MXPA06006162A - Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines - Google Patents

Abstract

A process for preparing substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compounds having an aminoalkyl substituent at the 7-position is disclosed.

Description

PROCEDURE FOR THE PREPARATION OF 5-AMINO-PIRAZOLO-r4,3-EM, 2.4-TRIAZOL? P, 5-ClPIRIMIDlNAS REPLACED This application claims the priority benefit of the E.U.A. Serial Number 60 / 525,925, filed on December 1, 2003.

FIELD OF THE INVENTION The present invention relates to a process for preparing substituted 5-amino-pyrazolo [4,3-e] -1, 2,4-triazolo- [1, 5-cjpyrimidine compounds, having an aminoalkyl substituent in the 7-position .

BACKGROUND OF THE INVENTION The substituted 5-amino-pyrazolo [4,3-e] -1, 2,4-triazolo- [1, 5-cjpyrimidine compounds, described in WO 01/92264 are useful as A2a receptor antagonists in the treatment of Central nervous system disease, in particular Parkinson's disease. WO 01/92264 describes a process for preparing 5-amino-2-substituted-pyrazolo [4,3-e] -1,2,4-triazole- [1, 5-c] pyrimidines, which comprises rearrangement by dehydration of hydrazines.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing the compounds of formula 7 formula 7 or a pharmaceutically acceptable salt or solvate thereof, wherein L is alkylene; R is aryl, heteroaryl, R 1 -aryl, R 1 -heteroaryl or cycloalkenyl; Y is -N (R2) CH2CH2N (R3) -, -OCH2CH2N (R2) -, - (CH2) 2-NH-, or and Z is aryl, R5-aryl, aralkyl, R5-aralkyl, heteroaryl, R5-heteroaryl, (aryl) 2alkyl, R6-C (O) -, HM-R6-SO2-, or. R5-aryl-CH (OH) - or aryl-CH (OH) -; or when v f Q is, H, Z is also phenylamino or pyridylamino; Z and Y together are R1 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, -CF3, halogen, -NO2, -NR12R13, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl; R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; m and n are each independently 2 or 3; What is it l i l i | -N- -C- -C- -C- or -c- i. i i V H CN 'OH COCH, R 4 is 1 to 2 substituents independently selected from the group consisting of hydrogen and alkyl, or two substituents R 4 on the same carbon can form = O; R5 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkylamino, -CF3, -OCF3, acetyl, -NO2, hydroxyalkoxy, alkoxyalkoxy, dialkoxy- alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO2-, alkyl-SO2-alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, SO2NH2 or phenoxy; or the adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O- or -O-CF2CF2-O-, and form a ring with the carbon atoms at the which are united; R6 is alkyl, aryl, R5-aryl, aralkyl, R5-aralkyl, heteroaryl, R5-heteroaryl, R5-cycloalkyl, cycloalkyl, alkyl-OC (O) -NH-alkyl (C6-C6) -, dialkyl aminomethyl or alkyl-; R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3, and alkoxy-alkoxy; - R 10 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH 2, alkylamine, dialkylamino, -CF 3, -OCF 3 and -S (O) 0.2 I rent; R 2 is hydrogen or alkyl; - 5. . and R13 is alkyl-C (O) - or alkyl-SO2-; - comprising (a) subjecting a compound of formula 6 to halogenation and formylation formula 6 to obtain a compound of formula 5 formula 5 0 wherein X is halogen (b) coupling the compound of formula 5 with a hydrazine of formula 4 formula in the presence of a base to form a compound of formula 3 formula 3 (c) reacting the compound of formula 3 with a compound of formula HO-L-NHNH2 to form a compound of formula 2 formula 2 (d) concurrently, (1) cyclizing and (2) halogenating the compound of formula 2 by reacting the compound of formula 2 in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent, to form a compound of formula 1 -. - formula 1 wherein A is halogen; and (e) preparing the compound of formula 7, coupling the compound of formula 1 with a compound of formula 8 Z-Y-H formula 8 in the presence of a base. In particular, the invention relates to the cyclization and halogenation of a compound of formula 1, together with the coupling of the compound of formula 1 with a compound of formula 8, to obtain a compound of formula 7.

DETAILED DESCRIPTION One aspect of the invention is a process for preparing the compounds of formula 7, wherein L is ethylene; R is R1-furanyl, R1-thienyl, R1-pyridyl, N-oxide of R1-pyridyl, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or cycloalkenyl; R1 is hydrogen or halogen; Cast < jH; Z is R5-phenyl, R5-heteroaryl, R6-C (O) - or R6-SO2-; and R6 is R5-phenyl. Another aspect of the invention is a process for preparing compounds of formula 7, wherein R is R 1 -furanyl; R1 is hydrogen or I halogen; Q is - N -; m and n are each 2; R4 is hydrogen; Z is R5-phenyl; and R5 is a substituent selected from the group consisting of alkoxy and alkoxyalkoxy. Another aspect of the invention is a process for preparing compounds of formula 7, wherein A is chloro or bromo. Another aspect of the invention is a process for preparing compounds of formula 7, wherein the compound of formula HO-L-NHNH2 is 2-hydroxyethylhydrazine.

Another aspect of the invention is a process for preparing compounds of formula 7, wherein the dehydrating agent is P2O5 or POCI3, preferably POCI3. Another aspect of the invention is a process for preparing compounds of formula 7, wherein the dehydrating agent is POCI3 and the metal halide is ZnBr2. Another aspect of the invention is a process for preparing compounds of formula 7, wherein R is R1-furanyl, R1 is hydrogen, Z is R5-phenyl and R5 is methoxyethoxy. Another aspect of the invention is a process for preparing compounds of formula 7, wherein the dehydrating agent is P2O5 and the salt - Halide is NaCl. Another aspect of the invention is a process for preparing compounds of formula 7A or a pharmaceutically acceptable salt or solvate thereof, comprising (a) subjecting a compound of formula 6 to halogenation and formylation formula 6 to obtain a compound of formula 5A Formula 5A (b) coupling the compound of formula 5A with a hydrazine of formula 4A 4A formula in the presence of a base to form a compound of formula 3A formula 3A (c) reacting the compound of formula 3A with the 2-hydroxyethyl hydrazine to form a compound of formula 2A formula 2A (d) concurrently (1) cyclizing and (2) halogenating the compound of formula 2A, by reacting the compound of formula 2A in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent to form a compound of formula 1A Formula 1A wherein A is halogen and (e) preparing the compound of formula 7A. coupling the compound of formula 1A with a compound of formula 8A formula 8A in the presence of a base. Preferably, in the process of forming a compound of formula 7A, the metal halide is ZnBr2 and the dehydrating agent is POCI3. Alternatively, cyclization and halogenation of formula 2A occur in the presence of NaCl and P2O5. A further aspect of the invention is a method for stopping the compounds of formula 1 Formula 1 wherein L is alkylene; R is aryl, heteroaryl, R 1 -aryl, R 1 -heteroaryl or cycloalkenyl; R1 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, -CF3) halogen, -NO2, -NR12R13, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R10 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH2, alkylamino, dialkylamino, -CF3, -OCF3 and -S (O) 0-2alkyl; comprising concurrently (1) cyclizing and (2) - halogenating. composed of formula 2 formula 2 reacting the compound of formula 2 in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent to form a compound of formula 1. A further aspect of the invention is a process for preparing compounds of formula 1, wherein the dehydrating agent is a phosphorus oxyhalide; preferably, P2O5 or POCI3. A further aspect of the invention is a process for preparing compounds of formula 1, wherein the dehydrating agent is POCI3 and the metal halide of zinc halide, preferably ZnBr2. Alternatively, a further aspect of the invention is a process for preparing compounds of formula 1, wherein the halide salt is NaCl and the dehydrating agent is P2O5.

The claimed procedure produces compounds of formula 7, which have an antagonistic activity of the A2a receptor, as well as those intermediary compounds used to produce the compounds of formula 7. In step (a), the compound of formula 6 is converted into a compound of formula 5. Typically, the conversion takes place in the presence of a phosphorus oxyhalide, such as POCI3, a solvent such as DMF or DME and at a temperature of about 95 ° C to about 105 ° C, preferably about 100 ° C. In step (a) POCI3 is a halogenating agent, however, it can be used as a dehydrating agent, as will be demonstrated later in step (d). - In step (b), the compound of formula 5 is coupled with a hydrazine of formula 4, to form a compound of formula 3. The reaction is carried out in a non-protic organic solvent such as CH 3 CN, and an inorganic base or an organic base, at a temperature of about 10 ° C to about 100 ° C, more preferably at a temperature of about 20 ° C to about 80 ° C, even more preferably, about 30 ° C to about 50 ° C, still preferably at about 40 ° C. Examples of suitable inorganic bases are Na2CO3, NaHCO3, KHCO3, NaOH, KOH, K3PO4, K2HPO4, Na3PO4 and Na2HPO4. Examples of the organic bases include, but are not limited to, triethylamine, DBU, pyridine and DIEA. In addition, aprotic solvents such as THF and toluene, etc., can also replace acetonitrile in this reaction. About 1-2 equivalents, preferably about 1 equivalent of a compound of formula 5, and about 1-2, preferably, about 1-1.1 equivalents of the hydrazine of formula 4 are preferably used. uses approximately 1 equivalent of the inorganic base. Preferably, the activated compound of formula 3 is not isolated before the reaction. In step (c), the compound of formula 3 is reacted with a compound of HO-L-NHNH2, to form a compound of formula 2. Preferably, L is ethylene. The reaction is carried out in the presence of a non-protic organic base and / or an inorganic base (see above), at a temperature range of 30 ° C to about 120 ° C, preferably from about 50 ° C to about 100 ° C, even more preferably from about 70 to 90 ° C, more preferably from about 80 ° C. Approximately 2 equivalents of the hydroxy alkyl hydrazine are used. In step (d), the compound of formula 2 is obtained concurrently by (1) cyclizing and (2) halogenating the compound of formula 2, by reacting the compound of formula 2 in the presence of a catalytic amount of a halide metal and a dehydrating agent or a catalytic amount of a halide salt and a dehydrating agent, to form a compound of formula 1, which has, non-exclusively, the following formulas: Although step (d) has been described as halogenation and concurrent cyclization of the compound of formula 2, the modifications, as a separate 2-step procedure, wherein halogenation and cyclization occur as separate steps, are intended to fall within the spirit and scope of the present invention. The reaction is carried out in an organic solvent such as toluene at a temperature range from about 80 ° C to about 120 ° C, more preferably from 90 ° C to about 110 ° C, most preferably 100 ° C. ° C, and then cooled and subsequently quenched at a temperature of about 0 ° C. Specific examples of metal halides include, but are not limited to, FeC, AICI3, ZnCl2 and ZnBr2. A combination of a phosphorous oxy cond and a metal salt (e.g., P2O5 and NaCl), may also result in the desired product. In step (e), the cond of formula 7 is formed by coupling the cond of formula 1 with a cond of formula 8, in the presence of a base. Preferred examples of the bases include, but are not limited to, amines, more preferably alkylamines, even more preferably trialkylamines, more preferably diisopropylethylamide. The reaction is carried out with an aprotic organic solvent (such as DMF, acetonitrile, toluene, THF, etc.), at a temperature range of from about 50 to about 120 ° C, preferably from 65 to 100 ° C, more preferably from 75 to 85 ° C, more preferably from 80 ° C. The reaction mixture is cooled in a water-ice bath at about 0 ° C, and stirred (preferably 2 hours). The resulting solid was filtered, washed (e.g., with a solution of acetonitrile and water), and dried to provide the product, a cond of formula 7. The present process provides an advantage over the procedures previously reported in the art. The known processes utilize highly toxic and corrosive NH2CN to form the six-membered heteroaryl of the final product. The claimed procedures currently avoid this cyclization step, using a raw material (a cond of formula 6), which already has a six-member ring. The cond of formula 6 is further processed by the claimed invention to provide the final product, the conds of formula 7. The present invention provides the use of toxic cyanogen halides, which in turn, therefore, allows the production to Large scale and high yields using milder conditions.

As used herein, "alkyl" means an aliphatic hydrocarbon group, which may be linear or branched and comprising from about 1 to about 6 carbon atoms in the chain. Branched means that one or more of the lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Alkylene" refers to a divalent alkyl group, similarly refers to straight or branched chains. "Alkoxy" means an alkyl-O- group, in which the alkyl group is - as previously described, unless otherwise indicated. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The link to the main portion is through the oxygen of the ether. "Cycloalkyl" means a non-aromatic ring system comprising from about 3 to about 6 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl and cyclohexyl, and the like. Cycloalkylene refers to a divalent cycloalkyl group. Cycloalkenyl refers to a cycloalkyl ring of C-C6, which comprises a double bond. "Cycloalkyl substituted on R 1 or R 5" refers to the groups wherein the substitutable ring carbon atoms have a substituent as defined above. "Heteroaryl" means a heteroaryl group of a single ring, bicyclic or benzofused of 5 to 10 atoms, comprising from 2 to 9 carbon atoms and from 1 to 4 heteroatoms selected independently from the group consisting of N, O and S , with the proviso that the rings do not include adjacent oxygen and / or sulfur atoms. Also included are the N-oxides of the ring nitrogens. Examples of the single-ring heteroaryl groups are pyridyl, pyridyl N-oxide, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. . Examples of the bicyclic heteroaryl groups are naphthyridyl (for example, 1, 5 or 1, 7), imidazopyridyl, pyrido [2,3] imidazolyl, pyridopyrimidinyl and 7-azaindolyl. Examples of benzofused heteroaryl groups are indoiyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (ie, thionaphtenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl. "Heteroaryl substituted on R1 or R5" refers to the groups wherein the substitutable carbon atoms of the ring have a substituent as defined above. "Alkylthio" means an alkyl-S- group, in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio and i-propylthio. The link to the main portion is through sulfur. - "Alkylsulfonyl" means an alkyl-S (O2) - group. The link to the -Main portion is through the sulfonyl. "Alkylsulfinyl" means an alkyl-S (O) - group. The link to the main portion is through sulfinil.

"Carbonyl" means a portion -C (O) -, for example, alkoxycarbonyl refers to a C (O) - alkoxy group (ie, alkyl-O-C (O) -). "Acetyl" means -C (O) CH3. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying the degree of ionic and covalent binding, including hydrogen bonding. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" covers both solvates in solution phase and isolated solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is H2O. Certain compounds of the invention can exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers in both pure form and in mixture, including racemic mixtures. Certain compounds can be of acidic nature, for example, those compounds that possess a carboxyl or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. Examples of such salts include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic compounds also form pharmaceutically acceptable salts, for example, acid addition salts. For example, pyrido-nitrogen atoms can form salts with strong acids, while compounds having basic substituents such as amino groups, also form salts with weaker acids. Examples of suitable acids for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, masonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other well-known mineral and carboxylic acids. those with experience in the technique. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable basic aqueous solution, such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the acidic and basic salts are, otherwise, equivalent to their respective free basic forms for the purposes of invention. All such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention.

-.- -. - The following are descriptions of the preparation of the compounds of formula 7, using the claimed procedure. The following abbreviations are used in the specification and in the claims: Ms (methylsulfonyl); Me (methyl); Et or Et (ethyl); THF (tetrahydrofuran); LOD (loss with drying); diisopropylethyl amine (DIEA); DMF (dimethylformamide); DBU (1,8-diazabicyclo [5.4.0] undec-7-ene); (DME) 1, 2- dimethoxyethane; and DMSO (dimethyl sulfoxide).

General Reaction Scheme 10 The reaction scheme below describes the raw materials of the process, a compound of formula 6, up to the final step, wherein - a compound of formula 1 is coupled with a formula pair to produce the final product, a compound of formula 7.

H NH, formula 2 formula 1 Z-Y-H formula 8 formula 7 1. Formation of the Compound for Formula 5 Initially, a compound of formula 6 is reacted with POCI3 in DMF and heated to a compound of formula 5.

The compound of formula 5 was subsequently treated (details to continued), to practice the procedure of the claimed invention. As noted below, a compound of formula 5, wherein X is chloro, is subsequently reacted to form an intermediate compound of formula II.

Procedures for the preparation of compound 11 compound V compound I! To Compound V (1.0 g, 1.0 equivalents), 2-furoic hydrazide (0.7 g, 1.1 equivalents) and sodium carbonate (0.55 g, 1.0 equivalents), you will be added acetonitrile (20 mL) and warmed to 40 ° C. After stirring at 40 ° C for 30 hours, the reaction was subsequently heated to 60 ° C. A solution of 2-hydroxyethyl hydrazine (0.7 mL, 2 equivalents) in water (5 mL) was added. The reaction mixture was then heated to 80 ° C and stirred for 2.5 hours. Once the reaction was complete, the reaction mixture was again cooled to 25 ° C, and 0.1 N HCl (10 mL) was added. The reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was then concentrated to approximately 10 mL under reduced pressure. Water (30 mL) was added and the reaction mixture was concentrated to about 10 mL under reduced pressure. The reaction mixture was stirred at 25 ° C overnight. The solid was filtered and washed with 2 mL of water, then with 2 mL of acetonitrile. The product (compound I) was dried under vacuum at 25 ° C, to provide 1.1 g (70%) of the desired product. LC / MS: m / z = 304 (M + 1). 1 H NMR (DMSO-de): d 10.65 (d, 1 H); 9.52 (d, 1 H); 7.98-7.88 (m, 1 H); 7.42-7.29 (m, 1 H); 6.73-6.70 (m, 1 H); 6.35 (s, 2H); 4.9 (s, 1H); 4.1 (m, 2H); 3.62 (m, 2H). 3. Procedures for the preparation of the compound X - Br / CI compound II compound! A mixture of intermediate II (500 mg, 1.0 equivalent), Zinc Bromide (100 mg) and POCI3 (5 ml) was heated to 100 ° C and stirred for 6 hours. After the reaction is complete, the reaction mixture is dried. then cooled again to 0 ° C, and cold water with ice (15 ml) was slowly added to quench the reaction. The resulting solid was filtered, washed with water and dried to provide 420 mg of the product, compound I (as a mixture of bromine and chlorine). Mass spectrum: M + 1 = 304 (X = Cl); M + 1 = 348 (X = Br). 1 H NMR (DMSO): 8.37 (s, 1 H), 8.26 (broad s, 2H), 7.95 (m, 1 H), 7.24 (m, 1 H), 6.74 (m, 1 H), 4.60 (m, 2H), 4.05 (m, 2H), 3.48 (m, 4H).

Procedures for the preparation of the compound Vil Y. = Br / Cl compound compound VIII compound VII A mixture of compound I (900 mg, 1.0 equivalents), compound VIII ((1.2 g, 2.0 equivalents) and diisopropylethyl amine (DIEA) (1.5 ml, 4.5 equivalents) in dimethylformamide (DMF) (7.2 ml), heated to 80 ° C and stirred for 10 hours After the reaction was completed, the reaction mixture was then cooled again in an ice-water bath at 0 ° C, and stirred for 2 hours. filtered, washed with acetonitrile, water and dried to provide 870 mg of the product, compound VII Mass spectrum: M + 1 = 504. 1 H NMR (DMSO): 8.37 (s, 1 H), 8.13 (broad s) , 2H), 7.95 (m, 1 H), 7.18 (m, 1 H), 6.78 (m, 4H), 6.70 (m, 1 H), 4.38 (m, 2H), 4.93 (m, 2H), 3.56 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H), 2.45 (m, 2H) Although the present invention has been described as a whole With the set of specific modalities shown above, many alternatives, modifications and variations will be evident from them to those with ordinary experience in the art. It is intended that all such alternatives, modifications and variations fall within the spirit and scope of the present invention.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing the compounds of formula 7 formula 7 or a pharmaceutically acceptable salt or solvate thereof, wherein; L is alkylene; R is aryl, heteroaryl, R1-aryl, R1-heteroaryl or cycloalkenyl; Y is -N (R2) CH2CH2N (R3) -, -OCH2CH2N (R2) -, - (CH2) 2-NH-, or Rachyl, heteroaryl, R5-heteroaryl, (aryl) 2alkyl, R6-C (O) -, R6-SO2-,, R5-aryl-CH (OH) - or -c aryl-CH (OH) -; or when Q is, H, Z is also phenylamino or pyridylamino; or Z and Y together are R1 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, -CF3, halogen, -NO2, -NR12R13, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; m and n are each independently 2 or 3; What is it 1 1 1 I i -N-) -c 1 -C- or _ I_> -c- H CN OH COCH3. R4 is 1 to 2 substituents independently selected from the group consisting of hydrogen and alkyl, or two substituents R4 on the same carbon can form = O; R5 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkylamino, -CF3, -OCF3, acetyl, -NO2, hydroxyalkoxy, alkoxyalkoxy, dialkoxy- alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkylamino-alkoxy, morpholinyl, alkyl-SO2-, alkyl-SO2-alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, SO2NH2 or phenoxy; or the adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O- or -O-CF2CF2-O-, and form a ring with the carbon atoms at the which are united; R6 is alkyl, aryl, R5-aryl, aralkyl, R5-aralkyl, heteroaryl, R5-heteroaryl, R5-cycloalkyl, cycloalkyl, alkyl-OC (O) -NH-alkyl (C Cd) -, dialkyl-aminomethyl or alkyl-O O; R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3, and alkoxy-alkoxy; R10 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH2, alkylamino, dialkylamino, -CF3 > -OCF3 and -S (O) o-2alkyl; R 12 is hydrogen or alkyl; and R13 is alkyl-C (O) - or alkyl-SO2-; comprising (a) subjecting a compound of formula 6 to halogenation and formylation formula 6 to obtain a compound of formula 5 wherein X is halogen (b) coupling the compound of formula 5 with a hydrazine of formula 4 H2N "R O formula 4 in the presence of a base to form a compound of formula 3 formula 3 (c) reacting the compound of formula 3 with a compound of formula HO-L-NHNH2 to form a compound of formula 2 formula 2 (d) concurrently, (1) cyclizing and (2) halogenating the compound of formula 2 by reacting the compound of formula 2 in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent, to form a compound of formula 1 Formula 1 wherein A is halogen; and (e) preparing the compound of formula 7, coupling the compound of formula 1 with a compound of formula 8 Z-Y-H formula 8 in the presence of a base.

2. The process according to claim 1, for preparing the compounds of formula 7, further characterized in that: L is ethylene; R is R1-furanyl, R1-thienyl, R1-pyridyl, N-oxide of R1-pyridyl, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or cycloalkenyl; R1 is hydrogen or halogen; And it is, where Q is - N- or -CH-; Z is R5-phenyl, R5-heteroaryl, R6-C (O) - or R6-SO2-; and R6 is R5-phenyl.

3. - The process according to claim 2, further characterized in that R is R 1 -furanyl; R1 is hydrogen or halogen; What is it - -; m and n are each 2; R4 is hydrogen; Z is R5-phenyl; and R5 is a substituent selected from the group consisting of alkoxy and alkoxyalkoxy.

4. The process according to claim 1, further characterized in that A is chlorine or bromine.

5. The process according to claim 1, further characterized in that X of the compound of formula 5 is Cl.

6. The process according to claim 1, further characterized in that the base of step (b) is Na2CO3, NaHCO3 , KHCO3, NaOH, KOH, K3PO4, K2HPO4l Na3PO4 and Na2HPO4.

7. The process according to claim 1, further characterized in that the base of step (b) is Na2CO3.

8. The process according to claim 1, further characterized in that the base of step (e) is a trialkylamine.

9. The process according to claim 1, further characterized in that the base of step (e) is diisopropylethylamide.

10. The process according to claim 1, further characterized in that the compound of formula HO-L-NHNH2 is 2-hydroxyethylhydrazine.

11. The process according to claim 1, further characterized in that the dehydrating agent of step (d) is P2O5 or POCI3.

12. - The process according to claim 11, further characterized in that the dehydrating agent of step (d) is POCI3 and the metal halide is ZnBr2.

13. The process according to claim 1, further characterized in that R is R1-furanyl, R1 is hydrogen, Z is R5-phenyl and R5 is methoxyethoxy.

14. The process according to claim 1, further characterized in that the dehydrating agent of step (d) is P2O5.

15. The process according to claim 14, further characterized in that the metal halide of step (d) is NaCl.

16. The process according to claim 1, for preparing a compound of formula 7A or a pharmaceutically acceptable salt or solvate thereof, comprising (a) subjecting to halogenation and formylation a compound of formula 6 formula 6 to obtain a compound of formula 5A formula 5A (b) coupling the compound of formula 5A with a hydrazine of formula 4A Formula 4A in the presence of base to form a compound of formula 3A formula 3A (c) reacting the compound of formula 3A with 2-hydroxyethyl hydrazine to form a compound of formula 2A formula 2A (d) concurrently (1) cyclizing and (2) halogenating the compound of formula 2A, by reacting the compound of formula 2A in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent to form a compound of formula 1A formula 1A wherein A is halogen and (e) preparing the compound of formula 7A. coupling the compound of formula 1A with a compound of formula 8A formula 8A in the presence of a base.

17. The process according to claim 16, further characterized in that the metal halide is ZnBr2 and the dehydrating agent is POCI3.

18. The process according to claim 16, further characterized in that the halide salt is NaCl and the dehydrating agent is P2O5.

19. - A process for preparing the compounds of formula Formula 1 wherein L is alkylene; R is aryl, heteroaryl, R 1 -aryl, R 1 -heteroaryl or cycloalkenyl; R1 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, -CF3, halogen, -NO2, -NR12R13, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl; and R10 is from 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH2, alkylamino, dialkylamino, -CF3, -OCF3 and -S (O) or- 2alkyl; comprising concurrently (1) cyclizing and (2) halogenating the compound of formula 2 formula 2 by reacting the compound of formula 2 in the presence of a catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent to form a compound of formula 1.

20. - The method according to claim 19, further characterized in that the dehydrating agent is a phosphorus oxyhalide.

21. The process according to claim 20, further characterized in that the dehydrating agent is P2O5 or POCI3.

22. The process according to claim 21, further characterized in that the dehydrating agent is POCI3.

23. The process according to claim 19, further characterized in that the metal halide is zinc halide.

24. The method according to claim 23, further characterized in that the metal halide is ZnBr2.

25. The method according to claim 24, - further characterized in that the metal halide is ZnBr2 and the dehydrating agent is POCI3.

26. The process according to claim 19, further characterized in that the halide salt is NaCl and the dehydrating agent is P2O5.