EA007415B1 - 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

This invention relates to substituted pyrrolopyrimidines, their preparation, pharmaceutical compositions containing these compounds, as well as their pharmaceutical use for treating disease states that can be modulated by inhibiting protein kinases.

Protein kinases are involved in signal transduction processes that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases are divided into several groups: kinases, preferably phosphorylation residues of serine and / or threonine, and kinases, preferably phosphorylation residues of tyrosine [8.K. Napkk apb T. Nip! Er, RA8EV. 1. 1995, 9, p. 576-596]. Serine / threonine kinases include, for example, protein kinase C isoforms [A.S. № \\ 1op. 1. ΒίοΙ. SNET. 1995, 270, p. 28495-28498] and a group of cyclin-dependent kinases, such as sbs2 [1. Rshek, Tgepbk ίη VusNetuya1 8aepse5, 1995, 18, p. 195-197]. Tyrosine kinases include growth factor receptors that connect membranes, such as the epidermal growth factor receptor [8. Mt. Shba Appb M. Kauhawaky, Celliner 81dpa11td, 1992, 4, p. 123-132], as well as cytosolic non-receptor kinases, such as p56! Ck, p591 ¥ n, ΖΑΡ-70 and cck kinase [S. Snap A1., App. Wow. 1, 1994, 12, p. 555-592].

An excessively high activity of protein kinase is observed in many diseases resulting from abnormal cellular function. It can arise directly or indirectly, for example, as a result of failure of the correct control mechanisms of the kinase, caused, for example, by mutation, overexpression or improper activation of the enzyme; or excessive or insufficient production of cytokines or growth factors, also taking part in the transduction of signals in the forward or reverse direction from the kinase. It is expected that in all these cases, selective inhibition of the action of a kinase may play a positive role.

8uk is a 72-kI cytoplasmic protein tyrosine kinase, expressed in many hematopoietic cells and an essential element of several cascades linking antigen receptors to cellular responses. Thus, 8uk plays a central role in the signaling of the 1DE receptor with high affinity, PseB1, in mast cells and in the receptor antigen signaling in T and B lymphocytes. Signal transduction pathways in obese, T and B cells share common features. The ligand-binding domain of the receptor does not possess intrinsic tyrosine kinase activity. However, they interact with transducer subunits containing a tyrosine immunoreceptor based on activation motifs (1TAM) [M. Wechat, IT!, 1989, 338, p. 383-384]. These motifs are present in both β- and γ-subunits of PseB1, in the ξ-subunit of the T-cell receptor (TSB), as well as in the 1dCa and Ι§β subunits of the B-cell receptor (BCB). [К8.уap Ogk apb A. Uekk, 8th step 5 of the 1st, 1995, 7, p. 227-236]. After antigen binding and multimerization, residues of 1TAM are phosphorylated by protein tyrosine kinases from the 8gc family. 8uk belongs to a unique class of tyrosine kinases, which has two-tandem domains 8gc homology 2 (8H2) and a C-terminal catalytic domain. These 8H2 domains bind to TATM with high affinity, and this 8H2-mediated association of 8uk with an activated receptor stimulates the activity of 8uk kinase and localizes 8uk in the plasma membrane.

In 8uk-deficient mice, mast cell degranulation is inhibited, making it possible to suggest that it is an important goal for the development of mast cell stabilizing agents [R.8. Colo11o, Opsodepe, 1996, 13, p. 2595-2605]. Such studies have shown the important role of 8us in the VSV and TSC alarm [A.M. Snepd, No.! ITET, 1995, 378, p. 303-306, (1995), and I.N. DOWNLOAD! A1., 1Typodojyu1 Veutete, 1998, 165, p. 167-180]. It turns out that 8uk also takes part in the survival of eosinophils in response to IB-5 and OM-C8P [8. Wakekay e! A1., 1. Exp. Meb., 1996, 183, p. 1407-1414]. Despite the key role of the 8uk in the mast cell, BCB and T-cell signaling, there is little information about the mechanism of transmission of 8uk effectors in the forward direction. It turned out that the two adapter proteins, BJIC (B-cell linker protein, 8BP-65) and 8BP-76, are substrates of 8uk in B-cells and mast cells, respectively, and cause a section of 8uk with effectors in the forward direction [M. Ιδίιίηί e! A1., 1, 1999, 10, p. 117-125, and B.V. Nepbsk§-Tau1og e! A1., 1. Vyu1. SNET. 1997, 272, p. 1363-1367]. In addition, 8uk, it turns out, plays an important role in the signaling pathway SI40, which, in turn, plays an important role in the proliferation of b-cells [M. Ratk e! A1., 1. Exp. Meb., 1994, 179, p. 1923-1931].

8uk also takes part in the activation of platelets, stimulated through the low affinity of the 1dO receptor (Pc gamma B11A) or stimulated by collagen [R. Wapada e! A1., VusNet. 1., 1995, 311, (P! .2), p. 471-478].

Focal adhesion kinase (PAK) is a receptor-free tyrosine kinase involved in integrin-mediated signal transduction pathways. The PAK co-exists with integrins at the focal contact sites and the activation of the PAK; it turned out that the phosphorylation of its tyrosine in many cell types depends on the integrins binding to their extracellular ligands. The results of several studies support the hypothesis that RAK inhibitors may be useful in the treatment of cancer. For example, cells with a PAC-deficient poorly migrate in response to chemotactic signals and overexpression of the C-terminal domain of PAC blocks blocks cell proliferation, as well as chemotactic migration (81ed e1., 1. Ce118c1epse, 1999, 112, 2677-2691; apb

- 1 007415

Parasop8, T., Ce11, 1997, 97, 221-231); In addition, tumor cells treated with PAK antisense oligonucleotides lose their attachment ability and undergo apoptosis (Chi et al., Ce11 6ΐΌ \ ν1ι, ITT. 1996, 4, 413-418). Overexpression of cancer in prostate, breast, thyroid, rectum and lung cancer has been described. The expression level of cancer is directly correlated with tumors that demonstrate the most aggressive phenotype.

Angiogenesis or the formation of new blood vessels as a result of growth from an already existing vascular network is of major importance for embryonic development and organogenesis. Abnormal increased neovascularization is observed in rheumatoid arthritis, diabetic retinopathy, and during tumor development (Roktosh, No. 1. May., 1995, 1, 27-31). Angiogenesis is a complex multistep process involving activation, migration, proliferation, and survival of endothelial cells. Extensive research in the field of tumor angiogenesis over the past two decades has revealed a number of therapeutic targets, including kinases, proteases and integrins, which led to the discovery of many new anti-angiogenic agents, including COC inhibitors, some of which are currently undergoing clinical trials (Decippe e1 a1. , Sapseg Tga1ten1 Keu., 1997, 23, 263286). Angiogenesis inhibitors can be used as primary, auxiliary or even prophylactic agents that prevent the occurrence or re-growth of malignant tumors.

Several proteins involved in chromosome segregation and spindle assembly have been identified in yeast and fruit flies. The rupture of such proteins leads to improper segregation of chromosomes and the formation of monopolar or broken spindles. These kinases include 1p11 and aigoga kinases from 8. segeuVae and Drosophila, respectively, which are necessary for centrosome separation and chromosome segregation. One human homologue of yeast 1p11 was recently cloned and characterized by various laboratories. Such a kinase, called Aigoga2, 8TK15 or BTAK, belongs to the serine / threonine kinase family. VSHYYGG e1 a1. showed that Aigoga 2 is oncogenic and amplified in human colorectal cancer (EMBO I., 1998, 17, 3052-3065). Her presence has also been confirmed by examples of cancers involving epithelial tumors, such as breast cancer.

This invention provides substituted pyrrolopyrimidines of formula (I) capable of inhibiting one or more protein kanases, more preferably, PAK, COC, 8k kinase or Aigoga 2, especially 8k kinase

wherein

K ¹ is hydrogen, C _1-4 alkyl or morpholinyl-4-yl ethanone;

K ² is OCH ₃ ;

K ³ is OCH3, triftomethyl, pyridyl or indolyl, optionally substituted by a methoxy group;

and their corresponding оксид-oxides, prodrugs, and their acid bioisosteres; as well as pharmaceutically acceptable salts and hydrates of such compounds; and their оксид-oxides, prodrugs and their acid bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients.

In this description, the term "compounds of the present invention" and similar expressions mean the compounds of formula (I) described above and also include prodrugs, pharmaceutically acceptable salts and solvates, for example, hydrates, where the context allows. Similarly, reference to intermediates, regardless of whether they themselves are the object of the claims, also applies to their salts and solvates where the context allows. For clarification, where the context allows, the description sometimes cites specific cases, but such cases are purely illustrative and do not exclude other cases.

Unless otherwise specified, in the text of the description of this invention, the following terms have the following meanings:

“Patient” refers to humans and other mammals.

"Acid bioisostere" means a group having chemical and physical similarity, providing obviously similar biological properties, with a carboxy group (see Bhrschzku, Aiiia1 Korogl sh MeSchsch11 SkepshVu, 1986, 21, p.283, VuNo ^ epzt 1n Ogid Oydp ^ ayak 8eke, 1993, 33, pp. 576-579, Arrysayop oG Vu18o81ep8t To Ogid Seep; / Kao, Niahie Topdiao, 1995, pp. 34-38, Wiu18o81epse Ke

- 2 007415 p1assssps1 apy Osus1ortsp1 OG bsai Sotroynyk 1p Aegis Isidn; Sgayat. Tychosist. 1995, 343, p. 105-109, T11SogsRsa1 §1iy1S8 LRrNSy That Aegis Ismdn: a1 1SHI E1ss1toshs O181g1BiIop5 1p Vyukoistsk). Examples of suitable acid bioisosteres include: -C (= O) -PNON, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ 8H, -C (= O)-ί'. sulfo, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl alcohol, heteroarylsulphonylcarbamoyl, α-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4oxadiazolidone, etc. and 3-hydroxy-1methylpyrazolyl.

"Acyl" means an H-CO- or alkyl-CO-group in which the alkyl group has the meanings indicated in this description.

"Acylamino" means an acyl-MH group in which acyl has the meaning given in this specification.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched, having from 2 to 15 carbon atoms in the chain. Preferred alkenyl groups have from 2 to 12 carbon atoms in the chain; more preferably from 2 to 6 carbon atoms (for example, from 2 to 4 carbon atoms) in the chain. “Branched” in this specification means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; in this case, to a linear alkenyl chain. "Lower alkenyl" means from 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" represents an alkenyl-O-group in which alkenyl has the meaning given in this specification. An example of alkenyloxy is allyloxy.

"Alkoxy" represents an alkyl-O-group in which the alkyl group is as defined in this specification. Examples of alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, npropoxy, iso-propoxy, n-butoxy, and heptoxy.

"Alkoxycarbonyl" represents an alkyl-O-CO-group in which the alkyl group has the meanings indicated in this description. Examples of alkoxycarbonyl groups include methoxy and ethoxycarbonyl.

Unless otherwise indicated, “alkyl” means an aliphatic hydrocarbon group that may have a straight or branched chain having from about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Specific alkyl groups have from 1 to 6 carbon atoms. "Lower alkyl" as a group or part of lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl groups means, unless otherwise specified, an aliphatic hydrocarbon group that may have a straight or branched chain having 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl. Illustrative alkyl groups substituted by one or more halogen atoms include trifluoromethyl.

“Alkylene” means an aliphatic divalent radical derived from a straight or branched alkyl group, in which the alkyl group has the meanings indicated in this description. Examples of alkylene radicals include methylene, ethylene and trimethylene.

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

"Alkylsulfonyl" means an alkyl-8O-group in which the alkyl group has the previously indicated meanings. Preferred alkylsulfinyl groups are those in which the alkyl group is C1-4 alkyl.

"Alkylsulfonyl" means an alkyl-8O ₂ group in which the alkyl group has the previously indicated meanings. Preferred alkylsulfonyl groups are those in which the alkyl group is C1-4 alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-8O ₂ -MH-C (= O) -group in which the alkyl group has the previously indicated meanings. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C _1-4 alkyl.

“Alkylthio” means an alkyl-8-group in which the alkyl group is as previously defined. Examples of alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which (group) can have a straight or branched chain containing from 2 to 15 carbon atoms. Preferred alkynyl groups have from 2 to 12 carbon atoms in the chain, most preferably from 2 to 6 carbon atoms (for example, from 2 to 4 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, 3-methylbut-2-ynyl, and n-pentenyl.

“Aroyl” means an aryl-CO-group in which the aryl group has the meanings indicated herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl.

"Aroylamino" means an aroyl-MH-group in which aroyl has the previously indicated meanings.

“Aryl” as a group or part of a group means: () an optionally substituted monocyclic or polycyclic aromatic carbocyclic residue having from 6 to 14 carbon atoms,

- 3 007415 such as phenyl or naphthyl; or (i) an optionally substituted, partially saturated polycyclic aromatic carbocyclic residue in which the aryl and cycloalkyl or cycloalkenyl group are condensed together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indenyl ring. Unless otherwise noted, aryl groups may be substituted by one or more aryl group substituents that may be the same or different, and the “aryl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl , aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid bioisostere), cyano, halogen, heteroaroyl, Roar, heteroarylalkyloxy, geteroaroilamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, -ΝΥ ³ Υ ^4, -ΟΟΝΥ ³ Υ ^4, -8Ο2ΝΥ ³ Υ ^4, -№ ^ ³ -C (= O) alkyl, Well ³ alkyl or 8O2alkil optionally substituted with aryl, heteroaryl, hydroxy or -ΝΥ ³ Υ ⁴ .

“Arylalkyl” means an arylalkyl group in which the aryl and alkyl radicals are as previously defined. Preferred arylalkyl residue containing C1 _-4 alkyl. Examples of arylalkyl groups include benzyl, 2-phenethyl and naphthalen methyl.

“Arylalkyloxy” means arylalkyl-O-group in which the arylalkyl groups have the previously mentioned meanings. Examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

"Arylalkyloxycarbonyl" means arylalkyl-O-CO-group, in which arylalkyl groups have the previously mentioned meanings. An example of arylalkyloxycarbonyl is benzyloxycarbonyl.

“Arylalkylthio” means arylalkyl-8-group, in which the arylalkyl group has the previously indicated meanings. An example of an arylalkylthio group is benzylthio.

"Aryloxy" means an aryl-O-group in which the aryl group has the previously indicated meanings. Examples of aryloxy groups include phenoxy and naphthoxy, each of which is optionally substituted.

"Aryloxycarbonyl" means an aryl-O-C (= O) -group in which the aryl group has the previously indicated meanings. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"Arylsulfinyl" means an aryl-8O-group in which the aryl group has the previously indicated meanings.

"Arylsulfonyl" means an aryl-8O ₂ group in which the aryl group has the previously indicated meanings.

"Arylsulfonylcarbamoyl" means aryl-8O ₂ -LN-C (= O) -group in which the aryl group has the previously indicated meanings.

"Arylthio" means an aryl-8-group in which the aryl group has the previously indicated meanings. Examples of arylthio groups include phenylthio and naphthylthio.

"Azaheteroaryl" means an aromatic carbocyclic residue having from 5 to 10 ring members, in which one of the ring members is nitrogen, and the other ring members are selected from carbon, oxygen, sulfur and nitrogen. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl, and tetrahydroindolizinyl.

"Cyclic amine" means a 3-8 membered monocyclic cycloalkyl ring system in which one of the ring carbon atoms is replaced by nitrogen and which (ί) may also contain an additional heteroatom-containing group selected from O, 8, 8O ₂ , or ΝΥ ⁵ (where Υ ⁵ represents hydrogen, alkyl, aryl, arylalkyl, -C (= O) -K ⁷ , -C (O) -OK ⁷ or -8O ₂ K ⁷ ); and (i) can be condensed with additional aryl (for example, phenyl), heteroaryl (for example, pyridyl), heterocycloalkyl or cycloalkyl rings to produce a bicyclic or tricyclic ring system. Examples of cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyridoline, tetrahydroquinoline, and the like.

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

"Cycloalkyl" means a saturated monocyclic or bicyclic ring system having from 3 to 10 carbon atoms, optionally substituted by oxo. Examples of monocyclic cycloalkyl rings include C 3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

“Cycloalkylalkyl” means a cycloalkylalkyl group in which the cycloalkyl and alkyl residues have the previously mentioned meanings. Examples of monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

“Halogen” means fluorine, chlorine, bromine or iodine. Fluorine and chlorine are preferred.

"Heteroaroyl" means a heteroaryl-C (= O) -group in which the heteroaryl group has the meanings indicated in this application. Examples of heteroaryl groups include pyridylcarbonyl.

"Heteroaroylamino" means a heteroaroyl-MH-group in which the heteroaryl residue has the previously indicated meanings.

- 007415 “Heteroaryl” as a group or part of a group means: () an optionally substituted aromatic monocyclic or polycyclic organic residue, having from about 5 to about 10 ring members, in which one or more ring members represents (-s) ) other than carbon, for example, nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazylyl, pyrodazinyl, pyrazinyl, pyrodazinyl, pyrazinyl, pyrodazinyl, pyrazinyl, pyridazinyl, pyrazinyl, pyridazinyl, pyrazinyl, pyridazinyl, pyrazinyl, pyridyl, pyrazinyl, pyridine, pyrazinyl, pyridine, pyrazinyl, pyridine, pyrazinyl, pyridazylated Idinov, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolilgruppy optionally substituted with one or more aryl group substituents having the meanings given above, except where otherwise stated); (i) an optionally substituted, partially saturated polycyclic heterocarbocyclic residue in which the heteroaryl and cycloalkyl or cycloalkenyl group are condensed together to form a cyclic structure (examples of such groups include the pyrindanyl groups optionally substituted by one or more “aryl group substituents” having the above values, with the exception of the specifically mentioned cases). Optional substituents include one or more “aryl group substituents” having the above meanings, unless otherwise indicated.

"Heteroarylalkyl" means a heteroarylalkyl group in which the heteroaryl and alkyl residues are as previously defined. Preferred heteroarylalkyl groups contain a C _1-4 alkyl residue. Examples of heteroarylalkyl include pyridylmethyl.

“Heteroarylalkyloxy” means a heteroarylalkyl-O-group in which the heteroarylalkyl group has the previously indicated meanings. Examples of heteroarylalkyloxy groups include optionally substituted pyridylmethoxy.

"Heteroaryloxy" means a heteroaryl-O-group in which the heteroaryl group has the previously indicated meanings. Examples of heteroaryloxy include optionally substituted pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a heteroaryl-8O ₂ -HH-C (= O) -group in which the heteroaryl group has the previously indicated meanings.

“Heterocycloalkyl” means: () a cycloalkyl group having from 3 to 7 ring members and containing one or more heteroatoms or heteroatom-containing groups selected from O, 8 and ⁵ , which may optionally be substituted with oxo; (p) a partially saturated polycyclic heterocarbocyclic residue in which an aryl (or heteroaryl) ring, each of which is optionally substituted with one or more “aryl group substituents,” and the heterocycloalkyl group are condensed together to form a cyclic structure. (Examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

“Heterocycloalkylalkyl” means a heterocycloalkylalkyl group in which the heterocycloalkyl and alkyl residues are as previously defined.

"Prodrug" means a compound that is converted ίη νίνο metabolic pathways (for example, hydrolysis) into a compound of formula (I), including its Ν-oxides. For example, an ester of a compound of formula (I) containing a hydroxy group can be converted by hydrolysis ίη νίνο into the parent molecule. Alternatively, an ester of a compound of formula (I) containing a carboxy group can be converted by hydrolysis ίη νίνο into the parent molecule.

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

Suitable esters of compounds of formula (I) containing a carboxy group are described, for example, E.Heber, Er, Aegis Me! Ab. Wes., 1987, 18, Rada 379.

Suitable esters of compounds of formula (I) containing, in the residue —L ¹ —U, both the carboxy group and the hydroxy group include lactones resulting from the loss of water between said carboxy and hydroxy groups. Examples of such lactones include caprolactones and butyrolactones.

A particularly useful class of esters of compounds of formula (I) containing a hydroxy group can be derived from acid residues selected from the residues described by Vipbdaag e! A1., 1. Meb. Syesh., 1989, 32, p. 2503-2507, and including substituted (aminomethyl) benzoates, for example dialkylaminomethyl benzoates, in which two alkyl groups can be joined together and / or interrupted by an oxygen atom or an optionally substituted nitrogen atom, for example, an alkylated nitrogen atom, more specifically, (morpholinomethyl) benzoates, for example, 3- or 4- (morpholinomethyl) benzoates, and (4 alkyl-piperazin-1-yl) benzoates, for example, 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

If the compound of the present invention contains a carboxy group or a sufficiently acidic bioisoster, then base addition salts can be obtained, which are simply a more convenient form for use; in practice, the use of the salt form is essentially equivalent to the use of the free acid form. Bases that can be used to obtain their additive salts preferably include bases which, after being combined with freedoms

- 5 007415 with hydrochloric acid leads to the preparation of pharmaceutically acceptable salts, i.e. salts whose cations are non-toxic to the patient in pharmaceutical doses in such a way that the beneficial inhibitory effect exerted by the free base is not eliminated by the side effects exerted by the cations. Pharmaceutically acceptable salts, including salts derived from alkali metal and alkaline earth metal salts, within the scope of this 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, Ν-methylglucamine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl, procaine, hydroxymethyl), piperazine, tris (hydroxymethyl) Id tetramethylammonium, etc.

Some of the compounds of the present invention are basic, and such compounds can be used in the form of the free base or in the form of its pharmaceutically acceptable acid addition salt.

Acid addition salts are a more convenient form for use; in practice, the use of the salt form is essentially equivalent to the use of the free base form. Acids that can be used to obtain their additive salts preferably include those which, after combining with a free base, result in pharmaceutically acceptable salts, i.e. salts whose anions are non-toxic to the patient in pharmaceutical doses in such a way that the beneficial inhibitory effect exerted by the free base is not eliminated by the side effects exerted by the anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all acid addition salts can be used as sources of the free basic form, even if the preparation of a particular salt of the regimen is desirable only as an intermediate product, such as when the salt is obtained only for the purpose of purification and identification, or when it is used as an intermediate to obtain a pharmaceutically acceptable salt by the ion exchange method. Pharmaceutically acceptable salts within the scope of this invention include salts derived from mineral and organic acids, and include hydrohalides, for example, hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-bishydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfates and chinates.

In addition to being useful as active compounds by themselves, salts of the compounds of this invention can be used to purify compounds, for example, by using different solubilities of salts and parent compounds, by-products and / or starting materials by methods well known to specialists in this area of technology.

With reference to the above formula (I), the following groupings are specific and preferred:

K ¹ may, in particular, represent (1) hydrogen;

(ϋ) —CHN;

T ~ \

-CH ~ C (= O) -O o (ϊϋ) '- Especially preferred are compounds of formula (I) in which K ^{1 is a} genus, -CH ₃ , or ____

-CH ~ C (= O) -k

Even more preferably, K ¹ is hydrogen.

K ³ may, in particular, represent:

(ι) OSNz;

(ΐΐ) trifluoromethyl;

(ΐΐΐ) optionally substituted indolyl (for example, unsubstituted pyridyl substituted indolyl

Especially preferred are the compounds of formula (I) in which K ^{3 is} dil or trifluoromethyl.

represents water or optionally represents pi-6 007415

Even more preferably, K ³ is —OCH ₃ .

K ^{2 is} preferably attached to position 5 of the indole ring.

The group is preferably attached to position 3 of the indole ring.

It is intended that the present invention includes all suitable combinations of specific and preferred moieties mentioned herein.

Particularly preferred compounds of this invention are the following compounds:

and the corresponding Ν-oxides, and their prodrugs; as well as pharmaceutically acceptable salts and hydrates of such compounds and their Ν-oxides and prodrugs.

Especially preferred compounds of this invention are

(HP)

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

and the corresponding Ν-oxides, and their prodrugs; as well as pharmaceutically acceptable salts and solvates (for example, hydrates) of such compounds and their Ν-oxides and prodrugs.

The compounds of this invention exhibit beneficial pharmacological activity and, accordingly, can be incorporated into pharmaceutical compositions and used to treat patients suffering from certain medical disorders. Thus, the present invention provides, in accordance with a further aspect, the compounds of this invention and compositions containing the compounds of this invention for use in therapy.

Compounds within the scope of the present invention, in accordance with the tests described in the literature, as well as the ίη νίίΓΟ methods described below, block the catalytic activity of the kinase, and it is assumed that the test results correlate with the pharmacological activity in humans and other mammals. Thus, a further embodiment of the present invention provides the compounds of the present invention, as well as compositions containing the compounds of the present invention, for use in treating a patient subject to or

- 7 007415 suffering from conditions that can be improved by administering protein kinase inhibitors (for example, 8uk, EAK, or Aigoga2), in particular, 8uk kinase inhibitor. For example, the compounds of the present invention are useful in the treatment of inflammatory diseases, for example, asthma; inflammatory dermatoses (for example, psoriasis, dermatitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease); allergic rhinitis and allergic conjunctivitis; arthritis, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. These compounds are also useful in the treatment of chronic obstructive pulmonary disease (COPD), acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, restenosis, myocarditis, aphoris lupus, graft versus host disease and other diseases associated with graft rejection, various types of cancer and tumors (such as colorectal cancer, prostate cancer, full-time, thyroid cancer, colon cancer and lung), and inflammatory bowel disease. In addition, these compounds are useful as tumor antiangiogenic agents.

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

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

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

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

Another special embodiment of the therapeutic methods of the present invention is the treatment of various types of cancer and tumors.

According to further features of the present invention, a method of treating a human or animal susceptible to or suffering from conditions that can be improved by administering protein kinase inhibitors (for example, 8uk, EAK, or Aigoga2), such as the above-described conditions, is included, including administering to the patient an effective amount of a compound of the invention or a composition comprising a compound of the invention. "Effective amount" means the amount of a compound of the present invention that effectively inhibits the catalytic activity of a protein kinase, such as 8uk, EAK, ΚΌΚ. or Aigoga2, and thus providing the desired therapeutic effect.

Treatment according to this description includes prophylactic treatment as well as treatment of established conditions.

Pharmaceutical compositions comprising at least one compound of this invention in combination with a pharmaceutically acceptable carrier or excipient are also included in the scope of the present invention.

The compounds of this invention may be administered by any suitable means. In practice, the compounds of the present invention can be administered parenterally, locally, rectally, orally or by inhalation, especially by the oral route.

The compositions of this invention can be obtained by known methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, among others, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, solutions for injections, elixirs or syrups, and may contain one or more agents selected from the group including sweeteners, flavoring agents, dyes or stabilizers, to obtain pharmaceutically acceptable drugs. The choice of carrier and content of the active substance in it is usually determined in accordance with the solubility and chemical properties of the active compound, the specific route of administration and the precautions observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrating agents such as starch, alginic acid, and some complex silicates in combination with lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc. To obtain capsules, it is preferable to use lactose and high molecular weight polyethylene glycols. The resulting aqueous suspensions may contain emulsifying agents or suspending agents. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerin and chloroform, or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products of the present invention are used in vegetable oil, for example sesame oil, peanut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol in organic esters for injection, such as ethyl oleate, also sterile aqueous solutions of pharmaceutically acceptable

- 8 007415 salts. Solutions of the salts of the products of this invention are particularly suitable for the administration of intramuscular or subcutaneous injections. Aqueous solutions, also containing solutions of salts in pure distilled water, can be used for intravenous administration, provided that their pH is appropriately adjusted, that they are properly buffered and made isotonic with sufficient glucose or sodium chloride, and that they are sterilized by heating by irradiation or microfiltration.

For topical use, gels (based on water or alcohol), creams or ointments containing the compounds of this invention may be used. These compounds can also be introduced into a gel or matrix base for use in the form of a patch, providing controlled release of the compound through the transdermal barrier.

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

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

The percentage of active ingredient in the compositions of this invention may be different, it is necessary that it was part of providing a suitable dosage. It is obvious that approximately at the same time several unit dosage forms can be administered. The dose applied is determined by the physician and depends on the desired therapeutic effect, the route of administration, the duration of treatment and the condition of the patient.

For adults, doses usually range from about 0.001 to 50, preferably from about 0.001 to 5 mg / kg body weight per day during inhalation; from about 0.01 to 100, preferably from 0.1 to 70, more preferably from 0.5 to 10 mg / kg body weight per day when administered orally; and from about 0.001 to 10, preferably from 0.01 to 1, mg / kg body weight per day for intravenous administration. In each case, the doses are determined according to factors inherent to the patient being treated, such as age, weight, general health, and other characteristics that may affect the effectiveness of the medical product.

The compounds of this invention can be administered with the required frequency in order to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and much lower maintenance doses may be adequate for them. For other patients, long-term treatment may be necessary at a level of 1 to 4 doses per day, in accordance with the physiological requirements of each individual patient. In general, the active product can be administered orally from 1 to 4 times per day. Of course, for some patients, you may need no more than one or two doses per day.

The compounds of this invention can be obtained as a result of the application or adaptation of known methods, including the methods used to date or described in the literature, for example, the methods described by V.S. Bagoek, Sotrgeyepuye Ogdashs TgapzGogtayopz, USN Ri18Jeg8, 1989.

In the interactions described below, protection of reactive functional groups may be required, for example, hydroxy, amino, imino, thio or carboxy groups, in cases where their presence is desired in the final product, in order to avoid their undesirable participation in the interactions. Known protecting groups may be used in accordance with standard practice; Examples are given in T.Sh. Ogepe, R.O.M. Shik Rgolesyue Ogoirz sh Ogadas Sjet1z1gu, .1oKp ShBeu upb Pops, 1991.

The compounds of formula (I), where K ¹ , B ² and B ³ have the above values, are obtained by reacting compounds of the formula (XXVIII):

n (HHUSH) in which B ³ is as defined above, and X represents a halogen atom, preferably iodine, or a triflate group, with compounds of the formula (XXIX)

- 9 007415

in which K ¹ and K ² have the above values. The coupling reaction can be expediently carried out, for example, in the presence of a complex metal catalyst, such as tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate, in aqueous dimethylformamide at a temperature up to reflux temperature. It is advisable to carry out this reaction with pyrrole ΝΗ in compound (XXVIII), protected, for example, by a tosyl group, and indole ΝΗ in compound (XXIX), protected, for example, by a tert-butoxycarbonyl group.

The compounds of formula (I) in which K ² and K ³ have the above meanings, and K ¹ represents optionally substituted alkyl, are obtained by reacting the corresponding compounds of formula (I) in which K ² and K ³ have the above meanings, and K ¹ represents hydrogen , with an appropriate haloalkyl of K ² ^ ² , in which K ² is an optionally substituted alkyl, and X ² is halogen. This interaction is particularly suitable for the preparation of compounds of formula (I) in which K ¹ is morpholinoacetyl.

The compounds of this invention can also be obtained by the mutual transformation of other compounds of this invention.

Thus, for example, compounds of formula (I) containing a carboxy group can be obtained by hydrolysis of the corresponding esters. The hydrolysis can be expediently carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, for example, 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 a temperature from about ambient temperature to reflux temperature. The esters can also be hydrolyzed by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous / inert organic solvent mixture using organic solvents, such as dioxane or tetrahydrofuran, at about 50 to 80 ° C. WITH.

As another example, compounds of formula (I) containing a carboxy group can be obtained by acid-catalyzed removal of the tert-butyl groups of the corresponding tert-butyl esters using standard reaction conditions, for example, reaction with trifluoroacetic acid at a temperature close to room temperature. .

As another example, compounds of formula (I) containing a carboxy group can be obtained by hydrogenating the corresponding benzyl esters. The reaction can be carried out in the presence of ammonium formate and a suitable metal catalyst, for example, palladium, on a substrate of an inert carrier, such as carbon, preferably in a solvent, such as methanol or ethanol, and at a temperature close to the reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, for example, platinum or palladium, on a substrate of an inert carrier, such as carbon, preferably in a solvent, such as methanol or ethanol.

As another example of the mutual transformation process, compounds of formula (I) containing the group —C (= Ο) -ΝΥ ¹ Υ ² can be obtained by combining the compounds of formula (I) containing a carboxy group with an amine of the formula ΗNΥ ¹ Υ ² for obtaining an amide bond as a result of the usual peptide binding process, for example, a combination 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 temperature This technique is particularly applicable to the preparation of (1) compounds of formula (I) in which K ³ is -ϋ (= Ο) -ΝΥ ¹ Υ ² , or (ίί) compounds of formula (I) in which K ² is ^^ φφ ^ ² . The combination can also be carried out by the interaction of compounds of formula (I) containing the carboxy group with the Ν-oxide of Ц-Cdimethylamino) (1H-1,2, 3-triazolo [4,5-Ь] pyridin-1-yl) methylene} -Y -methylmethanamine hexafluorophosphate in the presence of a suitable base, such as diisopropylethylamine, in an inert solvent, such as dimethylformamide, and at a temperature close to room temperature, followed by reaction with an amine of the formula ΗΝΥ ¹ Υ ² (ammonium chloride can be used to obtain compounds of the formula ( I) containing the group -ϋ (= Ο) -Ν _2). The combination can also be carried out by reacting compounds of formula (I) containing a carboxy group with 2- (1H-benzotriazol-1-yl) -1,1,3,3 tetramethyluronium hexafluorophosphate in dry dimethylformamide followed by reacting with the amine of the formula ΗΝΥ ¹ Υ ² in the presence of diisopropylethylamine.

- 10 007415

As another example of the process of mutual conversion, compounds of formula (I) containing the group —CH ₂ OH can be obtained by reducing the corresponding compounds of formula (I) containing the group —CHO or —CO ₂ B ⁷ (where B ⁷ is lower alkyl ). For example, the reduction can be expediently carried out by reacting with lithium aluminum hydride in an inert solvent, such as tetrahydrofuran, and at a temperature from about room temperature to refluxing temperature.

As another example of a mutual conversion process, compounds of formula (I) in which K ² is hydroxy can be obtained by reacting the corresponding compounds of formula (I) in which B ¹ is methoxy with a Lewis acid, such as boron tribromide, in an inert solvent, such as dichloromethane, and at a temperature of from about 0 ° C. to room temperature.

As another example of a mutual transformation process, compounds of formula (I) in which B ² is -OB ⁴ (where B ⁴ is an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) can be obtained by alkylation of the corresponding compounds of formula (I) in which B ² is hydroxy, with compounds of the formula (XXX)

B ⁴ -X ³ (XXX) in which B ⁴ is as defined above, and X ³ is halogen, preferably a bromine atom, or a tosyl group, using standard alkylation conditions. Alkylation, for example, can be carried out in the presence of a base, such as an alkali metal carbonate (for example, potassium carbonate or cesium carbonate), an alkali metal alkoxide (for example, tertiary potassium butoxide) or an alkali metal hydride (for example, sodium hydride) , in dimethylformamide or dimethyl sulfoxide at a temperature from about 0 to 100 ° C.

As another example of a mutual transformation process, a compound of formula (I) in which B ¹ is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted with —C (= O) XY ¹ U ² , —OB ⁷ , —C (= O ) -OB ⁷ , -ΝΥ ¹ Υ ² , can be obtained by alkylation of the corresponding compounds of the formula Pa), in which B ¹ is hydrogen, with the corresponding halide of the formula (XXXI)

BA ⁴ (XXXI) in which B ¹ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl or alkyl, substituted with -C (= O) NΥ Υ, -OV, -C (= O) -OV, -ΝΥ Υ, and X represents halogen preferably bromine, using standard alkylation conditions, such as those described above.

As another example of a mutual transformation process, compounds of formula (I) containing sulfoxide bonds can be obtained by oxidizing the corresponding compounds of formula (I) containing β-B bonds. For example, the oxidation can be expediently carried out by reacting with a peroxy acid, for example, 3-chloroperbenzoic acid, preferably in an inert solvent, for example, dichloromethane, preferably at room temperature or near it, or, alternatively, using a secondary acid peroxomonosulfate potassium in a medium such as aqueous methanol, buffered to about pH5, at a temperature from about 0 ° C to room temperature. This method is preferred for compounds containing an acid labile group.

As another example of a mutual transformation process, compounds of formula (I) containing sulfonic bonds can be obtained by oxidizing the corresponding compounds of formula (I) containing —B- or sulfoxide bonds. For example, the oxidation can be expediently carried out by reacting with a peroxy acid, for example, 3-chloroperbenzoic acid, preferably in an inert solvent, for example, dichloromethane, preferably at room temperature or close to it.

As another example of the process of mutual transformation, compounds of formula (I) containing a cyano group can be obtained by reacting the corresponding compounds of formula (I) containing the group —C (═O) —No ₂ with phosphorus pentachloride in the presence of triethylamine. The reaction may conveniently be carried out in an inert solvent, such as tetrahydrofuran, at a temperature close to the reflux temperature.

As another example of the mutual transformation process, compounds of formula (I) containing a group —C (═O) —MH ₂ can be obtained by reacting the corresponding compounds of formula (I) containing a cyano group with hydrogen peroxide in the presence of sodium hydroxide. The reaction may conveniently be carried out in methanol at a temperature close to room temperature.

As another example of the process of mutual transformation, compounds of formula (I) in which B ³ is -ΝΥ ¹ Υ ² (where Υ ¹ and Υ ² have the above values) can be obtained by reacting the corresponding compounds of formula (I) in which B ³ represents halogen (for example, chlorine), with an amine of the formula ΗΝΥ ¹ Υ ² (where Υ ¹ and Υ ² have the above values).

As another example of the mutual transformation process, compounds of formula (I), in which B ³ is cyano, can be obtained by reacting compounds of formula (I) in which X ¹

- 11 007415 is halogen, preferably chlorine, with zinc cyanide in the presence of zinc powder, [1'1-bis (diphenylphosphino) ferrocene] dichloropalladium complex (11) and dichloromethane (catalytic amount) and,-dimethyl acetamide at a temperature of approximately to 150 ° C.

As another example of the mutual transformation process, compounds of formula (I) containing the group —C (= O) —OK ⁵ (in which K ⁵ has the above values) can be obtained by reacting the corresponding compounds of formula (I) containing the group —C (= O) -OH, with alcohols of the formula K ⁵ -OH. For example, if K ⁵ is tert-butyl, then the reaction can be expediently carried out in the presence of 1,1'-carbonyldiimidazole and 1,8-diazabicyclo [5.4.0] undec-7-ene at a temperature close to room temperature.

It should be appreciated that the compounds of the present invention may contain asymmetric centers. Such asymmetric centers may independently of each other be in a K or 8 configuration. It will be understood by those skilled in the art that certain compounds of this invention may also have geometric isomerism. It is also understood that the present invention includes individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures, of compounds of the above formula (I). Such isomers can be isolated from their mixtures as a result of the application or adaptation of known methods, for example, methods of chromatography and recrystallization, or they can be obtained separately from the corresponding isomers of their intermediate compounds.

According to further features of the present invention, the acid addition salts of the compounds of this invention can be obtained by reacting the free base with an appropriate acid as a result of applying or modifying known methods. For example, acid addition salts of the compounds of this invention can be obtained either by dissolving the free base in water or an aqueous alcohol solution or other suitable solvent containing the corresponding acid, and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in this case, the salt is released directly or can be obtained by concentration of the solution.

Acid additive salts of the compounds of this invention can be obtained from salts as a result of application or adaptation of known methods. For example, the parent compounds of this invention can be obtained from their acid addition salts by treatment with alkali, for example, an aqueous solution of sodium bicarbonate or an aqueous solution of ammonia.

The compounds of this invention can be obtained from their basic additive salts as a result of applying or modifying known methods. For example, the parent compounds of this invention can be obtained from their basic additive salts by treatment with an acid, for example, hydrochloric acid.

The compounds of the present invention may be expediently prepared or formed in the process of the present invention in the form of solvates (for example, hydrates). Hydrates of the compounds of the present invention can be expediently obtained by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxane, tetrahydrofuran or methanol.

According to further features of the present invention, the base addition salts of the compounds of this invention can be obtained by reacting the free acid with an appropriate base as a result of applying or modifying known methods. For example, the basic addition salts of the compounds of this invention can be obtained either by dissolving the free acid in water or an aqueous alcohol solution or other suitable solvent containing the appropriate base, and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in this case, the salt is isolated directly or can be obtained by concentrating the solution.

The starting materials and intermediates may be obtained by the application or adaptation of known methods, for example the methods described in comparative examples or their obvious chemical equivalents.

Intermediate compounds of formula (XXVIII), in which K ³ has the above values, X ¹ is iodine, and pyrrole is protected by a tosyl group, can be obtained in accordance with scheme 1.

- 12 007415

Scheme 1

So, for example, the compounds of formula (XXXIV) can be obtained:

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

(ίί) by subsequent treatment of the obtained compound of formula (XXVIII) with butyllithium in tetrahydrofuran at a temperature of about -78 ° C;

(ίίί) interaction of the obtained anion with iodine.

Intermediate compounds of formula (XXVIII) in which K ³ is heteroaryl can be obtained by reacting compounds of formula (XXVIII) in which K ³ is halogen, for example, chlorine, with borane of formula K ³ BE1 ₂ , in which K ³ is heteroaryl . The reaction can be expediently carried out in the presence of tetrakis (triphenylphosphine) palladium (0) and potassium carbonate in tetrahydrofuran at a temperature up to the reflux temperature. This reaction is particularly suitable for the preparation of compounds of the formula (XXVIII) in which K ³ is pyridyl.

Intermediate compounds of formula (XXVIII), in which K ³ is heteroaryl, can also be obtained by reacting compounds of formula (XXVIII), in which K ³ is halogen, for example chlorine, with heteroarylboronic acids of formula K ³ B (OH) ₂ in the presence of tetrakis (triphenylphosphine) palladium (0) and aqueous sodium bicarbonate in dimethylformamide at a temperature up to the temperature of reflux. This reaction is particularly suitable for the preparation of compounds of formula (XXVIII), in which K ³ optionally represents substituted indolyl.

Intermediate compounds of formula (XXVIII), in which K ³ is OK ⁴ , where K ⁴ has the above values, can be obtained by reacting compounds of formula (XXVIII), in which K ³ is halogen, for example chlorine, with compounds of formula K. ⁴ O No. (obtained by the interaction of the alcohol of the formula K ⁴ HE with sodium) at a temperature of about 65 ° C. This interaction is particularly suitable for the preparation of compounds of the formula (XXVIII) in which K ³ is OMe.

Further, the present invention is illustrated by examples, but it is not limited to the following illustrative and comparative examples.

The conditions for the implementation of high performance liquid chromatography - mass spectrometry (BS-M8) to determine the retention time (K _t ) are as follows:

Method A: Nuregzy ΒΌ8 C-18 column (4.6 mm x 50 mm), working with reversed phase under conditions of gradient elution with mixtures (A) of water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05 % trifluoroacetic acid, as a gradient of the mobile phase: (0.00 min 100% A: 0% B; linear gradient up to 100% within 2 min; then hold for up to 3.5 min); a flow rate of 1 ml / min with approximately 0.25 ml / min cleavage on a mass spectrometer; injection volume 10 µl; The wavelength of the He \ '1e11 Rakegb Mobie1 HP1100 8epez detector CC of 200 nm; determination of light scattering during evaporation (ΕΙ .8) - temperature 46 ° С, nitrogen pressure 4 bar.

Method B: OPzop 251 injector model using a NuregP NURIKTU C-18-5 micron (4.6 mm x 50 mm) column operating under gradient elution with mixtures (A) of water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0.05% trifluoroacetic acid as the gradient of the mobile phase: (0.00 min 95% A: 5% B; linear gradient up to 95% B over 4 min; then up to 5% B over 4.5 min; then hold up to 6 min); the injection volume is 5 μl and the flow rate is 1 ml / min to the UV detector (ΌΑΟ) followed by approximately 0.100 ml / min by splitting on a mass spectrometer (positive electrospray) with the remainder to the detector EB8.

METHOD C: a device for determining micromass, a CCT model connected to a model of the HP 1100 model. The excess connection is determined using an HP photodiode antenna-array detector, model “1315”, in the wavelength range of 200-600 nm and a light scattering detector with evaporation 8beh, model 65.

Data of the mass spectrum is obtained in the range from 180 to 800. The data are analyzed using the computer program Mshgogaz Mazzyuh. The separation is carried out on a Nuregzy ΒΌ8 C18 column (50 x 4.6 mm) with a particle size of 3 μm, eluted by a linear gradient from 5 to 90% acetonitrile containing 0.05% (v / v) trifluoroacetic acid in water containing 0 , 05% (v / v) trifluoroacetic acid for 3.5 minutes at a flow rate of 1 ml / min. The total duration of the work, including column balancing, is 7 minutes.

- 13 007415

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

The compound of formula (I) in which K ¹ is

K ² is —OMe, K ³ is —CCP ₃ ,

is attached at position 3 of the indole ring, and group K ^{2 is} attached at

The group position 5 of the indole ring represented by formula (II)

(1) treating 7H-pyrrolo [2,3-b] pyrimidine (1) with 3-chloroperbenzoic acid in dichloromethane at about 0 ° C to obtain 7H-pyrrolo [2,3-b] pyrimidine-L-oxide (2) ;

- 14 007415 (ίί) the interaction of the compound (2) with phosphorus oxybromide at a temperature of about 50 ° C to obtain 4-bromo-7H-pyrrolo [2,3-b] pyrimidine (3);

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

(ΐν) the reaction of compound (4) with trifluoromethyltrimethylsilane in the presence of potassium fluoride and copper (I) iodide in dimethylformamide at a temperature of about 60 ° C to obtain 7- (toluene-4sulfonyl) -4-trifluoromethyl-7H-pyrrolo [2,3- B] pyrimidine (5);

(ν) treating compound (5) with lithium diisopropylamide in tetrahydrofuran at a temperature of about -78 ° C, followed by reacting the resulting anion with iodine to obtain 6-iodo-7- (toluene-4sulfonyl) -4-trifluoromethyl-7H-pyrrolo [2, 3-b] pyrimidine (6);

(νι) the combination of compound (6) with 1-tert-butyloxycarbonyl-5-methoxy-1H-indole-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate in aqueous dimethylformamide at a temperature close to the reflux temperature and removal of the tert-butyloxycarbonyl protecting group, followed by treatment with methyl iodide in the presence of sodium hydride in tetrahydrofuran to obtain 6- (5-methoxy-1H-indole-3-yl) -7- (toluene-4-sulfonyl) -4 trifluoromethyl-7H-pyrrolo [2 , 3-b] pyrimidine (7);

(ΐΐΐΐ) removing the tosyl-protecting group in compound (7) by treating with potassium hydroxide in methanol to obtain 6- (5-methoxy-1H-indole-3-yl) -4-trifluoromethyl-7H-pyrrolo [2,3-b] pyrimidine ( eight); and (νΐΐΐ) alkylation of compound (8) with 4- (2-chloroacetyl) morpholine in the presence of sodium hydride in dimethylformamide to produce 2- [5-methoxy-3- (4-trifluoromethyl-7H-pyrrolo [2,3-b] pyrimidine -6il) indol-1 -yl] -1 -morpholin-4-yl-ethanone (II).

Example 2 (2-Hydroxy-1,1-dimethylethyl) amide 1-methyl-3- (7H-pyrrolo [2,3-b] pyrimidin-6-yl) -1Nindole-5-carboxylic acid

The compound of formula (I) in which K ¹ is —CH ₃ ,

- 15 007415

(ι) reacting compound (9) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide in toluene to obtain compound (10);

(i) treating compound (10) with lithium diisopropylamide in tetrahydrofuran at a temperature of about -78 ° C, followed by reacting the resulting anion with iodine to obtain compound (11);

(ιϋ) the combination of compound (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 close to to reflux, and removing the tert-butyloxycarbonyl protecting group, followed by treatment with methyl iodide in the presence of sodium hydride in tetrahydrofuran to obtain 6 - [(1-methyl-5-carbomethoxyindole) -3-yl] -7H-pyrrolo [2,3-b] pyrimidine (13);

(ν) treatment of the compound (13) with aqueous methanolic potassium hydroxide at reflux to obtain 6 - [(1-methyl-5-carboxyindol) -3-yl] -7H-pyrrolo [2,3-b] pyrimidine ( 14); and (ν) the combination of compound (14) with 2-hydroxy-1,1-dimethylethylamine in the presence of O- (7azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to obtain (2- 1-methyl-3- (7H-pyrrolo [2,3-b] pyrimidine-6-yl) -1H-indole-5-carboxylic acid (III) hydroxy-1,1-dimethylethyl) amide.

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

The compound of formula (I) in which K ¹ is

and group K ^{2 is} attached at position 5 of the indole ring represented by formula (IV)

- 16 007415

receive in accordance with the following scheme

1-terttetrabutyloxycarbonyl-5-methoxyindole-3-boronic acid (15) in the presence of acid (triphenylphosphine) palladium (0) and sodium bicarbonate in aqueous dimethylformamide at a temperature close to the reflux temperature, and removing the tert-butyloxycarbonyl protecting group to obtain 6- [ (5-methoxyindole) -3-yl] -7- (toluene-4-sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine (16);

(ίί) treating compound (16) with aqueous methanolic potassium hydroxide at reflux to obtain 6 - [(5-methoxyindol) -3-yl] -7H-pyrrolo [2,3-b] pyrimidine (17); and (ϊίϊ) reacting compound (17) with sodium hydride in dimethylformamide followed by reaction with 2-bromoacetic acid with morpholinamide to obtain 2 - {[5-methoxy-3- (7Npyrrolo [2,3-b] pyrimidine-6-yl) indole-1-yl] -1-morpholin-4-yl} -ethanone (IV).

Example 4

The compound of formula (I) in which K ¹ is —CH ₂ CP ₃ , K ² is —OMe, K ³ is

is -CK, the group is attached at position 3 of the indole ring, and the group K ^{2 is} attached at position 5 of the indole ring, represented by formula (VII)

receive in accordance with the following scheme:

- 17 007415

(ί) reacting compounds (18) and (19) in the presence of potassium carbonate and sodium iodide to obtain compound (20);

(i) the interaction of the compound (20) with thiourea in the presence of sodium ethoxide in ethanol to obtain the compound (21);

(ίίί) cyclizing the compound (21) by heating in toluene under conditions close to reflux to obtain the compound (22);

(v) interaction of compound (22) with phosphorus oxybromide to produce 4-bromo-7N-pyrrolo [2,3-b] pyrimidine (23);

(ν) reacting compound (23) with 4-toluenesulfonyl chloride in the presence of tetrabutylammonium sulfate and aqueous sodium hydroxide in toluene to obtain compound (24);

(νί) treatment of compound (24) with lithium diisopropylamide in tetrahydrofuran at a temperature of about -78 ° C, followed by reaction of the resulting anion with iodine to obtain compound (25);

(νίί) the combination of compound (25) with 1-tert-butyloxycarbonyl-5-methoxyindole-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate in aqueous dimethylformamide at a temperature close to the reflux temperature, and the removal of tert-butyloxycarbonylylmethyl amide at groups for the preparation of 4-bromo-6 - [(5-methoxyindole) 3-yl] -7 (toluene-4sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine (26);

(νίίί) the reaction of compound (26) with sodium hydride in tetrahydrofuran, followed by reaction with 2-trifluorodiodoethane to obtain compound (27);

(ίχ) the interaction of compound (27) with zinc cyanide in the presence of palladium in dimethylaniline at a temperature of about 140 ° C to obtain compound (28); and (x) treating compound (28) with aqueous methanolic potassium hydroxide at reflux to obtain a compound of formula (VII).

Example 5

The compound of formula (I) in which K ¹ is —CH ₃ , K ² is —OMe,

- 18 007415

K ³ represents

Group

is attached at position 3 of the indole ring, and group K ^{2 is} attached at position 5 of the indole ring, represented by formula (IX)

receive in accordance with the following scheme:

(ί) reacting compound (26) with sodium hydride in tetrahydrofuran, followed by reaction with methyl iodide to obtain compound (29);

(ΐΐ) reacting compound (29) with carbon monoxide in the presence of palladium in methanol at reflux to obtain compound (30);

(111) treating compound (30) with aqueous methanolic potassium hydroxide at reflux to obtain compound (31); and (ΐν) the combination of compound (31) with 2-hydroxy-1,1-dimethylethylamine in the presence of O- (7azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to obtain the compound (IX ).

Example 6

The compound of formula (I) in which K ¹ is

_{/ C} in ₂ I 'SV _g "NME

K ² is -OMe, K ³ is

the group is attached at position 3 of the indole ring, and the group K ^{2 is} attached at position 5 of the indole ring, represented by formula (V)

- 19 007415

receive in accordance with the following scheme:

(26) Condmyun

(V) (1) the interaction of the compound (26) with methyl acrylate in the presence of palladium acetate, triphenylphosphine and triethylamine at a temperature of about 110 ° C to obtain the compound (32);

(ίί) hydrogenation of compound (32) in the presence of palladium on carbon to produce compound (33);

(ίίί) treating compound (33) with aqueous methanolic potassium hydroxide at reflux to obtain acid (34);

(ν) the combination of compound (34) with methylamine in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3 tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide to obtain compound (35); and (ν) alkylation of compound (35) with 4- (2-chloroacetyl) morpholine in the presence of sodium hydride in dimethylformamide to produce compound (V).

Example 7

The compound of formula (I) in which K ¹ is

K ² is -OMe, K ³ is

' Group

is attached at position 3 of the indole ring, and group K is attached at position 5 of the indole ring, represented by formula (VI)

- 20 007415

receive in accordance with the following scheme:

(ΐ) the combination of compound (26) with pyridine-3-boronic acid in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium bicarbonate in aqueous dimethylformamide at a temperature close to the reflux temperature to obtain 4- (pyridin-3-yl) -6 - [(5-methoxyindole) -3-yl] -7 (toluene-4-sulfonyl) -7H-pyrrolo [2,3-b] pyrimidine (36);

(ΐΐ) treating compound (36) with aqueous methanolic potassium hydroxide at reflux to obtain compound (37) (Example 9); and (111) alkylation of compound (37) (Example 9) with 4- (2-chloroacetyl) morpholine in the presence of sodium hydride in dimethylformamide to produce 2- [5-methoxy-3- (4- (pyridine-3yl) -7H-pyrrolo [2,3b] pyrimidine-6-yl) indol-1 -yl] morpholin-4-yl-ethanone (VI).

Example 8. The compound of formula (I) in which K ¹ is —CH ₂ CH ₃ ,

K ² is -OMe, K ³ is

- 21 007415

(ΐ) alkylation of compound (26) with ethyl iodide in the presence of sodium hydride in dimethylformamide to produce compound (38);

(ΐΐ) interaction of compound (38) with morpholine in a microwave oven at a temperature of about 200 ° C in α, α, α-trifluorotoluene to obtain compound (39); and () treating compound (39) with aqueous methanolic potassium hydroxide at reflux to obtain compound (VIII).

Example 9. 6- (5-methoxy-1H-indol-3-yl) -4-pyridin-3-yl-7H-pyrrolo [2,3-d] pyrimidine

A solution of 6-iodo-7 - [(4-methylphenyl) sulfonyl] -4-pyridin-3-yl-7H-pyrrolo [2,3-d] pyrimidine [260 mg, comparative example 1] and 1-tert-butylcarboxyl- 5-methoxy-1H-indole-3-boronic acid [178 mg, comparative example 12] in dimethylformamide (10 ml) is treated with palladium tetrakistriphenylphosphine (13 mg) and sodium bicarbonate (8 mg). The reaction mixture is stirred at reflux for 2 hours and allowed to cool to room temperature. The solution is evaporated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and methanol (95: 5, v / v) to obtain 6- (5-methoxy-1H-indol-3-yl) -4-pyridine-3yl- 7H-pyrrolo [2,3-d] pyrimidine (20 mg) as an amorphous solid. M8: 342 [MH] ⁺ , BSM8 (method A) K _t = 2.57 min.

Example 10. 4-methoxy-6- (5-methoxy-1-methyl-1H-indol-3-yl) -7H-pyrrolo [2,3-d] pyrimidine

MeO

rolo [2,3-d] pyrimidine [361 mg comparative example 4] in methanol (20 ml) is treated with potassium hydroxide (1.53 g). The reaction mixture is stirred for 16 hours at room temperature and boiled under reflux for one hour. The solution is evaporated under reduced pressure.

- 22 007415 and the residue is distributed between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is triturated with diethyl ether to give 4-methoxy-6- (5-methoxy-1-methyl-1H-indole-3-yl) -7H-pyrrolo [2,3-b] pyrimidine (155 mg) as a solid substances, so pl. = 184 ° C. M8: 309 [MP] ⁺ .

Example 11. 4-methoxy-6- (5-methoxy-1H-indole-3-yl) -7H-pyrrolo [2,3-b] pyrimidine

Mao

TO

A solution of 4-methoxy-6- (5-methoxy-1H-indole-3-yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine [448 mg, comparative example 5 ] in methanol (15 ml) is treated with potassium hydroxide (1.96 g). The reaction mixture is stirred for 2 hours at room temperature and the solvent is evaporated off under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (80:20, v / v) to produce 4-methoxy-6- (5-methoxy-1H-indole-3-yl) -7H- pyrrolo | 2,3-b | pyrimidine (320 mg) as a yellow solid, mp> 260 ° C. M8: 295 [MP] ⁺ .

Example 12. 4- (5-methoxy-1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indol-3-yl) -7H-pyrrolo [2,3-b] pyrimidine

A solution of 4- (5-methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5-methoxy-1-methyl-1Nindol-3-yl) -7 - [( 4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine [93 mg, comparative example 9] in methanol (5 ml) is treated with potassium hydroxide (249 mg). The reaction mixture is stirred for 16 hours at room temperature. The solution is evaporated under reduced pressure and the residue is distributed 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 HPLC to give 4- (5methoxy-1H-indol-3-yl) -6- (5-methoxy-1-methyl-1H-indole-3-yl) -7H-pyrrolo [2,3-b ] pyrimidine (9 mg) as a gum. M8: 424 [MH] ⁺ . LCM8 (Method B) K _t = 3.15 min.

Comparative example 1.

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

To a solution of 7 - [(4-methylphenyl) sulfonyl] -4-pyridin-3-yl-7H-pyrrolo [2,3-b] pyrimidine [1 g, comparative example 2] in tetrahydrofuran (20 ml) at -78 ° A solution of butyl lithium in hexane (2 ml, 1.6 M) is added dropwise in an inert atmosphere. The solution is stirred at the same temperature for 1.5 hours and iodine (796 mg) is added to it. The reaction mixture was stirred at -78 ° C for another 1 h and allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium sulfite. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a gradient of ethyl acetate and cyclohexane (50:50, up to 100, v / v) to obtain the title compound (260 mg) as an amorphous solid. M8: 477 [PL] ⁺ . YSM8 (Method B) K _t = 3.26 min.

Comparative example 2. 7 - [(4-Methylphenyl) sulfonyl] -4-pyridin-3-yl-7H-pyrrolo [2,3-b] pyrimidine

A solution of 4-chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine [4 g, comparative example 3] and diethyl-3-pyridylborane (2.1 g) in tetrahydrofuran ( 180 ml) is treated with palladium tetrakistriphenylphosphine (0.65 g) and potassium carbonate (3.59 g). The solution is stirred at reflux for 24 hours and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is twice subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and methanol (90:10, v / v), and

- 23 007415 with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to obtain the title compound (2.5 mg) as an amorphous solid. M8: 351 [MH] ⁺ . BCM§ (Method B) _T = 3.05 min.

Comparative example 3. 4-Chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine

A solution of 4-chloro-7H-pyrrolo [2,3-b] pyrimidine (reference: Set81et, Σοΐιη R .; Nshkyate, Vata B; Rope. Royapb K.; Hopekepb, Liyou B. rutgo1,3,3-b] rupt1better ppd. 1. Netergus1 Clet. (1969), - (2), 207-213) (20 g) and para-toluenesulfonyl chloride (28.6 g) in toluene (1 l) treated with sodium hydroxide solution (50 g) in water (800 ml) and tetrabutylammonium sulfate (462 mg). The solution is vigorously stirred at room temperature for 2 hours and partitioned between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate i and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v / v) to give the title compound (2.5 g) in the form of a solid, mp = 143 ° C. bCM§ (Method B) V _t = 2.78 min.

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

To a solution of 4-methoxy-6- (5-methoxy-1H-indole-3 -yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2.3 b] pyrimidine [448 g, comparative example 5 ] in dimethylformamide (20 ml), sodium hydride (44 mg, 60% dispersion in oil) and methyl iodide (156 mg) are added under an inert atmosphere. The solution is stirred for 1 hour at room temperature and the solvent is evaporated off under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (30:70, v / v) to obtain the title compound (260 mg) as an amorphous solid. Mg: 464 [MH] ⁺ . BCM§ (Method B) _T = 4.39 min.

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

A solution of 6-iodo-4-methoxy-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine [1.98 g, comparative example 6] and 1-tert-butylcarboxyl-5- methoxy-1H-indole-3-boronic acid [1.26 g, comparative example 12] in dimethylformamide (40 ml) is successively treated with a saturated aqueous solution of sodium bicarbonate (10 ml) and tetrakistriphenylphosphine palladium (165 mg). The reaction mixture is stirred at reflux for 3 hours and the solvent is evaporated off under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to obtain the title compound (1.8 g) as a gray solid, mp. = 131 ° C. Mg: 450 [MH] ⁺ .

Comparative example 6. 6-Iodine-4-methoxy-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine

To a solution of 4-methoxy-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine [2.23 g, comparative example 7] in tetrahydrofuran (35 ml) at -78 ° C A solution of butyl lithium in hexane (5 ml, 1.6 M) is added dropwise in an inert atmosphere. The solution is stirred at -70 ° C for one hour and iodine (2.05 g) is added. The reaction mixture is stirred at -70 ° C for another 1 hour, allowed to warm to room temperature and partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (2.64 g) as a solid, amorphous substance. Mg: 430 [MH] ⁺ . BCM§ (Method B) P _t = 4.15 min.

Comparative example 7. 4-Methoxy-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-b] pyrimidine

A solution of 4-chloro-7H-pyrrolo [2,3-b] pyrimidine [1.2 g, comparative example 8] and para-toluenesulfonyl chloride (1.77 g) in toluene (60 ml) is treated with sodium hydroxide solution (3.2 g) in water (30 ml), and also tetrabutylammonium sulfate (27 mg). The solution is stirred vigorously at room temperature for 4 hours and distributed between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was flash chromatographed on silica, eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v / v) to give the title compound (2.23 g) as an amorphous solid. Mg: 304 [MH] ⁺ . BCM§ (Method B) P _t = 3.88 min.

Comparative example 8. 4-Methoxy-7H-pyrrolo [2,3-b] pyrimidine

To a solution of sodium methoxide, obtained by the gradual addition of sodium (2 g) to methanol (100 ml) in an inert atmosphere, 4-chloro-7H-pyrrolo [2,3-b] pyrimidine is added (reference: Seg8 (er, 1y .; Nshkyate, Vagyaga S; VOshk, Royapb K .; Lotepkepb, Legoy V. 2), 207-13.) (3.5 g). The solution is stirred at 65 ° C for 16 hours and then distributed between ethyl acetate and brine. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate

- 24 007415 and cyclohexane (50:50, v / v) to obtain the title compound (1.2 g) as an amorphous solid. M8: 150 [MH] ⁺ . HCM8 (Method B) K _T = 2.39 min.

Comparative Example 9. 4- (5-Methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indole-3-yl) -6- (5methoxy-1-methyl-1H-indole-3 -yl) -7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine

To a solution of 4- (5-methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indole-3-yl) -6- (5-methoxy-1H-indole-3yl) -7 - [(4-methylphenyl ) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine [270 mg, comparative example 10] in dimethylformamide (10 ml) are added sodium hydride (10 mg, 60% dispersion in oil) and methyl iodide (0.025 ml) in inert the atmosphere. The solution is stirred for 16 hours at room temperature, and the solvent is evaporated off under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (50:50, v / v) to obtain the title compound (93 mg) as an amorphous solid. M8: 732 [PL] ⁺ . HCM8 (Method B) K _T = 4.68 min.

Comparative Example 10. 4- (5-Methoxy-1 - [(4-methylphenyl) sulfonyl] -1H-indol-3-yl) -6- (5methoxy-1H-indole-3-yl) -7 - [(4 -methylphenyl) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine

A solution of 4-chloro-6-iodo-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine [1.72 g, comparative example 11] and 1-tert-butylcarboxyl-5- methoxy-1H-indole-3-boronic acid [1.26 g, comparative example 12] in dimethylformamide (36.5 ml) is successively treated with a saturated aqueous solution of sodium bicarbonate (9.1 ml) and tetrakistriphenylphosphine palladium (0.3 g) . The reaction mixture was stirred at reflux for 2 hours, and the solvent was evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic phase is separated, then dried over magnesium sulphate and evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (30:70, v / v) to obtain the title compound (270 mg) as a gum. M8: 718 [PL] ⁺ . Bc8 (method B) K _T = 4.44 min.

Comparative example 11. 4-Chloro-6-iodo-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine

To a solution of 4-chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-th] pyrimidine [5.4 g, comparative example 3] in tetrahydrofuran (96 ml) at -78 ° C a solution of butyl lithium in hexane (12.1 ml, 1.6 M) is added dropwise in an inert atmosphere. The solution is stirred at -78 ° C for 3 hours and iodine (8.9 g) is added. The reaction mixture was stirred at -78 ° C for 2 hours and allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium sulfite, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to flash column chromatography on silica, eluting with a gradient of ethyl acetate and cyclohexane (50:50, up to 100, v / v) to give the title compound (1.52 g) as an amorphous solid. M8: 434 [MH] ⁺ . HCM8 (Method B) K _T = 4.26 min.

Comparative example 12. 1-tert-butylcarboxyl-5-methoxy-1H-indole-3-boronic acid

A stirred solution of the complex tert-butyl ester of 3-bromo-5-methoxyindole-1-carboxylic acid [50 g, comparative example 13] in tetrahydrofuran (800 ml) is treated with tributyl borate (49.5 ml) in nitrogen atmosphere, then cooled to -100 ° C, then treated with a solution of n-utility in hexano (94 ml, 2.5 M), maintaining the temperature below -90 ° C. After the addition is complete, the mixture is allowed to slowly warm to room temperature over an hour, and then quench it by adding ice (10 g). The organic phase is removed under reduced pressure, and the residue is partitioned between ethyl acetate (500 ml) and water (400 ml). The organic layer was dried over magnesium sulfate, and then evaporated to give the title compound as a cream-colored solid (28 g). М8 314 | МН + №1 | '. 1. SM8 (Method C) K _T = 4.07 min.

Comparative Example 13. 3-Bromo-5-methoxyindole-1-carboxylic acid t-butyl ester

Bromine (4 ml) is added dropwise to a solution of 5-methoxyindole (10 g) in dry dimethylformamide (150 ml) at ambient temperature, making sure that the temperature does not rise above about 30 ° C. The mixture is immediately treated with triethylamine (28 ml) and 4dimethylaminopyridine (0.5 g), and then with a solution of di-tert-butyl dicarbonate (18 g) in dry dimethylformamide (80 ml), continuing stirring for another 4 hours. The reaction mixture is evaporated, and the residue is distributed between ethyl acetate (250 ml) and water (200 ml). The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic phases are washed with water (100 ml), then brine (100 ml), then dried over magnesium sulfate and evaporated. The residue is subjected to flash chromatography on silica, eluting with a mixture of pentane and ethyl acetate (19/1, v / v) to give the title compound (23.4 g) as a colorless solid, mp. 111-112 ° C.

- 25 007415

Тестη νϊίΐΌ test method for 8uk

Inhibitory effect of compounds on 8uk kinase

The inhibitory effect of the compounds on the 8-kinase is determined using a time-resolved fluorescence assay.

The catalytic domain of the 8uk kinase (residues Α340-Ν635) is expressed as a fusion protein in yeast cells and purified to a homogeneous state. The kinase activity is determined in 50 mM Tris-HCl buffer, pH 7.0, containing 50 mM NaCl, 5 mM MdCl ₂ , 5 mM MnCl ₂ , 1 μM adenosine triphosphate and 10 μM of the synthetic peptide Biotin - ((A-Alanine) ₃ -OEOEUYE1PP -MN ₂ .

Enzymatic reactions are stopped by adding a buffer containing 0.4 M CU, 133 mM EDTA, pH 7.0, containing a streptavidin-CH665 conjugate, and a monoclonal phosphospecific antibody conjugated with europium crypt (Ei-K). The description of both fluorophores, CH-665 and Ei-K, is given in 6. Masc with! a1., Apbsapsg Xsatsy, 1997, 17, p. 3011-3014. The specific long-term signal CH-665, which is obtained only by phosphorylation of the synthetic peptide 8uk, is measured on an apparatus for reading plates of LH VyuHspApaluCh AO. The inhibition of the activity of a §Ac by compounds of the present invention is expressed as a percentage of the inhibition of the control activity shown in the absence of the test compounds. Specific preferred compounds of the present invention inhibit the activity of §uk with 1C ₅₀ in the range from 100 micromoles to 100 nanomoles. Particularly preferred compounds of the present invention inhibit the activity of Acu with 1C ₅₀ in the range from 1 micromol to 100 nanomoles.

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

2.1 Cell culture, labeling cells KVB-2N3 and the implementation of the study

RVB-2H3 cells are contained in T75 flasks at 37 ° C and 5% CO ₂ and are resealed every 3-4 days. To collect the cells, 5 ml of trypsin-EDTA was used, washing the flask once, then 5 ml of trypsin was added to each flask and incubated at room temperature for 2 minutes. The cells are transferred to a tube containing 14 ml of medium, centrifuged at a rate of 1100 rpm at room temperature for 5 minutes and resuspended to 2x10 ⁵ / ml. Cells are sensitized by adding 1 μl of α-specific 1 dЕ to each 10 ml of cells. In each well of a flat-bottomed 96-well plate (40,000 cells / well), 200 μl of cells are added, after which the plate is incubated overnight at 37 ° C and 5% CO ₂ . The next day, compounds are prepared in 100% DMSO at 10 mM. Each compound is then diluted 1: 100 in assay buffer, and then re-diluted in 1% DMSO assay buffer to obtain a final concentration of 0.03-30 μM. 80 μl of assay buffer are added to each well, followed by 10 μl of the diluted compound, followed by incubation for 5 minutes. 10 μl of м-Β8Α (100 ng / ml) is added to each well and incubated at 37 ° C (without CO ₂ ) for 30 minutes. As one type of control, only 1% DMSO (without compound) is added to the row of wells to determine the overall level of release. As another type of control, a buffer is added to another row of wells instead of О№-Н8А to determine the background analysis value. After 30 minutes, the supernatants are transferred to a new 96-well plate. 50 μl of the supernatant is added to each well of the test plate. 100 μl of substrate solution is added to each well and incubated at 37 ° C for 90 minutes. In order to terminate the reaction, 50 μl of a 0.4 M solution of glycine is added and the plate is read at 405 nm on an apparatus for reading the plates of Microcluster PCs.

2.2 Calculation of Results (ί) Calculate the mean + 8E (standard deviation) of each set of wells of three repetitions.

(ίί) Maximum response means positive control wells containing antigen (100 ng / ml) without compound.

(ΐϊϊ) Minimal response means control wells containing buffer (without antigen) and not containing compounds.

(ίν) Using these values as the maximum (100%) and minimum (0%), respectively, receive experimental data to determine the percentage of the maximum response (indicated as% control).

(ν) A dose response curve is constructed and 1C ₅₀ compounds are calculated using the Rtkt StarRay computer program and nonlinear least squares regression analysis.

The compounds of this invention inhibit antigen-induced degranulation of rat basophilic leukemia (KVb) cells with an EC ₅₀ in the range from 100 to 1 μmol.

- 26 007415

Claims (21)

CLAIM 1. The compound of the formula in which B ¹ represents hydrogen, C _1-4 alkyl or morpholinyl-4-yl ethanone; B ² represents OCH ₃ ; B ³ represents OCH ₃ , triftomethyl, pyridyl or indolyl, optionally substituted by a methoxy group; or Ν-oxide, prodrug, acidic bioisostere, a pharmaceutically acceptable salt or hydrate of such a compound; or Ν-oxide, prodrug or acid bioisostere of such salt or hydrate. 2. The compound according to claim 1, in which B ¹ is CH ₃ . 3. The compound according to claim 1, in which B ¹ is -CH. 4. The compound according to claim 1, in which B ¹ is hydrogen. 5. The compound according to any one of claims 1 to ⁴ , in which B ³ is OCH ₃ . 6. The compound according to any one of claims 1 to ⁴ , in which B ³ is pyridyl or trifluoromethyl. 7. The compound according to any one of claims 1 to 6, in which B ^{2 is} attached at position 5 of the indole ring. 8. The compound according to any one of claims 1 to 7, in which the group is attached in position 3 of the indole ring. 9. The compound according to claim 1, which represents MeO Ν ', oh or Ν-oxide, prodrug, pharmaceutically acceptable salt or hydrate of such a compound; or an oxide or prodrug of such a salt or hydrate. 10. The compound according to claim 1, which represents - 27 007415 mao Ν-oxide, prodrug, pharmaceutically acceptable salt or hydrate of such a compound; either an oxide or a prodrug of such a salt or hydrate. 11. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, together with one or more pharmaceutically acceptable carriers or excipients. 12. A method of treating a patient exposed or suffering from conditions that can be improved by administering an 8uk catalytic activity inhibitor, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11 . 13. 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 according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11. 14. A method of treating a patient exposed or suffering from conditions that can be improved by administering an inhibitor of the catalytic activity of RAK, including administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11 . 15. A method of treating a patient exposed or suffering from conditions that can be improved by administering an inhibitor of the catalytic activity of COC, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11 . 16. A method of treating a patient exposed or suffering from conditions that can be improved as a result of administering the catalytic activity inhibitor Aigoga2, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11 . 17. A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of a composition according to claim 11. 18. The method according to claim 13, wherein the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis, or inflammation of the joints. 19. The method of claim 13, wherein the inflammatory disease is asthma, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, cutaneous vasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, arthritis, rubella, psoriatic arthritis or osteoarthritis. 20. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of the compound according to any one of claims 1 to 10, or a pharmaceutically effective amount of the composition according to claim 11. 21. The method of claim 17, wherein the cancers to be treated include colorectal, prostate, breast, thyroid, skin, rectal, or lung cancer.