylene group is as defined above. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is an alkyl group having 1 to 4 carbon atoms.

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

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

Aroyl is an aryl-CO- group, wherein the aryl group is as defined herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl groups.

9 «« 9 ·>

• 9 • 9 • 9

"Aroylamino is an aroyl-ΝΗ- group wherein the aroyl group is as defined above.

"An aryl group as a single group or as part of a group is: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic group having 6 to 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic group in which an aryl group and a cycloalkyl group or a cycloalkenyl group are condensed to form a cyclic structure such as tetrahydronaphthyl, indenyl or indanyl. Unless otherwise indicated, aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, wherein "aryl substituent" is, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio , aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, heteroaryl, heteroaryl, carboxyl, (or) heteroaroylaminoskupina, heteroaryloxy, hydroxyl, nitro, trifluoromethyl, -NY ³ Y group ^4, -CON ³ Y ^4, -SO ₂ NY ³ Y ^4, -NY ³ -C (= 0) alkyl, -NY ^{3 C 1-4} alkyl or alkyl optionally substituted by aryl, heteroaryl, hydroxyl or -NY ³ Y ⁴ .

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

"Arylalkyloxy is an arylalkyl-Ο- group wherein the arylalkyl group is as defined above. Examples of arylalkyloxy include benzyloxy and 1- or 2-naphthalenmethoxy.

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

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

"Aryloxy" is an aryl-Ο- group in which the aryl group is as defined above. Examples of aryloxy include phenoxy and naphthoxy, each of which is optionally substituted.

Aryloxycarbonyl is an aryl-O-C (= O) - group in which the aryl group is as defined above. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

Arylsulfinyl is an aryl-SO- group wherein the aryl group is as defined above.

Arylsulfonyl is an aryl-SCg- group as defined above.

where aryl

Arylsulfonylcarbamoyl is an aryl-SO ₂ -NHC (= O) - group wherein the aryl group is as defined above.

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

"Azaheteroaryl is an aromatic carbocyclic group containing 5 to 10 ring atoms, one of which is a nitrogen atom and the other ring members are a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl and tetrahydroindolizinyl.

"A cyclic amino group is a 3- to 8-membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by a nitrogen atom and which (i) may contain another heteroatom-containing group selected from oxygen, sulfur, SO ₂ , or NY ⁵ (wherein Y ⁵ is hydrogen, alkyl, aryl, arylalkyl, -C (= O) -R ⁷ , -C (= O) -OR ^7, or -SO ₂ R ⁷ ); and (ii) may be fused to another aryl group (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic ring system. Examples of cyclic amino groups include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like.

A cycloalkenyl group is a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and containing 3 to 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

"A cycloalkyl group is a saturated monocyclic or bicyclic ring system containing 3 to 10 carbon atoms, optionally substituted with an oxo group. Examples of monocyclic cycloalkyl rings include cycloalkyl groups containing 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

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

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

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

"Heteroaroylamino" is a heteroaroyl-NH- group wherein the heteroaryl group is as defined above.

"A heteroaryl group as a single group or as part of a group is: (i) an optionally substituted aromatic monocyclic or multicyclic organic group containing 5 to 10 ring members in which one or more ring members

is / are other than a carbon atom such as a nitrogen atom, an oxygen atom or a sulfur atom (such groups include, for example, benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl , oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl, optionally substituted by one or one or more a plurality of aryl group substituents as defined above, except where expressly stated otherwise); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic group in which the heteroaryl group and the cycloalkyl group or the cycloalkenyl group are condensed to form a cyclic structure (e.g., groups containing pyrindanyl groups optionally substituted with one or more aryl group substituents, unless otherwise indicated ). Optional substituents include one or more "aryl group substituents" as defined above, unless explicitly stated otherwise.

"Heteroarylalkyl is a heteroaryl-alkyl- group in which the heteroaryl group and the alkyl group are as defined above. Preferred heteroarylalkyl groups contain alkyl groups having 1 to 4 carbon atoms. Examples of heteroarylalkyl groups include pyridylmethyl.

"Heteroarylalkyloxy is a heteroarylalkyl-O- group in which the heteroarylalkyl group is as defined above. Examples of heteroaryloxy groups include optionally substituted pyridylmethoxy.

• • •

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

"Heteroarylsulfonylcarbamoyl" is a heteroaryl-SO ₂ -NH-C (= O) group in which the heteroaryl group is as defined above.

"A heterocycloalkyl group is: (i) a cycloalkyl group having 3 to 7 ring members which contains one or more heteroatoms or groups containing heteroatoms selected from oxygen, sulfur and NY ⁵ and may be optionally substituted with oxo; (ii) a partially saturated multicyclic heterocarbocyclic group in which the aryl group (or heteroaryl group) is optionally substituted with one or more aryl group substituents, and the heterocycloalkyl group are condensed to form a cyclic structure. (Examples include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl).

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

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

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

Suitable esters of compounds of formula I containing a carboxyl group are, for example, those described in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.

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

A particularly suitable class of esters of compounds of formula I containing a hydroxyl group may be formed from acidic groups selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, pages 2503-2507, and includes substituted (aminomethyl) benzoates, for example dialkylaminomethylbenzoates, in which two alkyl groups may be joined together and / or interrupted by an oxygen atom or an optionally substituted nitrogen atom, for example an alkylated atom nitrogen, especially (morpholinomethyl) benzoates, e.g.

4- (morpholinomethyl) benzoates, and (4-alkylpiperazin-1-yl) benzoates, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

When a compound of the present invention contains a carboxyl group or a sufficiently acidic bioisoster, base addition salts may be formed and are a more convenient form for use; in practice, corresponding salts are formed when using salt

The amount as when using the acid in free form. Bases which can be used for the preparation of basic addition salts preferably include those which, in combination with the free acid, provide pharmaceutically acceptable salts, the cations being non-toxic to patients whose use, i.e., salts, at pharmaceutical dosages of salts, so beneficial inhibitory effects own free base caused by cations.

The pharmaceutically acceptable salts, including those derived from the alkali metal and alkaline earth metal salts of the present invention, include salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide , magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, piperazine) aminomethane, tetramethylammonium hydroxide, and the like.

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

Acid addition salts are more suitable for use in the present invention; and in practice the salt forms the corresponding amount as when using the free base form. Acids which can be used for the preparation of acid addition salts preferably include those which, in combination with the free base, produce pharmaceutically acceptable salts, i.e. salts whose anions are nontoxic to patients in pharmaceutical doses of salts, so that the beneficial inhibitory effects that are intrinsic free base, are not adversely affected by side effects caused by anions. Although pharmaceutically acceptable salts are mentioned

of the basic compounds preferred, all acid addition salts are useful as sources of the free base forms even when the corresponding salt as such is only required as an intermediate, for example when the salt is formed solely for purification and identification purposes or when used as an intermediate in the preparation of a pharmaceutically acceptable salts by ion exchange procedures. Pharmaceutically acceptable salts of the present invention include those derived from inorganic and organic acids and include hydrogen halides such as hydrochlorides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates , fumarates, maleates, methylene-bis-beta-hydroxynaphthoates, gentisates, isethionates, dip-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

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

With respect to the compounds of formula (I) above, the following groups of compounds are preferred and preferred:

In particular, R ¹ may be:

(i) hydrogen; (ii) C 1 -C 4 alkyl [e.g., -CH ₃ or -CH ₂ CH ₃ ];

(iii) a C 1 -C 4 alkyl group substituted with a halogen atom [e.g., -CH ₂ CF ₃ ];

(iv) a C 1 -C 4 alkyl group substituted with a hydroxyl group [e.g., -CH ₂ OH, -CH ₂ CH ₂ OH, or -CH ₂ CH ₂ CH ₂ OH];

(v) C 1 -C 4 alkyl substituted with -N (R ⁶ ) C (= O) -R ⁷ [for example, -CH ₂ CH ₂ CH ₂ NHC (= O) CH ₃ ];

-C (= O) -nyl (vi) an alkyl group having from 1 to about 1 substituted by a carbon atom subs [e.g.

-CH-C (= O) -O]:

(vii) a hydroxyl-substituted cycloalkylalkyl group

u-CTU TI \ c- ^CH 2 l · _CH2 OH group [e.g., a group

Compounds of formula I wherein R ¹ is hydrogen, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF _3, or t

-CH-C1-O) -NO are particularly preferred. R ¹ is particularly preferably hydrogen atom.

R ² is preferably:

(i) a carboxyl group or an acidic bioisoster (e.g.

N '/' ‘NH

I);

(ii) a hydroxyl group;

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

(iv) a heteroaryl group [e.g., a group or a pyridyl group];

(v) -OR ⁴ where R ⁴ is an alkyl group [e.g., -OCH 3];

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

-o-c-ch ₂ CH ₂ OH or -OCH ₂ CH (OH) CH ₂ OH];

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

(viii) -OR ⁴ where R ⁴ is an alkyl or cycloalkyl group substituted with one or more carboxyl groups [e.g., -OCH ₂ CO ₂ H, -OCH (CH ₃ ) CO ₂ H ττ f * —- ΓΠ ⁿ 2y y ^and 2-o-c-ch ₂ ];

CO „H or a group

99 [ix] -OR ⁴ , wherein R ⁴ is a cycloalkyl group substituted with -O-C-CH 2, -C (= O) -NY ¹ Y ² [for example

CONH ₂ or h ₂ c-ch ₂ -o-c-ch ₂ J;

group

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

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

(xii) -N (R ⁶ ) -C (= O) -R ⁷ [e.g. -NHC (= O) CH ₃ ] group.

Compounds of formula I wherein R ² is -OCH 3 or a group -CONHC (CH3) 2CH2OH, are particularly preferred. More preferably, R ² is -OCH 3.

R ³ can preferably be:

(i) a hydrogen atom;

(ii) cyano;

(iii) an optionally substituted aryl group (e.g., a phenyl group);

• · »

(Iv) optionally substituted heteroaryl (for example optionally substituted pyridyl or optionally substituted indolyl, especially

i //

N or a group

);

(v) an alkyl group (for example a methyl group or an ethyl group);

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

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

(viii) an alkyl group substituted with -OR ⁷ (for example, -CH ₂ -CH ₂ -OCH ₃ );

(ix) -ZR ⁴ , especially -OCH ₃ , -OCH ₂ CH ₃ , -OF ₂ H, or -OCH ₂ -CH ₂ -OCH ₃ ;

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

(xi) -C (= O) -NY ^X Y ² , especially -C (= O) NHCH ₃ or -C (= O) -NH-C (CH ₃ ) ₂ -CH ₂ OH; ar ~ \

-NO (xii) -NY ^X Y ² group, especially the group ·· ···· · · · ···

Compounds of formula I wherein R ³ is hydrogen, cyano, pyridyl, trifluoromethyl, -CH ₂ CH ₂ -C (= O) NHCH ₃ , -OCF ₂ H, -C (= O) -NHr ~ \

C (CH ₃ ) ₂ -CH ₂ OH or a group More preferably R ³ is -OCH ₃ .

are particularly preferred.

R ² is preferably bonded in the 5-position of the indole ring.

Indole group

circle.

is preferably bound in a position that the present invention is particular and preferred

It should be noted the appropriate combination above.

The following compounds are particularly preferred:

The compounds include all of the groups listed herein

(ΙΠ) ····················· · 9 · 99

ΟΜθ

(IN)

(VI) (VII)

(IX)

(XVIQ) (XIX) (XX) ····

• ····

(xxm) (xxm) (xxm)

(XXIV)

(XXV)

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

Particularly preferred compounds of the present invention are the following:

99

9 9

9

Ή (ΧΠ)

9 9

9 9 9

9 9 9

99

9999

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

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

The compounds of the present invention possess advantageous pharmacological activity and are therefore formulated into pharmaceutical compositions and are used in the treatment of patients suffering from certain diseases. Accordingly, the present invention provides as a further aspect the compounds of the present invention and compositions comprising the compounds of the present invention for use in therapy. The compounds of the present invention block the catalytic kinase activity according to the tests described in the literature and in vivo procedures described below, and the results of these tests are believed to be consistent with the pharmacological activity in humans and other mammals. Thus, in another embodiment, the present invention relates to compounds of the present invention and compositions comprising compounds of the present invention for use in treating patients suffering from diseases that can be alleviated by administration of protein kinase inhibitors (e.g. Syk, FAK, KDR or Aurora2), particularly a Syk kinase inhibitor. For example, the compounds of the present invention are useful in the treatment of inflammatory diseases such as asthma; inflammatory dermatoses (eg, psoriasis, dematitis herpetiformis, eczema, necrosis and cutaneous vasculitis, bullous disease); allergic rhinitis and allergic conjunctivitis; arthritis, including arthritis, rheumatoid arthritis, and other arthritic diseases such as rheumatoid spondylitis, gout arthritis, traumatic arthritis, measles arthritis, psoriatic arthritis, and osteoatritis. The compounds are also useful in the treatment of chronic obstructive pulmonary disease (COPD), acute synovitis, autoimmune diabetes, acute encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus disease, and other organ rejection in transplantation; cancer and tumors (such as colorectal cancer, prostate cancer, breast cancer, thyroid cancer, colon cancer and lung cancer) and inflammatory bowel disease. Further, the compounds of the present invention are useful as tumor anti-angiogenic agents.

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

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

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

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

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

According to a further aspect, the present invention provides a method of treating a human or animal suffering from or at risk of a disease which may be alleviated by administering a proteinaceous inhibitor. Kinases (e.g., Syk, FAK, KDR or Aurora2), such as the disease described above, wherein the method comprises administering an effective amount of a compound of the present invention or a composition comprising a compound of the present invention to a patient. An effective amount means an amount of a compound of the present invention effective in inhibiting the catalytic activity of a protein kinase such as Syk, FAK, KDR or Aurora2, and thereby achieving the desired therapeutic effect.

It is understood that references to treatment include prophylactic treatment as well as the treatment of diseases that have arisen.

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

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

The compositions of the present invention can be prepared using conventional procedures using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be prepared in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of sweetening, flavoring, coloring or stabilizing agents to provide acceptable compositions. The choice of vehicle and the active compound content of the vehicle are usually determined by the solubility and chemical properties of the active compound,

4 © © © · © © © © © © © · • • • • • • • • • • • • • • • • • • The particular mode of administration and the conditions that are common in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and disintegrating agents such as starch, alginic acid and some complex silicates associated with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used to prepare the tablets. For the preparation of capsules, it is preferable to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they may contain emulsifying agents or agents which promote suspension stability. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products of the present invention in vegetable oils, for example, 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 also sterile aqueous solutions of pharmaceutically acceptable salts. Salts of the products of the present invention are particularly suitable for administration by intramuscular or subcutaneous injection. Aqueous solutions, including salt solutions in pure distilled water, may be used for intravenous administration provided that their pH is appropriately adjusted, suitably buffered and isotonic with sufficient glucose or sodium chloride, and sterilized by heating, irradiation or microfiltration .

Gels (based on water or alcohol), creams or ointments containing the compounds of the present invention may be used for topical administration. The compounds of the present invention may also be added to a gel or base for administration in a vein

in the form of a patch, which may allow a controlled release of the compound across the transdermal barrier.

For inhalation administration, the compounds of the present invention may be dissolved or suspended in a suitable carrier for use as a nebulizer or suspension or aerosol solution, or may be absorbed or adsorbed onto a suitable solid carrier for use in dry powder inhalers.

Solid compositions for rectal administration include suppositories prepared by known methods and containing at least one compound of the present invention.

The percentage of active ingredient in the composition of the present invention may be varied, with a ratio necessary to allow for appropriate dosing of the compound. Of course, it is possible to administer several unit dosage forms simultaneously. The appropriate dose will be determined by the physician and will depend upon the desired therapeutic effect, the mode of administration and the duration of treatment, and the condition of the patient being treated.

In an adult patient, the dose will generally be between 0.001 to 50, preferably 0.001 to 5, mg / kg body weight per day by inhalation, between 0.01 to 100, preferably 0.1 to 70, more preferably 0.5 to 10 mg / kg of body weight per day by oral administration, and between 0.001 to 10, preferably 0.01 to 1, mg / kg of body weight per day by intravenous administration. In each particular case, the dosage will be determined according to factors related to the patient to be treated, such as age, weight, general condition and medical condition, and other characteristics that may affect the efficacy of the medicinal product.

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

The compounds of the present invention can be prepared by applying or modifying known procedures, by the methods described herein or in the literature, for example those described in R. C. Larock, Comprehensive Organic Transformations, VCH publishers, 1989.

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

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

(XXVIII) wherein R ³ is as defined above X ¹ is a halogen atom, preferably an iodine atom, or a triflate group, with a compound of formula XXIX:

(XXIX) wherein R ¹ and R ² are as defined above. The condensation reaction may conveniently be carried out, for example, in the presence of a metal catalyst complex such as tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate in aqueous dimethylformamide at a temperature up to the boiling point of the reaction mixture. This reaction is usually carried out with a pyrrole NH in a compound XXVIII protected for example with a tosyl group and an indole NH in a compound XXIX protected for example with a tert-butyloxycarbonyl group.

Compounds of formula I wherein R ² and R ³ are as defined above and R ¹ is an optionally substituted alkyl group are prepared by reaction of the corresponding compounds of formula I wherein R ² and R ³ are as defined above and R ¹ is hydrogen, with the appropriate allyl halide R ² -X ² wherein R ² is an optionally substituted alkyl group and X ² is a halogen atom. This reaction is particularly suitable. · · · · Reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce reakce For the preparation of compounds of formula I wherein R ¹ is morpholinoacetyl.

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

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

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

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

As another example of the interconversion process, compounds of formula I containing a -C (= O) NY ¹ Y ^{2 group can be} prepared by condensing compounds of formula I containing a carboxyl group with an amine of formula HNY ¹ Y ² to obtain an amide bond using standard peptide coupling, for example, condensation in the presence of O- (7-azabenzotriazol-1-yl) 1,1,3.3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature. This process is particularly suitable for the preparation of (i) compounds of formula I wherein R ³ is -C (= O) -NY ¹ Y ² or (ii) compounds of formula I wherein R ² is -C (= O) ) -ΝΥ ³ Υ ² . The condensation can also be carried out by reacting compounds of formula I containing a carboxyl group with N - {(dimethylamino) (1H-1,2,3-triazolo [4,5-b] pyridin-1-yl) methylene} - N -oxide - N-methylmethanaminium hexafluorophosphate in the presence of a suitable base such as diisopropylethylamine in an inert solvent such as dimethylformamide and at room temperature, and then by reaction with an amine of formula vzorce ² Υ ² (for the preparation of compounds of formula I containing -C (= O) -NH ₂ can be used ammonium chloride). The condensation can also be carried out by reacting compounds of formula I containing a carboxyl group with 2- (ΙΗ-benzotriazol-1-yl) 1,1,3.3-tetramethyluronium hexafluorophosphate, in dry dimethylformamide, followed by reaction with an amine of formula HNY ¹ Y ² in the presence of diisopropylethylamine .

As another example of the interconversion process, compounds of formula I containing a -CH 2 OH group can be prepared by reducing the corresponding compounds of formula I containing a -CHO group or a -CO ₂ R ^{7 group} (where R ⁷ is a lower alkyl group). For example, the reduction can be carried out by reaction with lithium aluminum hydride, in an inert solvent such as tetrahydrofuran, and at a temperature between room temperature and the boiling point of the reaction mixture.

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

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

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

Fcfc

As another example of the interconversion process, compounds of formula I wherein R ¹ is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted with -C (= () NY ¹ Y ² , -OR ⁷⁾ , may be -C (= O) -OR ⁷ , -NY ¹ Y ² , by alkylation of the corresponding compound of formula Ia, wherein R ¹ is hydrogen, with a suitable halide of formula XXXI:

R ¹ -X ⁴ (XXXI) wherein R ¹ is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted with -C (= O) NY ¹ Y ² , -OR ⁷ , -C (= O) -OR ⁷ , -NY ¹ Y ² , and X ⁴ is halogen, preferably boron, using standard alkylation conditions, such as those described above.

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

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

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

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

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

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

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

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

by reaction of the free base of known methods. For example, the compounds of

According to another aspect of the present invention, addition salts of the compounds of the present invention may be prepared with an appropriate acid, by means of which acid addition salts of the present invention may be prepared either by dissolving the free base in water or aqueous alcoholic solution or other suitable solvent containing the appropriate acid and isolating the salt by evaporation solution or by reacting the free base and acid in an organic solvent, wherein the salt is separated directly or can be obtained by evaporating the solution.

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

The compounds of the present invention can be regenerated from the base addition salts by known methods. For example, the parent compound of the present invention can be regenerated from the base addition salt by treatment with an acid, such as hydrochloric acid.

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

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

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

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

Scheme 1

(XXXH)

Tosyl (xxxm)

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

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

(ii) subsequently reacting the obtained compound of formula XXXIII with butyllithium in tetrahydrofuran, at a temperature of about -78 ° C;

(iii) reacting the obtained anion with iodine.

Intermediates of formula XXXIII wherein R ³ is heteroaryl may be prepared by reaction of compounds of formula

XXXIII, where R ³ is a halogen atom such as a chlorine atom,

with a borane of formula R ³ BEt ₂ , wherein R ³ is a heteroaryl group. The reaction is conveniently carried out in the presence of tetrakis (triphenylphosphine) palladium (0) and potassium carbonate, in tetrahydrofuran at the boiling point of the reaction mixture. This reaction is particularly suitable for the preparation of compounds of formula XXXIII wherein R ³ is a pyridyl group.

Intermediates of formula XXXIII wherein R ³ is a heteroaryl group may also be prepared by reacting compounds of formula XXXIII wherein R ³ is a halogen atom such as a chlorine atom with a heteroarylboronic acid of formula R ³ B (OH) ₂ in the presence of tetrakis (triphenylphosphine) of palladium (0) and an aqueous solution of sodium bicarbonate, in dimethylformamide, at the boiling point of the reaction mixture. This reaction is particularly suitable for the preparation of compounds of formula XXXIII wherein R ³ is an optionally substituted indolyl group.

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

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

DETAILED DESCRIPTION OF THE INVENTION

The conditions of high pressure liquid chromatography - mass spectrometry (LC-MS) to determine retention times (R _T ) were as follows:

• · • ··

Method A: Hypersil BDS C-18 reverse phase column (4.6 mm x 50 mm) operating under elution gradient conditions with a mixture of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05% acid trifluoroacetic mobile phase: (0.00 min 100% A: 0% B; linear gradient up to 100% B in 2 min; then held for 3.5 min); a flow rate of 1 ml / minute at a flow rate to the mass spectrometer of about 0.25 ml / minute; injection volume 10 μΐ; Hewlett Packard Model HPI 100 Series W detector 200nm wavelength; Evaporative light scattering (ELS) detection - temperature 46 ° C, nitrogen pressure 400 kPa (4 bar).

Method B: Gilson 215 Hypersil HyPURITY C-18 Injection Model 5 µm column (4.6 mm x 50 mm) operating under elution gradient conditions with a mixture of (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0, 05% trifluoroacetic acid as mobile phase: (0.00 minutes 95% A: 5% B; linear gradient to 95% B in 4 minutes; then 5% B in 4.5 minutes, then held for 6 minutes); Injection volume 5 µL and flow rate 1 ml / min to UV (DAD) detector, then flow 0.100 ml / min to mass spectrometer (positive electrospray), rest to ELS detector.

Method C: Model LCT Elemental Analysis Device attached to HP 1100. Compound detection was detected using an HP G1315A photodiode detector with a wavelength of 200 to 600 nm and a Sedex 65 launch light detector. The mass spectrum was recorded between 180 and 800 Data is analyzed using Micromass MassLynx software. Separation is carried out on a Hypersil BDS C18 column with a particle size of 3 µm (50 x 4.6 mm) eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% by volume trifluoroacetic acid in water containing 0.05% by volume acid

• · · · · · · · · · · · · ·

9 9 9

19 Trifluoroacetate over 3.5 minutes at a flow rate of 1 mL / minute. Total time including re-equilibration of the column is 7 minutes.

Example 1

2- [5-Methoxy-3- (4-trifluoromethyl-7H-pyrrolol-2,3-b] pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-ylethanone

Compound of Formula I

R ² is -OMe, R ³ is -CF ₃ , is attached at the 3-position of the indole ring at the 5-position of the indole ring of formula II:

MeO

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

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

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

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

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

(v) reacting the compound of formula (5) with lithium diisopropylamide in the presence of tetrahydrofuran, at -78 ° C, and then reacting the obtained anion with iodine to give 6-iodo-7- (toluene-4sulfonyl) -4-trifluoromethyl-7H-pyrrolo (2,3-b) pyrimidine (6).

(vi) condensing a compound of formula (6) with 1-tert-butyloxycarbonyl-5-methoxy-1H-indole-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) sodium bicarbonate, in aqueous dimethylformamide at boiling point and removing the tert -butyloxycarbonyl protecting groups in the presence of sodium hydride and then reaction 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 compound (7) by treatment with potassium hydroxide in methanol to give 6- (5-methoxy-1H-indol-3-yl) -4-trifluoromethyl-7H-pyrrolo [2,3-b] pyrimidine (8); and (ix) alkylating the compound of formula (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-6-yl-indol-1-yl] -1-morpholin-4-yl-ethanone (II).

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

A compound of formula I wherein R ¹ is -CH ₃ , R ² is

About me

And “X

N CHOH

H ²

R is bonded at the 3-position at the 5-position of the indole is a hydrogen atom, an indole ring of the ring of formula III and a group R ²

is a tie

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

(III) (i) reacting a compound of formula (9) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate and an aqueous solution of sodium hydroxide in toluene, to obtain a compound of formula (10);

(ii) reacting the compound of formula (10) with lithium diisopropylamide in tetrahydrofuran, at -78 ° C, then reacting the obtained anion with iodine to obtain the compound of formula (11);

(iii) condensing the compound of formula (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 a temperature fcfc · fcfc · fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfcfc Tert -butyl tert-butyloxycarbonyl protecting group in the presence of sodium hydride, in tetrahydrofuran, to obtain 6 - [(1-methyl-5-carbomethoxyindol) 3-yl] -7H-pyrrolo [2,3b] pyrimidine (13);

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

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

Example 3

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

A compound of formula I wherein R ¹ is v

,AND

-CHf N

R ² is -OMe, R ³ is hydrogen, the group is bonded to the 3-position of the indole ring and the group R ² is bonded to the 5-position of the indole ring of formula IV:

• ·· · « * ·· * • · «· · · 4 4 « • ··· • · • 4 • • · · • · • 4 • · ·· ·· ··· ·· • · ··

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

(IV) (i) condensation of 6-iodo-7- (toluene-4-sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine of formula (11) and 1-tert-butyloxycarbonyl-5-methoxy-

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

(ii) reacting the compound of formula (16) with an aqueous methanolic potassium hydroxide solution while boiling to give 6 - [(5-methoxyindol) -3-yl] -7H-pyrrolo [2,3-b] pyrimidine of formula (17); and (iii) reacting the compound of formula (17) with sodium hydride in dimethylformamide, then reacting with 2-bromoacetic acid morpholinamide to give 2 - {[5-methoxy-3- (7H-pyrrolo [2,3-b] pyrimidin-6-yl)]. 1-Indol-1-yl] -1-morpholin-4-yl} -ethanone of formula (IV).

Example 4

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

-OMe, R ³ is -CN, ~ is bound at the 3-position of the indole ring and R ² is bound at the 5-position of the indole ring of formula VII:

ΜθΟ

cf ₃ (VB) was prepared according to the procedure illustrated in the following scheme:

(i) reacting the compound of formula (18) and potassium tannate and sodium iodide to form a salt

19) in the presence of carbonization of a compound of formula (20);

(ii) reacting a compound of formula (20) with thiourea in the presence of sodium ethoxide in ethanol to obtain a compound of formula (21);

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

(Iv) reacting a compound of formula (22) with phosphorus oxybromidein to give 4-bromo-7H-pyrrolo [2,3b] pyrimidine of formula (23);

(v) reacting a compound of formula (23) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate in an aqueous solution of sodium hydroxide in toluene to obtain a compound of formula (24);

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

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

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

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

Example 5

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

P Me Me

Λ.Χ

N CHOH

H ² group

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

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

(ii) reacting the compound of formula (26) with sodium hydride in tetrahydrofuran and then reacting with methyl iodide to obtain a compound of formula (29);

(ii) reacting the compound of formula (29) with carbon monoxide in the presence of palladium in methanol at boiling to give a compound of formula (30);

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

Example 6 ο

χ

-CH / N

A compound of formula I wherein R ¹ is υ

Λ.

'NHMe «φ φφ φφφφ φ · · φ · φ · ·

R ² is -OMe, R ³ is a group,

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

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

KOHSN.MeOH

(i) reacting a compound of formula (26) with methyl acrylate in the presence of palladium acetate, triphenylphosphine and triethylamine at a temperature of about 110 ° C to give a compound of formula (32);

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

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

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

· »

»9

9 99 99

Example 7

A compound of formula I wherein R ¹ is a group

O

Λ

-CH <N

R ² is group -OMe, R ³ is group \ _ // '-N F group O IN- N Λ H is bound in position 3 indole circle and group R ² is bonded at 5-position indole ring, formula VI:

is prepared according to the procedure illustrated in the following diagram.

(37) (VI) (i) condensing a compound of formula (26) with pyridine-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate, in aqueous dimethylformamide, boiling to give 4- (pyridine-3- yl) -6 - [(5-methoxyindol) -3-yl] -7 (toluene-4-sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine of formula (36);

(ii) reacting the compound of formula (36) with aqueous methanolic potassium hydroxide solution at boiling to give the compound of formula (37, Example 9); and (iii) alkylating the compound of formula (37, Example 9) with 4- (2-chloroacetyl) morpholine in the presence of sodium hydride in dimethylformamide to give 2- [5-methoxy-3- (4- (pyridin-3-yl) -7H) - pyrrolo [2,3b] pyrimidin-6-yl) -indol-1-yl] -1-morpholin-4-yl-ethanone of formula (VI).

· «· · · · · · © ©

Example 8

Compound of Formula I wherein R ¹ is -CH ₂ CH ₃ , R ² is / X

-NO ¹ ₃ \ _ / -OMe, R is a group,

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

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

·· ··· ·

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

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

Example 9

6- (5-Methoxy-1H-indol-3-yl) -4-pyridin-3-yl-7H-pyrrolo [2,3d] pyrimidine * · flfl ······ fl ··· fl ··· · · · · · flfl flfl flflflfl flfl flfl flflfl flflflfl flfl flfl

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

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

Example 10

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

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

M.p. = 184 ° C. MS: 309 [MH] ^&lt; ^{+ &gt;} .

Example 11

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

A solution of 448 mg of 4-methoxy-6- (5-methoxy-1H-indol-3-yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (reference • ft · Example 5) in 15 ml of methanol is treated with 1.96 g of potassium hydroxide. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a mixture of ethyl acetate and cyclohexane (80:20, v / v) to give 320 mg of 4-methoxy-6- (5-methoxy-1H-indol-3-yl) -7H-pyrrolo [2, 3-d] pyrimidine as a yellow solid, m.p. &gt; 260 ° C.

MS: 295 [MH] ^&lt; ^{+ &gt;} .

Example 12

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

A solution of 93 mg of 4- (5-methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) - 7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 9) in 5 ml of methanol was treated with 249 mg of potassium hydroxide. The reaction mixture was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by HPLC to give 9 mg of 4- (5-methoxy-1H-indol-3-one).

4 4 ···· 4 4 4

444 4 4444

4444 4

444 44 4444

444 44 444 4444 44 44 yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) -7H-pyrrolo [2,3-d] pyrimidine as a gum.

MS: 424 [MH] ^&lt; ^{+ &gt;} . LC-MS (Method B) R _t = 3.15 min.

Reference Example 1

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

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

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

Reference Example 2

7 - [(4-Methylphenyl) sulfonyl] -4-pyridin-3-yl-7H-pyrrolo [2,3d] pyrimidine

A solution of 4 g of 4-chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidine (Reference Example 3) and 2.1 g of diethyl 3-pyridylborane in 150 ml of tetrahydrofuran is treated with 0 65 g pallaΊΟ

Diumtetrakistriphenylphosphine and 3.59 g of potassium carbonate. The solution was stirred at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified twice by silica gel flash column chromatography eluting with a mixture of ethyl acetate and methanol (90/1, v / v) and a mixture of ethyl acetate and cyclohexane (50:50, v / v) to give 2.5 g of the title compound as an amorphous, solid substances.

MS: 351 [MH] ^&lt; ^{+ &gt;} . LCMS (Method B) R _t = 3.05 min.

Reference Example 3

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

A solution of 20 g of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (reference: Gerster, John F.; Hinshaw, Barbara C., Robins, Roland K., Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo [2,3d] pyrimidine ring, J. Heterocycl Chem. (1969), (2),

207-213) 28.6 g of para-toluenesulfonyl chloride in toluene are treated with a solution of 50 g of sodium hydroxide in 800 ml of water and 462 mg of tetrabutylammonium sulfate. The solution was stirred vigorously for 2 hours at room temperature and partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a gradient of ethyl acetate: cyclohexane (50:50 to 80:20, v / v) to give 2.5 g of the title compound as a solid, m.p. = 143 ° C.

LCMS (Method B) R _t = 2.7 8 min.

· ♦ ·· »·

Reference Example 4

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

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

MS: 464 [MH] ^&lt; ^{+ &gt;} . LC-MS (Method B) R _t = 4.39 min.

Reference Example 5

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

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

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

Reference Example 6

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

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

MS: 430 [MH] ^&lt; ^{+ &gt;} . LC-MS (Method B) R _t = 4.15 min.

Reference Example 7

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

A solution of 1.2 g of 4-methoxy-7H-pyrrolo [2,3-d] pyrimidine (Reference Example 8) and 1.77 g of para-toluenesulfonyl chloride in 60 ml of toluene is treated with a solution of 3.2 g of sodium hydroxide in 30 ml. water and 27 mg of tetrabutylammonium sulfate. The solution is stirred vigorously for 4 hours at room temperature and extracted between. 73 ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a gradient of ethyl acetate: cyclohexane (50:50 to 80:20, v / v) to give 2.23 g of the title compound as an amorphous solid.

MS: 304 [MH] ^&lt; ^{+ &gt;} . LC-MS (Method B) R _t = 3.88 minutes.

Reference Example 8

4-Methoxy-7H-pyrrolo [2,3-d] pyrimidine

To a solution of sodium methoxide prepared by the sequential addition of 2 g of sodium to 100 ml of methanol under an inert atmosphere is added 3.5 g of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (reference: Gerster, John F .; Hinshaw, Barbara C. Robins, Roland K. Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo [2,3-d] pyrimidine ring, J. Heterocycl Chem (1969), (2), 207-13. ).

The solution was stirred at 65 ° C for 16 h and partitioned between ethyl acetate and brine. The organic phase was separated, dried over magnesium sulphate and then evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to give

1.2 g of the title compound as an amorphous solid.

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

Reference Example 9

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

To a solution of 270 mg of 4- (5-methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1H-indol-3-yl) -7 - [(4 -methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (reference example) in 10 ml of dimethylformamide was added in an inert atmosphere 10 mg of aosium hydride as a 60% dispersion in mineral oil and 0.025 ml of methyl iodide. The solution was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to give 93 mg of the title compound as an amorphous solid.

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

Reference Example 10

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

A solution of 1.72 g of 4-chloro-6-iodo-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (Reference Example 11) and 1.26 g of tert-butyl-carboxyl-5. of methoxy-1H-indole-3-boronic acid (Reference Example 12) in 36.5 ml of dimethylformamide is successively treated with 9.1 ml of a saturated aqueous solution of sodium bicarbonate and 0.3 g of palladium tetrakistriphenylphosphine. (0.3g). The reaction mixture was stirred at reflux for 2 hours and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane ο ·

(30:70, v / v) to give 270 mg of the title compound as a gum.

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

Reference Example 11

4-Chloro-6-iodo-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine

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

MS: 434 [MH] ^&lt; ^{+ &gt;} . LC-MS (Method B) R _t = 4.26 min.

Reference Example 12 1-tert-butyl-carboxyl-5-methoxx-1H-indole-3-boronic acid

A stirred solution of 50 g of 3-bromo-5-methoxyindole-1-carboxylic acid tert-butyl ester (Reference Example 13) in 800 mL of tetrahydrofuran was treated with 49.5 mL of tributylborate under nitrogen, then cooled to -100 ° C. and then treated with 94 ml of a 2.5M solution of n-butyllithium in hexane, whereby

Ί6 the temperature is maintained at -90 ° C. When the addition is complete, the mixture is allowed to warm slowly to room temperature over 1 hour and quenched by the addition of 10 g of ice. The organic solvents were evaporated under reduced pressure and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The organic layer was dried over magnesium sulfate and then evaporated to give 28 g of the title compound as a cream colored solid.

MS: 314 [M + Na] ^+. LC-MS (Method C) R _t = 4.07 min.

Reference Example 13 3-Bromo-5-methoxy-indole-1-carboxylic acid tert-butyl ester

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

··

• Γ »

In vitro test procedure for SYK

Inhibitory activity of compounds to Syk kinase

The catalytic domain of Syk kinase (residue A340-N635) is expressed as a fusion protein in yeast and purified to homogeneity. Kinase activity is determined in 50 mM Tris-HCl buffer pH 7.0 containing 50 mM NaCl, 5 mM MgCl ₂ , 5 mM MnCl ₂ , 1 μΜ adenosine triphosphate and 10 μΜ synthetic peptide Biotin- (β-Alanine) ₃ DEEDYEIPP-NH ₂ . The enzyme reaction is terminated by the addition of a buffer containing 0.4M KF, 133mM EDTA, pH 7.0, containing a streptavidin-XL665 conjugate and a monoclonal phosphospecific antibody-europiumeryptate (Eu-K) conjugate. The properties of both fluorophores, XL-665 and Eu-K, are reported in G. Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014. The specific long-term XL-665 signal, produced only when the synthetic peptide is phosphorylated by Syk, is measured on a LJL Biosystems Analyst AD microtiter plate reader. Inhibition of syk activity by the compounds of the present invention is expressed as percent inhibition of control activity exhibited in the absence of test compounds. Particularly preferred compounds of the present invention inhibit syk activity at an IC 50 in the range of 100 µm to 100 nmol. Particularly preferred compounds of the present invention inhibit syk activity at an IC 50 in the range of 1 µπιοί to 100 nmol.

2. Antigen induced degranulation of basophilic leukemia cells in rats (RBL)

2.1 Cell culture, RBL-2H3 cell labeling and assay run

RBL-2H3 cells are stored in T75 flasks at 37 ° C and

5% CO ₂ , and passaged every 3-4 days. Cells are harvested, the flask is washed with 5 ml trypsin-EDTA, 5 ml trypsin is added to each flask and incubated for 2 minutes at room temperature. The cells are transferred to a tube with 14 ml of medium, centrifuged at 1100 rpm at room temperature for 5 minutes and resuspended at 2x10 ⁵ / ml. Cells are sensitized by adding 1 μΐ DNP specific IgE for every 10 ml of cells. Add 200 μΐ cells to each well of a flat-bottom 96-well microtiter plate (40,000 cells / well) and incubate overnight at 37 ° C and 5% CO ₂ . The next day compounds were prepared in 100% dimethylsulfoxide at 10 mM. Each compound is then diluted 1: 100 with assay buffer and then further diluted with 1% DMSO in assay buffer to give a final concentration of 0.03 to 30 μΜ. Add 80 μΐ of assay buffer, then 10 μΐ of the diluted compound to each well. Incubate for 5 minutes. Add 10 μΐ of DNP-HSA (100 ng / ml) to each well and incubate for 30 minutes at 307 ° C (no CO ₂ ). complete release. As a further control, buffer is added instead of DNP-HSA to another set of wells to determine the background of the assay. After 30 minutes incubation, the supernatants are transferred to a 96 well microtiter plate. Add 50 μΐ of the supernatant to each well of the assay plate. Add 100 μΐ of substrate solution to each well and incubate for 90 minutes at 37 ° C. To terminate the reaction, add 50 μΐ of a 0.4 M glycine solution and read the plate at 405 nm on a Molecular Devices SpectraMax 250 microplate reader.

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

«·

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

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

(iv) Using these data as the maximum (100%) and minimum (0%) values respectively, the experimental data was calculated as a percentage of the maximum response (indicated as% control).

(v) Using the Prism GraphPad software and non-linear least squares regression analysis, a dose response curve was plotted and the IC 50 value was calculated.

The compounds of the present invention inhibit antigen-induced degranulation of basophilic leukemia cells in rats (RBL) at an EC 50 in the range of 100 pmol to 1 µπιοί.

Claims (25)

Claims A compound of formula I wherein R ¹ is hydrogen, -C (= O) -ΝΥ-Ύ ² , -C (O) -OR ⁵ , -SO ,N ^ ² , -SO ² -R ⁷ , -C (= O) R ⁷ , or R ^{1 is} alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more groups selected from, which consists of an aryl group, a cycloalkyl group, a cyano group, a halogen atom, a heteroaryl group, a heterocycloalkyl group, a -CHO group or a five-membered, six-membered or seven-membered cyclic acetal derivative of -CHO, -C (= O) -NY ² Y ² , - C (= O) -OR ⁵ , -NY ¹ Y ² , N (R ⁶ ) -C (= O) -R ⁷ , -N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , -N (R ⁶⁾ -SO 2 R ^7, -N (R ⁶⁾ -SO ₂ -NY ³ Y ^4, -OR ^7, -C (= O) ^-R7, hydroxy, alkoxy and carboxy sk upina; R ² is one or more selected from the group consisting of hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, aryl, cyano, halogen, hydroxyl, heteroaryl, heterocycloalkyl, nitro, R ⁴ , -C (= O) -ΝΥΝΥΎ ² , -C (= O) -OR ⁵ , -NY ¹ Y ² , -N (R ⁶ ) -C (= O) -R ⁷ , -N (R ⁶ ) -C (= O) NY ³ Y ⁴ , -N (R ⁶ ) -C (= O) -OR ⁷ , -N (R ⁶ ) -SO 2 -R ⁷ , N (R ⁶ ) -SO ₂ -NY ³ Y ⁴ , -SO ₂ -NY ⁴ Y ^2, and -ZR ⁴ ; R ³ is hydrogen, cyano, halogen, hydroxyl, nitro, R ⁴ , NY ⁴ Y ² , -ZR ⁴ , -C (= O) -OR ⁵ , -C (= O) - R ⁷ , -C (= O) -NY ⁴ Y ² , -N (R ⁸ ) -C (= O) -R ⁴ , -N (R ⁸ ) -C (= O) -NY ¹ Y ^2, N (R ⁸⁾ -C (= 0) -OR ⁵ group, -SO 2 NY ³ Y ^4, or -N (R ⁸⁾ -SO 2 -R ^7, or R ³ is aryl, heteroaryl, alkenyl, or alkynyl, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cyano, halogen, hydroxyl, heteroaryl, heterocycloalkyl, nitro, -C (= O) -NY ¹ Y ² , -C (= O) -OR ⁵ , -NY ⁴ Y ² , -N (R ⁶ ) -C (= O) -R ⁷ , - N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , N (R ⁶ ) -C (= O) -OR ⁷ , -N (R ⁶ ) -SO ² R ⁷ , -N (R ⁶⁾ -SO ₂ -NY ³ Y ⁴ , -SO ₂ NY ¹ Y ^2, or -ZR ⁴ ; R ⁴ is allyl, cycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more groups selected from the group consisting of aryl, cycloalkyl, cyano, halogen, heteroaryl, heterocycloalkyl, hydroxyl, -CHO or a five-membered, six-membered or seven-membered acetal derivative of such a group -CHO, -C (= O) -NY ⁴ Y ² , -C (= O) -OR ⁵ , NY ¹ Y ² , -N (R) ^S ) -C (= O) -R ⁷ , -N (R ⁶ ) -C (= O) -NY ³ Y ⁴ , -N (R ⁶ ) -SO ₂ - R ⁷ , -N (R ⁶ ) -SO 2 -NY ³ Y ⁴ , -OR ^7, and -C (= O) -R ⁷ ; R ⁴ may also contain a group selected from the group consisting of oxygen, S (O) n, -NR ⁶ ; R ⁵ is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R ⁶ is hydrogen or lower alkyl; R ⁷ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R ⁸ is hydrogen or lower alkyl; Y ¹ and Y ² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted with one or more groups selected from the group consisting of aryl, halogen, heteroaryl, hydroxyl, -C (= O) NY ³ Y ⁴ , -C (= O) -OR ⁵ , -NY ³ Y ⁴ , -N (R ⁶ ) -C (= O) -R ⁷ , -N ^(R6) -C (= 0) -NY ³ Y ^4, -N (R ⁶⁾ -SO 2 R ^7, -N (R ⁶⁾ -SO 2 NY ³ Y ⁴ and -OR ^7; or the group -NY ⁴ Y ² may form a cyclic amine; Y ³ and Y ⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY ³ Y ⁴ may form a cyclic amine; Z is O or S (O) _n ; N is zero or an integer of 1 or 2; or An N-oxide, prodrug, acid bioisoster, pharmaceutically acceptable salt or solvate thereof; or an N-oxide, prodrug, or acidic bioisoster of this salt or solvate. The compound of claim 1, wherein R ¹ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by halogen, C 1 -C 4 alkyl substituted by hydroxyl, C 1 -C 4 alkyl substituted by - N (R ⁶⁾ C (= 0) -R ^7, alkyl having 1 to 4 carbon atoms substituted with a -C (= 0) ^-NY] Y ^2, or cycloalkylalkyl substituted by hydroxy. The compound of claim 1, wherein R ¹ is hydrogen, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF _3, or a group The compound of claim 1, wherein R ¹ is hydrogen. A compound according to any one of claims 1 to 4, wherein R ² is a carboxyl group or an acidic bioisoster, a hydroxyl group, a carboxyl-substituted alkyl group, a heteroaryl group, or is a R ² group -OR ⁴⁵ where R ⁴ is an alkyl group, -OR ⁴ where R ⁴ is an alkyl group or cycloalkylalkyl a group substituted with one or more hydroxyl groups, a -OR ⁴ group wherein R ⁴ is an alkyl group substituted with one or more alkoxy groups, a -OR ⁴ group wherein R ⁴ is an alkyl group or a cycloalkyl group substituted with one or more carboxyl groups, a group - OR ⁴ wherein R ⁴ is a cycloalkyl group substituted with -C (= O) -NY ^] Y ² or -C (= O) -R wherein R is alkyl or R ² is -Ο (= Ο) - Nebo ^Χ Υ ² or the group N (R ⁶ ) -C (= O) -R ⁷ . A compound according to any one of claims 1 to 4, wherein R ² is -OCH ₃ or -CONHC (CH ₃ ) ₂ CH ₂ OH. A compound according to any one of claims 1 to 4, wherein R ² is -OCH ₃ . A compound according to any one of claims 1 to 7, wherein R ³ is hydrogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, alkyl, alkyl substituted with one or more halogen atoms, alkyl substituted with C (= O) -NY ¹ Y ² , alkyl substituted with - oR ⁷ or R ³ group -zr ^4, -C (= 0) -OR ^5, -C (= 0) ^ -ΝΥ Ύ ^2, or -NY ¹ Y ^2nd A compound according to any one of claims 1 to 7, wherein R ³ is hydrogen, cyano, pyridyl, trifluoromethyl, -CH ₂ -CH ₂ -C (= O) NHCH ₃ , -OCF ₂ H, r group ~ \ -C (= O) -NH-C (CH ₃ ) ₂ -CH ₂ OH or a group A compound according to any one of claims 1 to 7, wherein R ³ is -OCH ₃ . A compound according to any one of claims 1 to 10, wherein R ² is bonded at the 5-position of the indole ring. A compound according to any one of claims 1 to 11, wherein the group is bound at the 3-position of the indole ring. The compound of claim 1 which is ΟΜβ o • ·· · MgO \ Or an N-oxide, prodrug, pharmaceutically acceptable salt or solvate thereof; or an N-oxide or prodrug of such a salt or solvate. The compound of claim 1 which is or an N-oxide, prodrug, pharmaceutically acceptable salt or solvate thereof; or an N-oxide or prodrug of such a salt or solvate. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 together with one or more pharmaceutically acceptable carriers or excipients. A method of treating a patient suffering from or susceptible to a disease which may be alleviated by administering a Syk catalytic activity inhibitor, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. ·· ··· « A method of treating an inflammatory disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. A method of treating a patient suffering from or susceptible to a disease that may be alleviated by administering an inhibitor of FAK catalytic activity, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of a composition according to claim 15. A method of treating a patient suffering from or susceptible to a disease that may be alleviated by administering a KDR catalytic activity inhibitor, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. A method of treating a patient suffering from or susceptible to a disease that may be alleviated by administering an inhibitor of Aurora2 catalytic activity, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. • · • ·· · ♦ 22. The method of claim 17 wherein the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis, or joint inflammation. The method of claim 17, wherein the inflammatory disease is asthma, psoriasis, dermatitis herpetiformis, eczema, necrosis vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, measles arthritis, psoriasis arthritis, psoriasis, psoriasis, psoriasis, psoriasis, psoriasis, psoriasis, psoriasis. or osteoarthritis. 24. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutically effective amount of a composition of claim 15. 25. The method of claim 21, wherein the cancer being treated is colorectal cancer, prostate cancer, breast cancer, thyroid cancer, skin cancer, colon cancer, or lung cancer.