Azaindoleoxoacetic derivatives of piperazine and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to azaindoleoxoacetic derivatives of piperazine of the general formula (I): wherein Q is chosen from the group consisting of the following compounds: ; -W- represents compound of the formula: . Proposed compounds possess antiviral activity both in separate using and in combination with other antiviral, anti-infectious agents, immunomodulating agents or inhibitors HIV entering. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

55 cl, 10 tbl, 169 ex

 

The scope of the invention

The present invention relates to compounds having drug and bio-active properties, their pharmaceutical compositions and method of their application. In particular the present invention relates to derivatives of azaindolizines that possess unique antiviral activity. In particular, the present invention relates to compounds applicable for the treatment of HIV infection and AIDS.

The level of technology

HIV-I (virus-1, human immunodeficiency) remains a major medical problem, taking into account existing approximately 33.6 million infected worldwide people. The number of cases of HIV infection and AIDS (acquired immunodeficiency syndrome) has recently increased sharply. In 1999 it was reported 5.6 million newly infected patients and 2.6 million people died from AIDS. Currently, the drugs that are available for the treatment of HIV infection include six nucleoside reverse transcriptase inhibitors (RT) (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz) and six coworkers peptide protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, APV and LPV). Each of these preparation is tov can only fleeting to contain viral reproduction when used separately. However, when used in combination, these drugs have a prolonged effect on virasami and disease progression. In fact, a significant reduction in mortality among patients with AIDS who were newly registered, are a consequence of the widespread use of combination therapy. However, despite these significant results, 30-50 % of patients will ultimately not help combined drug therapy. Insufficient strength of the medicinal product, nesoglasovannoe in action, limited penetration into the tissue and restrictions that are specific to the drug, within certain types of cells (for example, most nucleoside analogues cannot be phosphorylated in resting cells) can lead to complete suppression of sensitive viruses. In addition, a high degree of reproduction and rapid turnover of HIV-I, together with the frequent occurrence of mutations leads to the emergence of drug resistant variants, as well as to the inability of treatment, when present above the optimal concentration of a drug (Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al (Links 6-14)). Thus, new anti-HIV agents, demonstrating a clear sustainable properties and benefits is pleasant pharmacokinetics, as well as possessing safe profiles, to provide a greater number of optimal treatment options.

Currently marketed HIV-I drugs are mainly or nucleoside analog reverse transcriptase inhibitor or coworkers peptide protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIS), recently played an increasingly important role in the treatment of HIV infection (Pedersen & Pedersen, Reference 15). At least 30 different classes of NNRTIS have been described in the literature (De Clercq, Reference 16), and several NNRTIS have passed clinical trials. Derivatives of dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine (delavirdine) have been approved for clinical use. However, the main drawback in the development and use of NNRTIs is their tendency to rapid emergence of strains resistant to medicines in cell tissue culture and treated, especially when conducting monotherapy. As a consequence, there is considerable interest in determining NNRTIS, less prone to resistance development (Pedersen & Pedersen, Reference 15).

Several indole derivatives, including derivatives of indole-3-sulfones, piperazinonyl and 5H-indole[3,2-b][1,5]benzothiazepine, have been described as inhibitors of HIV reverse transcriptase-1 (Greenlee et al, the reference 1; Williams et al, Reference 2; Romero et al. Link 3; Font et al, Reference 17; Romero et al. Reference 18; Young et al, Reference 19; Genin et al. Reference 20; Silvestri et al, Reference 21). Indole 2-carboxamide also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al, US 5,424,329, Reference 4). Finally, the 3-substituted indole natural products (Semicolonial a and b, decamethylferrocene and socklining) were identified as inhibitors of HIV protease-1 (Fredenhagen et al. Reference 22). Other indole derivatives exhibiting antiviral activity, suitable for the treatment of HIV, are disclosed in PCT WO 00/76521 (Reference 93). Also indole derivatives are disclosed in PCT WO 00/71535 (Reference 94).

Structurally related isoindoline amide derivatives have been previously disclosed (Kato et al, Reference 23; Levacher et al, Reference 24; Dompe Spa, WO-09504742, Link 5(a); SmithKline Beecham PLC, WO-09611929, Link 5(b); Sobering Corp., US-05023265, Reference 5(C)). However, these patterns differ from those stated in the present invention because they are isoindoline monoamide and not asymmetric diamine azaindolizines derivatives, and there is no mention of the use of these compounds for the treatment of viral infections, in particular HIV infection. Other azaindole were also disclosed by Wang et al. The link 95. However, nothing in these citations, as well as other, presented below, may not be considered as a disclosure or suggestion of new compounds p the present invention and their use for the inhibition of HIV infection.

CITED BIBLIOGRAPHY

Patent documents:

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BRIEF description of the INVENTION

The present invention includes compounds of formula I or their pharmaceutically acceptable salts, which are effective antiviral agents, particularly as inhibitors of HIV infection, and pharmaceutical compositions based on them. The object inventions are the compounds of formula I, including their pharmaceutically acceptable salt,

where:

Q is selected from the group consisting of:

R1represents hydrogen;

R2and R3are independently selected from the group consisting of hydrogen, halogen, XR57where X is oxygen and R57- C 1-6)alkyl

R4represents a group C(O)R57C(O)NR55R56or group,

- - represents a carbon-carbon bond;

m is 1 or 2;

R5represents hydrogen;

R6no;

And selected from the group consisting of C1-6alkoxy, aryl and heteroaryl; where specified aryl represents phenyl or naphthyl; the specified heteroaryl selected from the group consisting of pyridinyl and furanyl;

W represents

In selected from the group consisting of aryl, heteroaryl, heteroalicyclic ring, where the specified aryl, heteroaryl and heteroalicyclic ring are optionally substituted from one to three same or different halogen atoms or from one to three identical or different substituents selected from the group F; where aryl is a substituted phenyl; where heteroaryl is a mono or bicyclic system which includes 5-6 atoms in the monocyclic ring system and up to 12 atoms in a condensed bicyclic system, including from 1 to 4 heteroatoms; where the heterocyclic ring is a 5-6 membered monocyclic ring, which may contain 1 to 2 heteroatoms in the base ring and which may be condensed with benzene is whether the pyridine ring;

F is selected from the group consisting of (C1-6)alkyl, heteroaryl, hydroxy, (C1-6)alkoxy, halogen, C(O)R57, -NR42C(O)-(C1-6)alkyl, -NR42S(O)2-(C1-6)alkyl, NR42R43C(O)NR42R43, COOR54where heteroaryl is a monocyclic system which contains 5 atoms in the ring, including 1 nitrogen atom;

R9, R10, R11, R12, R13, R14, R15, R16each is independently selected from the group consisting of hydrogen and (C1-6)alkyl;

R42and R43are independently selected from the group consisting of hydrogen and (C1-6)alkyl;

R55and R56are independently selected from the group consisting of hydrogen and (C1-6)alkyl; and

R57selected from the group consisting of hydrogen and (C1-6)alkyl.

Most preferred are compounds, are summarized in Table 2 or Table 4 description of the present invention.

Since the compounds of the present invention may have centers of asymmetry and therefore occur as a mixture of diatomea and the enantiomers, the present invention includes individual diastolicheskoe and enantiomerically form compounds of the formula I in addition to their mixtures.

DEFINITION

The term "C1-6alkyl," as used in this izopet the Institute and in the claims (unless otherwise specified), means a straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl and the like.

"Halogen" refers to chlorine, bromine, iodine or fluorine.

"Aryl" group refers to all-carbon monocyclic or condensed-ring polycyclic (i.e. rings, which have adjacent pairs of carbon atoms) groups having a completely conjugated e π-system. Examples, without limitation, the aryl groups are phenyl, naphthalenyl and anthracene. The aryl group may be substituted or unsubstituted. In the case of replacement, the replacement group(s) preferably selected from one or more alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic ring, hydroxy, alkoxy, aryloxy, heteroaromatic, heteroalicyclic, digitoxin, diarylike, togetherforpeace, togetheraclose, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinil, sulfonyl, sulfonamide, trihalomethyl, ureido, amino, and-NRxRywhere Rxand Ryare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl and combined in a five - or six-membered heteroalicyclic to what ICO.

As used in the present invention, "heteroaryl" group refers to monocyclic or condensed ring (i.e. the ring have joint adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulphur and optionally having a fully conjugated e π-system. It should be noted that the term heteroaryl includes N-oxide source heteroaryl, if such N-oxide is chemically suitable, as known from the prior art in this field. Examples, without limitation, heteroaryl groups are furyl, thienyl, benzothiazyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, thiazolyl, tetrazolyl, isoxazolyl, isothiazolin, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidyl, chinoline, ethenolysis, purinol, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazines, pyrazin, triazinetrione, tetrazines and tetrazolyl. In the case of replacement, the replacement group(s) preferably selected from one or more alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic ring, hydroxy, alkoxy, aryloxy, heteroaromatic, heteroalicyclic, digitoxin, diarylike, togetherforpeace, togetheraclose, cyano, halogen is, nitro, carbonyl, O-carbamyl, N-carbamyl, O-amido, N-amido, C-carboxy, O-carboxy, sulfinil, sulfonyl, sulfonamide, trihalomethyl, ureido, amino, and-NRxRyin which Rxand Rydefined above.

As used in the present invention, "heteroalicyclic" group refers to monocyclic or condensed ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. Rings may also have one or more double bonds. However, the rings do not have a fully conjugate e π-system. Examples, without limitation heteroalicyclic groups are azetidinol, piperidyl, piperazinil, imidazolines, thiazolidine, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholine and tetrahydropyranyl. In the case of replacement, the replacement group(s) preferably vybiraetsya of one or more alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic ring, hydroxy, alkoxy, aryloxy, heteroaromatic, heteroalicyclic, digitoxin, dialkoxy, diarylike, togetherforpeace, togetheraclose, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamide, N-amido, C-carboxy, O-carboxy, sulfinil, sulfonyl, sulfonamide, trigalogenmetany is bonamigo, trihalomethane, Silla, Gualala, guanidino, ureido, phosphonyl, amino, and-NRxRyin which Rxand Rydefined above.

The term "Alkyl" group refers to a saturated aliphatic hydrocarbon, including straight and branched chain. Preferably the alkyl group has from 1 to 20 carbon atoms (whenever a specified numerical range; e.g., "1-20", this means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so forth, including 20 carbon atoms). The preferred average size of alkyl having from 1 to 10 carbon atoms. The most preferred lower alkyl having from 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. In the case of replacement, the replacement group(s) preferably represents one or more selected from trihalomethyl of cycloalkyl, aryl, heteroaryl, heteroalicyclic ring, hydroxy, alkoxy, aryloxy, heteroaromatic, heteroalicyclic, digitoxin, dialkoxy, diarylike, togetherforpeace, togetheraclose, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamide, N-amido, C-carboxy, O-carboxy, sulfinil, sulfonyl, sulfonamide, trigalogenmetany the bonamigo, trihalomethane, or a combination of a five - or six-membered heteroalicyclic ring.

"Cycloalkyl" group refers to an all-carbon monocyclic or condensed ring (i.e. the ring are adjacent pair of carbon atoms) group, in which one or more of the rings does not have a fully conjugate e π-system. Examples, without limitation cycloalkyl groups are cyclopropane, CYCLOBUTANE, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, Cycloheptane, cycloheptatrien and adamantane. Cycloalkyl group can be substituted or unsubstituted. In the case of replacement, the replacement group(s) preferably individually selected from one or more alkyl, aryl, heteroaryl, heteroalicyclic ring, hydroxy, alkoxy, aryloxy, heteroaromatic, heteroalicyclic, digitoxin, dialkoxy, diarylike, togetherforpeace, togetheraclose, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamide, N-amido, C-carboxy, O-carboxy, sulfinil, sulfonyl, sulfonamide, trihalomethane, trihalomethane, silila, Gualala, guanidino, ureido, phosphonyl, amino, and-NRxRy, Rxand Rydefined above.

The term "Alkenyl" means alkylen the th group, as defined in the present invention, comprising at least two carbon atoms and at least one carbon-carbon double bonds.

The term "Quinil" means an alkyl group, as defined in the present invention, comprising at least two carbon atoms and at least one carbon-carbon triple bond.

The term "Hydroxy" group refers to-IT group.

The term "Alkoxy" group refers to both-O-alkyl and-O-cycloalkyl group, as defined in the present invention.

The term "Aryloxy" group refers to both-O-aryl and-O-heteroaryl group, as defined in the present invention.

The term "Heteroaromatic" group refers to heteroaryl-O - group with heteroaryl, as defined in the present invention.

The term "Heteroalicyclic" group refers to heteroalicyclic-O - group with heteroalicyclic ring, as defined in the present invention.

The term "DigiTrace" group refers to an-SH group.

The term "Dialkoxy" group refers to both an S-alkyl and-S-cycloalkyl group, as defined in the present invention.

The term "Diarylike" group refers to both-S-aryl and-S-heteroaryl group, as defined in the present invention.

The term "Togetherforpeace" group refers to heteroaryl-S - group with Goethe what aerilon, as defined in the present invention.

The term "Togetheraclose" group refers to heteroalicyclic-S-group with heteroalicyclic ring, as defined in the present invention.

The term "Carbonyl" refers to the group-C(=O)-R", where R" is selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, cycloalkyl, aryl, heteroaryl (linked via a carbon ring) and heteroalicyclic ring linked via a carbon ring), as each is defined in the present invention.

The term "Aldehyde" refers to a carbon group, in which R" represents hydrogen.

The term "Thiocarbonyl" refers to-C(=S)-R" group, with R"as defined in the present invention.

The term "Keto" group refers to a-CC(=O) - group in which the carbon on either or both positions C=O can be alkyl, cycloalkyl, aryl or-heteroaryl carbon or heteroalicyclic group.

"Trigalogenmetany" group refers to Z3CC(=O)- group with the specified Z being halogen.

The term "C-carboxy" group refers to-C(=O)O-R" group, with R"as defined in the present invention.

The term "O-carboxy" group refers to a R"C(O)O-group, with R"as defined in the present invention.

"Carbonilla" group refers to a-carboxyl group, in which R" represents hydrogen.

p> The term "Trihalomethyl" group refers to a-CZ3the group, in which Z represents a halogen group, as defined in the present invention.

The term "Trihalomethanes" group refers to Z3CS(=O)2the groups Z as defined above.

The term "Trihalomethane" group refers to Z3CS(=O)2NRx-group with Z and Rxas defined in the present invention.

The term "Sulfinil" refers to-S(=O)-R" group, with R"as defined in the present invention and, in addition, only as a link; that is,- S(O)-.

The term "Sulfonyl" refers to-S(=O)2R" group, with R"as defined in the present invention and, in addition, only as a link; that is,- S(O)2-.

The term "S-sulfonamide" refers to-S(=O)2NRxRywith Rxand Ryas defined in the present invention.

The term "N-sulfonamide" refers to a R"S(=O)2NRx- group with Rxas defined in the present invention.

The term "O-carbarnoyl" refers to-OC(=O)NRxRyas defined in the present invention.

The term "N-carbarnoyl" refers to RxOC(=O)NRythe group Rxand Ryas defined in the present invention.

The term "O-thiocarbamyl" refers to-OC(=S)NRxRythe group Rxand Ryas defined in the present invention.

the Ermin "N-thiocarbamyl" refers to R xOC(=S)NRy- group with Rxand Ryas defined in the present invention.

The term "Amino" refers to-NH2group.

The term "C-amido" refers to-C(=O)NRxRythe group R" and Ryas defined in the present invention.

The term "C-thioamide" refers to-C(=S)NRxRythe group R" and Ryas defined in the present invention.

The term "N-amido" refers to RxC(=O)NRy- group with R" and Ryas defined in the present invention.

The term "Ureido" refers to-NRxC(=O)NRyRy2the group R" and Ryas defined in the present invention, and Ry2defined as Rxand Ry.

The term "Guanidino" refers to-RxNC(=N)NRyRy2the group Rx, Ryand Ry2as defined in the present invention.

The term "Guanyl" refers to RxRyNCC(=N)- group, Rxand Ryas defined in the present invention.

The term "Cyano" refers to the-CN group.

The term "Silyl" refers to an-Si(R")3with R"as defined in the present invention.

The term "Phosphonyl" refers to P(=O)(ORx)2with Rxas defined in the present invention.

The term "Hydrazino" refers to-NRxNRyRy2the group Rx, Ryand Ry2as defined in the present invention.

Lubiewo adjacent R groups can join together, to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring condensed with the ring, originally bearing the above R groups.

It is known in this field of knowledge that the nitrogen atoms in the heteroaryl system may be involved in the heteroaryl ring double bond" and refers to the formation of double bonds in two tautomeric structures that contain a five-membered ring heteroaryl groups. This determines whether the nitrogen atoms can be substituted as is well understood chemists in this field of knowledge. The description and claims of the present invention is based on the well-known General principles of chemical bonding. It is clear that the claims did not cover patterns, known as unstable or is not capable of existence as described in the literature.

Physiologically acceptable salts and prodrugs of the compounds disclosed in the description, are within the scope of the present invention. The term "pharmaceutically acceptable salt", as used in the present invention and in the claims, is intended to determine a non-toxic fundamental additive salt. Suitable salts also include derivatives of organic and inorganic acids, such as, without limitation, hydrochloric acid, Hydrobromic acid, phosphoric Ki the lot, sulfuric acid, methanesulfonate, acetic acid, tartaric acid, lactic acid, Sultanova acid, citric acid, maleic acid, fumaric acid, sorbic acid, konitova acid, salicylic acid, phthalic acid and the like. The term "pharmaceutically acceptable salt", as used in the present invention is also intended to include salts of acidic groups, such as carboxyl, such counterions as the ammonium salt of an alkali metal, especially sodium or potassium, salts of alkaline earth metals, particularly calcium or magnesium, and salts with appropriate organic bases, such as lower alkylamines followed (methylamine, ethylamine, cyclohexylamine and the like), or substituted lower alkylamines followed (for example, hydroxylamine the bonds alkylamines, such as diethanolamine, triethanolamine or Tris(hydroxymethyl)-aminomethan), or by reason such as piperidine or morpholine.

In the description of the present invention, the term "effective antiviral amount" means the total amount of each active component of the method, which is sufficient to provide significant patient benefit, i.e., the removal of acute conditions characterized by the inhibition of HIV infection. When the term is used in relation to individually is the active ingredient, entered once, it refers to that ingredient alone. When the term is used in relation to the combination, he refers to the total number of active ingredients, which result in a therapeutically effective input or in combination, sequentially or simultaneously. The terms "treat, cleansing, treating," as used in the present invention and in the claims, means to prevent or stop the disease associated with HIV infection.

The present invention is also directed to combinations of compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of the present invention can effectively be entered, either pre-and/or after, in combination with effective amounts of antivirals, immunomodulators, anti-bacterial drugs or vaccines against AIDS, such as shown in the following Table.

Additionally, the compounds of the present invention can be applied in combination with another class and is having treatment of AIDS, called entry inhibitors HIV (entrance gate infection). Examples of such inhibitors entrance HIV considered in DRUGS OF THE FUTURE 1999, 24(12), pp.1355-1362; CELL, Vol.9, pp.243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol.5, No. 5, 2000, pp.183-194.

It will be clear that the possibilities of combinations of the compounds of the present invention with Spotovymi with antivirals, immunomodulators, antibacterial agents, inhibitors sign of HIV or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.

The preferred combination can be administered simultaneously or interleaved in the treatment with the compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. Optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. Preferably the inhibitor of HIV protease is indinavir, which is a sulfate of N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N'-(tert-BUTYLCARBAMATE)-piperazinil))-pentanone ethanolate, which is synthesized in accordance with methods described in U.S. 5,413,999. Indinavir, usually administered dose of 800 mg three times a day. Other pre is respectful protease inhibitors are nelfinavir and ritonavir. Another preferred HIV protease inhibitor is saquinavir, which is injected dose of 600 or 1200 mg three times a day. Preferably a non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. Receiving ddC, ddl, and AZT is also described in EPO 0,484,071. These combinations can have unexpected results on the limiting distribution and the level of HIV infection. Preferred combinations include the following: (1) indinavir with efavirenz and, optionally, AZT and/or 3TC and/or ddl, and/or ddC; (2) indinavir, and any of AZT and/or ddl, and/or ddC and/or 3TC, particularly indinavir and AZT and 3TC; (3) DDI, and 3TC and/or ZDV; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.

In combinations of the compound of the present invention and other active agents can be introduced separately or together. In addition, the introduction of an individual agent can occur before, simultaneously or after the insertion of the other agent(s).

The processes of obtaining and anti-HIV-1 activity of new derivatives of azaindolizines formula I are summarized in Schemes 1-64 below.

Reduction

The following abbreviations, which most often are the usual abbreviations are well known in this field of knowledge, applied everywhere in the description of the invention and the examples. Some of the abbreviations used in the following way:

h = hour(s)

at room temperature = room temperature

mol = mole(s)

mmol = millimoles(and)

u = gram(s)

mg = milligram(s)

ml = milliliter(s)

TFA = Triperoxonane acid

DCE = 1,2-Dichloroethane

CH2Cl2= Dichloromethane

TRR = perruthenate of tetrapropylammonium

THF = Tetrahydrofuran

DEPBT = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he

DMAP = 4-dimethylaminopyridine

P-EDC = 1-(3-dimethylaminopropyl)-3-

ethylcarbodiimide on polymer substrates

EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF = N,N-dimethylformamide

Hunig's Base = N,N-Diisopropylethylamine

mCPBA = meta-Chloroperbenzoic acid

azaindole = 1H-pyrrolopyridine

4-azaindole = 1H-pyrrolo[3,2-6]pyridine

5-azaindole = 1H-pyrrolo[3,2-C]pyridine

6-azaindole = 1H-pyrrolo[2,3-C]pyridine

7-azaindole = 1H-pyrrolo[2,3-6]pyridine

RMV = 4-Methoxybenzyl

DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

OTf = Triftormetilfullerenov

NMM = 4 Methylmorpholin

PIP-COPh = 1-Benzoylpiperazine

NaHMDS = Hexamethyldisilazide sodium

EDAC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

TMS = Trimethylsilyl

DCM = Dichloromethane

DCE = Dichloroethane

Meon = Methanol

THF = Tetrahydrofuran

EtOAc = ethyl Acetate

LDA = Diisopropylamide lithium

TMP-Li = 2,2,6,6-tetramethylpiperidine lithium

DME = Dimethoxyethane

DIBALH = Hydride Diisobutyl the aluminium

NOUT = 1-hydroxybenzotriazole

CBZ = Benzyloxycarbonyl

RCC = Chlorproma pyridinium

Chemistry

The present invention provides compounds of formula I, their pharmaceutical kompoziziii and their use for the treatment of palatov suffering from or predisposed to HIV infection. The compounds of formula I include their pharmaceutically acceptable salts.

General processes of formation of substituted diamide azaindolizines formula I and intermediate compounds suitable for their synthesis, are described in the following diagrams.

Stage As in figure 1 reflects the synthesis of intermediate azaindole, 2, through the well-known reaction Bartoli, in which vinylmania bromide reacts with aryl or heteroaryl nitrogroup, such as 1, to form a five-membered ring containing nitrogen, as shown in the diagram. Some references for the above reaction include: by Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem. Soc. Perkin Trans. 1, 1991, 2757. (C) J. Chem. Soc. Perkin Trans. II, 1991, 657. d) Synthesis (1999), 1594. In a preferred method the solution vinylmania bromide in THF (usually 1.0M, but from 0.25 to 3.0M) is added dropwise to a solution of nitropyridine in THF at a temperature of -78°in an inert atmosphere or nitrogen, or argon. After completion of addition, the temperature of the reaction mixture raised to -20°and then it is stirred for about the olo 12 hours before cooling down to 20% aqueous solution of ammonium chloride. The reaction mass is extracted with ethyl acetate and then treated in the usual way, using a drying agent such as anhydrous magnesium sulfate or sodium sulfate. The products usually are cleaned, using chromatography on silica gel. Better results can usually get using their vinylmania bromide. In some cases vinylmania chloride can replace vinylmania bromide.

Substituted azaindole can be obtained using the methods described in the prior art, or they may be available from commercial sources. Thus, there are many ways of describing the stage And in the prior art, the specific examples are so numerous that it is difficult to enumerate. Alternative synthesis of azaindole and General methods of performing stage And include, but are not limited to those described in the following reference (a-k below): a) Prokopov, A.A.; Yakhontov, L.N. Khim.-Farm. Zh. 1994, 28(7), 30-51; (b) Lablache-Combier, A. Heteroaromatics. Photoinduced Electron Transfer 1988, Pt. C, 134-312; (C) Saify, Zafar Said. Pak. J. Pharmacol. 1986, 2(2), 43-6; (d) Bisagni, E. Jerusalem Symp. Quantum Chem. Biochem. 1972, 4, 439-45; (e) Yakhontov, L.N. Usp. Khim. 1968, 37(7), 1258-87; (f) Willette, R.E. Advan. Hetrocycl. Chem. 1968, 9, 27-105; u) Mahadevan, I.; Rasmussen, M. Tetrahedron 1993, 49(33), 7337-52; (h) Mahadevan, I.; Rasmussen, M. J. Hetrocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A.C.; Fekner, T.; Spey, S.E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j) Spivey, A.C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922; k) Advances in Heterocyclic Chemistry (Academic press) 1991, Vol.52, pg 235-236 and [daln] is isie links.

Stage C. the Intermediate compound 3 can be obtained by reaction of azaindole, intermediate 2, with excess ClCOCOOMe in the presence of AlCl3(aluminium chloride) (Sycheva et al, Ref. 26, Sycheva, T.V.; Rubtsov, N.M.; Sheinker, Yu.N.; Yakhontov, L.N. Some of the reactions of 5-cyano-6-chloro-7-azaindole and lactam-lactim tautomerism of 5-cyano-6-hydroxy-7-azaindole. Khim. Geterotsild. Soedin., 1987, 100-106). Usually used inert solvent such as CH2Cl2but others , such as THF, Et2O DCE, dioxane, benzene or toluene, a solvent can be used or by themselves or in a mixture. Other oxalate esters, such as ethyl or benzyl of monoether oxalic acid, can also satisfy any method listed above. More lipophilic esters facilitate allocation during water extraction. Phenol or substituted phenol (such as pentafluorophenol) esters can directly bind HW(C=O)A group such as piperazine, at the stage D without activation. The catalyst, a Lewis acid such as tin tetrachloride, titanium chloride IV and aluminium chloride are used on stage, while aluminum chloride is more preferred. Alternatively, azaindole is treated with a Grignard reagent, such as MeMgI (Metalmania iodide), meilani bromide or etimani bromide and zinc halide, such as ZnCl 2(zinc chloride or zinc bromide, followed by the addition of monoether of oxalicacid, such as ClCOCOOMe (methylchlorothiazide) or another ether, as described above, to obtain the Glyoxylic ester azaindole (Shadrina et al, Ref. 25). Use the esters of oxalic acid, such as Metrocall, ethylacetat or as indicated above. Aprotic solvents such as CH2Cl2Et2O, benzene, toluene, DCE or the like, can be applied to either as themselves or in combination in sequence. In addition to monoethers of oxalicacid, oxalicacid itself can react with azaindole, and then, further, to react with an appropriate amine such as piperazine derivative (see scheme 52, for example).

Stage C. the Hydrolysis of the methyl ester (intermediate compound 3, scheme 1) gives the potassium salt of intermediate compound 4, which is associated with monobenzone with piperazine derivatives as shown in stage D scheme 1. Some typical conditions include methanolic or ethanolic sodium hydroxide followed by careful acidification with an aqueous solution of hydrochloric acid variable polyarnosti, but 1M HCl is preferred. In many cases, the acidification is not used as described above for the preferred conditions. May also be applied to the lithium hydroxide sludge is potassium hydroxide, and various amounts of water may be added to the alcohol. Propanol or butanol can also be used as solvents. The increase of temperature up to the boiling point solvents may be used if the ambient temperature is not suitable. Alternatively, the hydrolysis can be carried out in non polar solvent such as CH2Cl2or THF in the presence of Triton Century Can be applied temperature in the range from -78°C to the boiling point of the solvent, but temperature -10°is preferred. Other conditions of the hydrolysis of the ester shown in the link 41 and as the terms of reference and many other conditions hydrolysis of the ester is well known to chemists with average skills.

Alternative techniques for stage b and C

Chloroaluminate imidazole

It was found that the ionic liquid chloroaluminate 1-alkyl-3-alkylimidazole is, as a rule, suitable for promotion process acylation of indoles and azaindole by Friedel-Crafts. The ionic liquid obtained by mixing the chloride of 1-alkyl-3-alkylimidazole with aluminium chloride at room temperature and vigorous stirring. The molar ratio of 1:2 or 1:3 chloride 1-alkyl-3-alkylimidazole to the aluminum chloride is preferred. One particularly suitable chloroaluminate imidazole for acylation asain the ol with methyl or ethyl chlorocatechol is chloroaluminate 1-ethyl-3-methylimidazole. The reaction is usually carried out at ambient temperature and azaindolizines ether can be selected. It was found that more suitable when Glyoxylic ester can be hydrolyzed in situ at ambient temperature with prolonged reaction time (typically overnight)to obtain the corresponding Glyoxylic acid for the formation of amide (scheme 1).

The presented experiment is as follows: 1-ethyl-3-methylimidazolium chloride (2 equiv.; obtained from TCI; suspended in a stream of nitrogen) is stirred in a completely dry round bottom flask at room temperature under nitrogen atmosphere and then added aluminium chloride (6 equiv.; anhydrous powder, Packed in argon atmosphere in the ampoule, preferably obtained from Aldrich; suspended in a stream of nitrogen). The mixture is vigorously stirred with the formation fluid, which is then added azaindole (1 equiv.) and stirred until a homogeneous mixture is formed. To the reaction mixture is added dropwise ethyl or methyl chlorocatechol (2 equiv.), and then stirred at room temperature for 16 hours. After this time the mixture is cooled in a bath of ice water, and the reaction mixture was quenched with careful addition of excess water. The precipitate is filtered, washed with water and dried in high the m vacuum, to get azaindolizines acid. Some examples may require 3 equivalent of 1-ethyl-3-methylimidazolium chloride and chlorocatechol.

Related links: (1) Welton, T. Chem Rev. 1999, 99, 2071; (2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 2753; (3) Saleh, R. Y. WO 0015594.

Stage D. Acid intermediate compound 4 with stage circuit 1 is connected with the amine A(C=O)WH, preferably in the presence of DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and N,N-diisopropylethylamine, generally known as the basis Janiga to get diamides azaindolizines. DEPBT receive in accordance with the methodology of links 28, Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 7, 91-93. Usually used inert solvent, such as DMF or THF, but can be applied to other aprotic solvents. The group W as defined, is a

Reaction on building amide bond can be carried out preferably using the conditions described above, the EDC conditions described below, other conditions of interaction described for this application, or alternatively through the use of conditions or bonding agents to build amide bond shown later in the description with the introduction of the substituents R1-R4. Some specific non-limiting examples provided in the OPI is offering.

Derivatives one-deputizing piperazine can be obtained in accordance with well known processes such as those described in Desai et al, reference 27(a), Adamczyk et al, Ref. 27(b), Rossen on et al, Ref. 27(C) and Wang et al, 27(d).

Additional methods of synthesis, modification and joining groups (C=O)m-WC(O)-A, see PCT WO 00/71535.

Scheme 2 represents a more specific example of the transformations previously described in scheme 1. Intermediate compounds 6-10 obtained using the methods described for intermediate compounds 1A-5A in scheme 1. Scheme 2A is another embodiment of the transformations presented in schemes 1 and 2. The conversion of phenol chloride (stage S, Scheme 2A) can be carried out in accordance with the techniques described in Reimann, E.; Wichmann, P.; Hoefher, G.; Sci. Pharm. 1996, 64(3), 637-646; and Katritzky, A.R.; Rachwal, S.; Smith, T.P.; Steel, P.J.; J. Hetrocycl Chem. 1995, 32(3), 979-984. Stage T circuit 2A can be carried out as described for stage And scheme 1. Poslednee intermediate compound can then be converted into alkoxy, chloro or fluoro-substituted intermediate compound, as shown at stage U scheme 2A. Scheme 2A describes the preferred method of obtaining the intermediate 6C or other related compounds containing the 4 methoxy group in the 6-azaindole system. When stage U represents the t of a conversion of bromide in alkoxybenzenes, the transformation can be carried out using the reaction of bromide with excess of sodium methoxide in methanol in the presence of copper salts such as copper bromide (I, iodide copper I and copper cyanide I. the temperature Range may be from ambient temperature up to 175°With, but may be most appropriate temperature of about 115°or 100°C. the Reaction can be carried out in the chamber under pressure or in a sealed tube to prevent leakage of volatile substances, such as methanol. Preferred conditions include 3 EQ. of sodium methoxide in methanol, CuBr as the catalyst (0.2 to 3 equivalents, preferably with 1 EQ. or less) and the reaction temperature 115°C. the Reaction is carried out in a sealed tube or a hermetically reaction vessel. Conversion of bromide in the alkoxy derivative may also be carried out in accordance with the techniques described in Palucki, M.; Wolfe, J.P.; Buchwald, S.L.; J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.; Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky, S.D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of bromide in fluoro-substituted derivative (phase U, Scheme 2A) can be carried out in accordance with Antipin, I.S.; Vigalok, A.I.; Konovalov, A.I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of bromide in the derived chlorine (stage U, Scheme 2A) can be performed with the availa able scientific C methods, described in Gilbert, E.J.; Van Vranken, D.L.; J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.; Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996, 37(37), 6695-6698; and O'connor, K.J.; Burrows, C.J.; J. Org. Chem. 1991, 56(3), 1344-1346. Stage V, W and X scheme 2A is carried out in accordance with the methods previously described for stages b, C and D of scheme 1, respectively. Stage circuit 2A can be performed in a different order, as shown in figure 2B and the Circuit 2C.

Scheme 3 shows the synthesis of 4-anandapresley 1b-5b, 5-azaindole derivatives 1C-5C and 7-azaindole derivatives 1d-5d. The methods applied for the synthesis of 1b-5b, 1C-5C and 1d-5d are similar to the methods described for the synthesis of 1A-5A, as described in scheme 1. Clearly, to perform the circuit 3, which 1b applied for the synthesis of 2b-5b, 1C provides reception 2C-5C and 1d provides obtaining 2d-5d.

Compounds that have one carbonyl group between azaindole and group W can be obtained using the method described in Kelarev, V.L; Gasanov, S.Sh.; Karakhanov, R.A.; Polivin, Yu.N.; Kuatbekova, K.P.; Panina, M.E.; Zh. Org. Khim 1992, 28(12), 2561-2568. In this way azaindole react with trichloroacetamido in pyridine, and then with KOH in methanol to obtain 3-carbomethoxy azaindole, shown in figure 4, which can then b shall be hydrolyzed to the acid, which is passed through a sequence of combinations with HW(C=O)A, to obtain the compounds of formula I, in which one carbonyl binds part of azaindole and group W.

An alternative way of implementing a given sequence of stages B-D (shown in scheme 5) includes processing azaindole, such as 11, obtained using the techniques described in the prior art or from commercial sources, with MeMgI and ZnCl2with the subsequent addition ClCOCOCl (oxalyl chloride) in THF, and Et2O, to obtain a mixture of glyoxylide of azaindole, 12A and acylchlorides of azaindole, 12b. The mixture of glyoxylide of azaindole and acylchlorides of azaindole then associated with monobenzone derivative of piperazine in basic conditions to obtain products of stage D in the form of a mixture of compounds 13A and 13b, in which either one or two carbonyl groups linked azaindole and group W. the Separation by chromatographic methods, which are well known to specialists in this field, gives a clean 13A and 13b. This sequence is summarized below in scheme 5.

Scheme 6 illustrates a General method modification Deputy A. Binding of N-W,-C(O)OtBu, using the conditions described previously for W in scheme 1, stage D, especial obtain Boc-protected intermediate compound 15. From intermediate 15 then remove the protection by treatment with acid, such as TFA, hydrochloric acid or formic acid, using standard solvents or additives such as CH2Cl2, dioxane or anisole, and the temperature between -78°and 100°C. Other acids, such as aqueous hydrochloric or perchloro acid, can also be applied to remove the protection. Alternative other azatadine group W, such as Cbz or TROC, can be applied and can be removed by hydrogenation or by treatment with zinc, respectively. Sustainable silyl protective group, such as phenyldimethylsilane may also be applied as azatadine group on W and can be removed sources of fluoride, such as tetrabutylammonium fluoride. Finally, the free amine attached to the acid a-C(O)HE, using standard conditions for the combination of the amine-acid, such as those that applied to join the group W, or as shown below for the formation of amide at position R1-R4to get the connection 16.

Some specific examples of common ways of obtaining functional azaindole or ways interchangeability functionalities on azaindole that will be suitable for obtaining compounds of the present invention, shown in the following illustrate with whom mentah schemes. It should be clear that the present invention includes substituted 4, 5, 6 and 7 azaindole and what methods below can be applied to all of the above series, while the other below will be specific for only one or more. The average expert in the art can determine this difference when no difference. Many methods are intended to be applied to all series, especially to the inclusion of functional groups or their vzaimoprevrascheny. For example, a common strategy for the implementation of further functional transformations of the present invention is to place or include halogen, such as bromine, chlorine or iodine, aldehyde, cyan or carboxyl group on azaindole, and then transform this functional group to produce the desired compounds. In particular, the conversion to substituted heteroaryl, aryl, and amide groups on the ring is of particular interest.

General directions for functionalization isoindoline rings shown in schemes 7, 8 and 9. As depicted in scheme 7, azaindole, 17, can be oxidized to the corresponding N-oxide derivative, 18, when using mCPBA (meta-chloroperbenzoic acid) in acetone or DMF (EQ. 1, Harada et al, the link 29 and Antonini et al, reference 34). N-oxide, 18 may bytereverse in different substituted asingapore when using the well-known reagents, such as phosphorus oxychloride (POCl3) (EQ. 2, Schneller et al, reference 30), Tetramethylammonium fluoride (Me4NF) (EQ. 3), reagents Grignard reagent RMgX (R = alkyl or aryl, X = Cl, Br or I) (EQ. 4, Shiotani et al, reference 31), trimethylsilylacetamide (TMSCN) (EQ. 5, Minakata et al, reference 32) or AU2On (EQ. 6, Klemm et al. Reference 33). In these conditions may be placed on the pyridine ring chlorine (19), fluorine (20), nitrile (22), alkyl (21), aromatic (21) or hydroxyl group (24). Nitration of N-oxides azaindole occurs as a result of the introduction of the nitro group in isoindoline ring as shown in scheme 8 (EQ. 7, Antonini et al, reference 34). The nitro-group can be substituted with various nucleophilic agents, such as OR, NR1R2or SR, in the well-known chemical methods (EQ. 8, Regnouf De Vains et al, reference 35(a), Miura et al, reference 35(b), Profit et al, reference 35). The N-oxides, 26, quickly reduced to the corresponding azaindole, 27 using trichloride phosphorus (PCl3) (EQ. 9, Antonini et al, the Link 34 and Nesi et al, reference 36). Similarly nitro-substituted N-oxide, 25, can be restored to azaindole, 28 using trichloride phosphorus (EQ. 10). The nitro-group of 28 can be restored either to hydroxylamine (NHOH), as at 29, (EQ. 11, Walser et al, reference 37(a) and Barker et al, reference 37(b)) or amino (NH2) group, as at 30, (EQ. 12, Nesi et al, the link 36 and Ayyangar et al, Ref is and 38) by careful selection of the conditions of recovery.

Alkylation of the nitrogen atom in position 1 of derivative azaindole can be done using NaH as base in DMF as solvent and alkylhalides or sulfonate as the alkylation agent, in accordance with the methods described in the prior art (Mahadevan et al, reference 39) (Scheme 9).

General directions to replace isoindoline rings described above, each process can be used repeatedly, and combinations of these processes are valid in order to get azaindole containing different substituents. The use of such processes provides additional compounds of formula I.

Synthesis of 4-iminoisoindolin, which are suitable precursors for 4, 5 and/or 7-substituted azaindole shown in scheme 10, privedennoi above.

Synthesis of 3,5-dinitro-4-methylpyridine 32, described in the following two links at Achremowicz et.al.: Achremowicz, Lucjan. Pr. Nauk. Inst. Chem. Org. Fiz. Politech. Wroclaw. 1982, 23, 3-128; Achremowicz, Lucjan. Synthesis 1975, 10, 653-4. In the first stage of the process according to scheme 10, the reaction of dimethylformamide with dimethylacetal in an inert solvent or pure form in the conditions of obtaining the predecessors of Batco-Leimgruber (Batcho-Leimgrub), PR is, as shown, the cyclization precursor, 33. Although phase is, as shown, pyridine can be oxidized to N-oxide prior to the reaction using percolate, such as MSRA or a more powerful oxidant, type meta-trifluoromethyl, or mechanicalproperties acid. In the second stage of the process scheme 10 the restoration of the nitro group using, for example, hydrogenation over Pd/C catalyst in a solvent such as Meon, EtOH or EtOAc, provides cyklinowanie product 34. Alternatively, recovery may be carried out using tin dichloride and HCl, hydrogenation over Raney Nickel or other catalyst or by using other methods to nitroacetanilide, such as described elsewhere for this application.

Aminoindole, 34, can now be converted into the compounds of formula I using, for example, by diazotization of the amino group, followed by conversion of diazonium salts in fluoride, chloride or alkoxygroup. The discussion of such transformations are given in the descriptions of the circuits 17 and 18. The transformation of the amino group in the desired functional group can then be carried out by introducing oxoazetidin balance using the standard techniques described above. 5 or 7-substitution azaindole can occur through the formation of N-oxide in position 6 and the subsequent substitution of chlorine in the us is the conditions, such as POCl3in chloroform, acetic anhydride, and then POCl3in DMF or alternative TsCl in DMF. References for these and other conditions are described in some more recent schemes. Synthesis of 4-bromo-7-hydroxy or protected hydroxy-4-azaindole described below, since it is a suitable precursor for 4 and/or 7-substituted 6-azaindole.

Synthesis of 5-bromo-2-hydroxy-4-methyl-3-nitropyridine 35 may be implemented as described in the following references: Betageri, R.; Beaulieu, P.L.; Llinas-Bmnet, M; Ferland, J.M.; Cardozo. M.; Moss, N.; Patel, U.; Proudfoot, J. R. PCT Int. Appl. WO 9931066,1999. The intermediate connection 36 is obtained from 35 in accordance with the method described for stage 1 scheme 10. PG is the best hydroxy protecting group, such as trialkylsilyl or the like. The intermediate connection 37 is then obtained from 36 through selective reduction of the nitro group in the presence of bromide and subsequent cyclization as described in the second stage circuit 10. Fe(OH)2in DMF with a catalytic amount of tetrabutylammonium bromide may also be applied to nitrogroup reduction. Bromide can then be converted to a fluoride by substitution of anions of fluorine or other substituents. The connection is then converted into the compounds of formula I, as described above.

An alternative way of obtaining the replacement of the seal 6-azaindole shown below in schemes 12 and 13. You must distinguish that there may be some deviations in the modifications shown below. For example, the reaction of acylation at the 3 position of the remnant that will be isoindoline the five-membered ring before the flavoring azaindole, can be carried out in order to obtain higher yields. In addition to the pair-methoxybenzyloxy group (RNG) benzyl group can be saved through the sequence to be removed during formation of azaindole using TsOH, p-chloranil in benzene as oxalates if DDQ is not optimal. Benzyl intermediate connection, 38, was described by Ziegler et al. in J. Am. Chem. Soc. 1973, 95(22), 7458. The conversion of 38 to 40 is similar to the transformation described in Heterocycles 1984, 22, 2313.

Scheme 13 describes the various transformations of the intermediate connection 40, which ultimately give the compounds of formula I. the Transformation of phenolic residue in another functional group in position 4 (R2the position in figure 13), can be carried out using the following methods: 1) the conversion of phenol in the methoxy group with silver oxide and MeI or diazomethane; 2) the transformation of phenolic hydroxy-group in the chlorine, using a catalyst ZnCl2and N,N dimethylaniline in CH2Cl2or PCl5and POCl3together; 3) a substitution of the phenolic the hydroxy-group in the fluorine, using diethylamin-SF3as in Org. Prep. Proc. Int. 1992, 24(1), 55-57. The method described in EP 427603, 1991, using chloroformiate and HF, will also be suitable. Other transformations are possible. For example, phenol can be converted into triflate using standard methods and used in the related chemical processes, described later, for this application.

1) Alkylation of the ketone to the introduction of R3.

2)DDQ oxidation for the formation of azaindole.

3) the Conversion of phenol (R2=HE) methyl ether or substitution by fluorine, chlorine and so on.

4) Use the C-7 guide groups for functionalization of R4or the formation of N-oxide and POCl3to create R4= chlorine.

5) Conversion into compounds of formula I, as described above.

Stage E

Scheme 14 illustrates the nitration of azaindole, 41, (R2=N). Many different conditions for the nitration of azaindole can be effective, and they have been described in the prior art. Can be applied N2O5in nitromethane, and then an aqueous solution of sodium bisulfite in accordance with the method Bakke, J..; Ranes, E.; Synthesis 1997, 3, 281-283. Nitric acid in acetic acid may also be applied, as described in Kimura, N.; Yotsuya, S.; Yuki, S.; Sugi, H.; Shigehara, I.; Haga, T.; Chem. Pharm. Bull 1995, 43(10), 1696-1700. Sulfuric acid, following nitric acid, can be applied CA is in Ruefenacht, K.; Kristinsson, H.; Mattem, G.; Helv Chim Acta 1976, 59, 1593. Coombes, R.G.; Russell, L.W.; J. Chem. Soc., Perkin Trans. 1 1974, 1751 describe the application based on the Titan system reagent for nitration. Other conditions for the nitration of azaindole can be found in the following references: Lever, O.W.J.; Werblood, H.M.; Russell, R..; Synth. Comm. 1993, 23(9), 1315-1320; Wozniak, M.; Van Der Plas, H.C.; J. Hetrocycl Chem. 1978, 75, 731.

Stage F

As shown above in scheme 15, step F, substituted azaindole containing chlorine, bromine, iodine, triflate or phosphonate capable of condensation reactions with boronate (reaction of Suzuki type) or stannane to obtain the substituted azaindole. Stannane and boronate get using standard techniques described in the prior art, or as described in the experimental part of the present description. Substituted indoles can enter into the condensation reaction initiated by metal, to obtain the compounds of formula I in which R4represents, for example, aryl, heteroaryl or heteroalicyclic ring. Poslednie isoindoline intermediate compounds (or asiandaily or iodides) may react condensation on Still (Stille) heteroarylboronic, as shown in figure 15. Conditions for this reaction are well known in this field of knowledge, and has the following three examples of references (a) Farina, V.; Roth, G.P. Recentadvances in Stille reaction; Adv. Met.-Org. Chem. 1996, 5, I-53. b) Farina, V.; Krishnamurthy, V.; Scott, W.J. The Stille reaction; Org. React. (N. Y.) 1997, 50, 1-652, and (C) Stille, J. K. Angew. Chem. Int. Ed Engl. 1986, 25, 508-524. Other references of General conditions of condensation are also available in the publication in Richard C. Larock Comprehensive Organic Transformaton 2nd Ed. 1999, John Wiley and Sons New York. All of these references disclose a variety of conditions known in this field in addition to the specific examples illustrated in figure 15 and in the specific embodiments of the invention. It should be recognized that standan indole can also be condensed with heterocyclic or aryl halides or triflate, when creating compounds of formula I. Condensation Suzuki (Norio Miyaura and Akiro Suzuki Chem Rev. 1995, 95, 2457) between triflate, bromine or horizantally intermediate connection and a suitable boronate can also be carried out, and some specific examples are given for this application. Catalyzed by palladium condensation of stannane and boronates between horizantally intermediate compounds are also real and widely applicable in the present invention. In preferred methods of the condensation process of horizantal and stannane apply dioxane, stoichiometric or excess amount of reagent tin (up to 5 equivalents), from 0.1 to 1 EQ. palladium (O) tetranitroaniline in dioxane is heated for 5 to 15 hours in the range of temperaturet 110 to 120° C. Can be applied to other solvents, such as DMF, THF, toluene or benzene. In preferred methods of the condensation process on Suzuki of horizantal and boronate using a mixture of 1:1 DMF/ water as solvent, 2 equivalents of potassium carbonate as the base, stoichiometric or excess amount of boron reagent (up to 5 equivalents), from 0.1 to 1 EQ. palladium (O) tetracationic phosphine, heated for a period of 5 to 15 hours in the temperature range from 110 to 120°C. If the standard conditions is not enough, can be used a new specialized catalyst and conditions. Some links (and other references)that describe the catalyst which is suitable for condensation of aryl and heteroarylboronic are as follows:

Littke, A.F.; Dai, C.; Fu, G.. J Am. Chem. Soc. 2000, 122(17), 4020-4028; Varma, R.S.; Naicker, K.P. Tetrahedron Lett. 1999, 40(3), 439-442; Wallow, .L; Novak, V. M. J. Org. Chem. 19: 4, 59(17), 5034-7; Buchwald, S.; Old, D.W.; Wolfe, J.P.; Palucki, M.; Kamikawa, K.; Chieffi, A.; Sadighi, J.P.; Singer, R. A.; Ahman, J PCT Int. Appl. WO 0002887 2000; Wolfe, J.P.; Buchwald, S.L. Angew. Chem., Int. Ed. 1999, 38(23), 3415; Wolfe, J.P.; Singer, R. A.; Yang, B.H.; Buchwald, S.L. J. Am. Chem. Soc. 1999, 121(41), 9550-9561; Wolfe, J.P.; Buchwald, S.L. Angew. Chem., Int. Ed. 1999, 38(16), 2413-2416; Bracher, F.; Hildebrand, D.; LiebigsAnn. Chem. 1992, 12, 1315-1319; Bracher, F.; Hildebrand, D.; LiebigsAnn. Chem. 1993, 8, 837-839.

Alternatively, boronat or stannane can be formed on azaindole using methods known in this field of knowledge, and condensation implemented Aut in reverse order based on the halogen or triflate the aryl or heteroaryl.

Known agents boronate or stannane can be obtained from any commercial source or obtained in accordance with processes disclosed in the following documents. Additional examples of the preparation of reagents tin or boronated reagents are contained in the experimental part.

New Scandanavia agents can be obtained in one of the following ways.

Boronate reagents receive, as described in the link 71. The reaction of lithium or Grignard reagents with trialkylborane leads to boronates. Alternatively, catalyzed by palladium condensation alkoxyamine or alkylboronic reagents with aryl halides or heteroaryl leads to boron reagents for use in the condensation on Suzuki. Some examples of the process of condensation of halogen with (MeO)EXPLOSIVES(OMe)2include the use of PdCl2(dppf), KOAc, dimethyl sulfoxide, at a temperature of 80°until the reaction is not fully complete, as determined using TLC or HPLC analysis.

Similar examples are presented in the following experimental part.

Methods of direct addition of aryl and heteroaryl ORGANOMETALLIC reagents to the nitrogen-containing heterocyclic compounds having chlorine in the alpha position, or N-oxides azospermic the heterocycle is in, known, and they are applicable to azaindole. Some examples are given in Shiotani et. Al. J. Heterocyclic Chem. 1997, 34(3), 901-907; Fourmigue et. al. J. Org. Chem. 1991, 56(16), 4858-4864.

Obtain the key intermediate aldehyde, 43, using the adapted method method, described by Gilmore et. Al. Synlett 1992, 79-80 above in scheme 16. Deputy aldehyde shown in the R4position only for clarity and cannot be considered as a limitation of the methodology. Bromine or idatabase intermediate compound is transformed into the intermediate aldehyde, 43, using the metal-halogen exchange and subsequent reaction with dimethylformamide in a suitable aprotic solvent. Typical used bases include, but without limitation, the grounds alkylate, such as n-utility, Deut.-utility or tert-utility, or metal, such as lithium. Preferred aprotic solvent is THF. Usually transmetallation begin at a temperature of -78°C. the Reaction can be allowed to warm up to ensure completion of transmetilirovania dependent reational ability prosteradlo intermediate compounds. The reaction mass is then cooled to a temperature of -78°and give her the opportunity to respond with dimethylformamide (heat of reaction may be necessary to enable the e complete), to obtain the aldehyde, which is transformed into the compounds of formula I. Other ways of introducing aldehyde groups to obtain the intermediate compounds of formula 43 include carbonylation catalyzed by transition metals suitable bromine, trifloromethyl or stannyl of azaindole.

Alternative aldehydes can be obtained by reacting indolering anions or indolenine reagents Grignard reagent with formaldehyde, followed by oxidation of MnO2or TPAP/NMO or other suitable oxidizing agents to obtain the intermediate compound 43.

The procedure described in .Fukuda et. al. Tetrahedron 1999, 55, 9151 and M.Iwao et. Al. Heterocycles 1992, 34(5), 1031, discloses methods of obtaining of indoles with substituents in the 7-position. References Fukuda disclose methods of introducing functional groups at the C-7 position of indoles under the protection of the indole nitrogen using 2,2-diethylpropane groups, and then the deprotonation of the 7-position with Deut/Buli TMEDA in order to obtain the anion. This anion can be suppressed by using DMF, formaldehyde or carbon dioxide, to obtain the aldehyde, benzyl alcohol or carboxylic acid, respectively, with the subsequent removal of the protective group in an aqueous solution of tert-butoxide. Such transformations can be produced by transformation of indoles in indoline, liceali on C-7, and then back to the on oxidation of indole, as described in the above link Iwao. The level of oxidation of any of these products can be picked up by methods that are well known in this field of knowledge, because the mutual transformation of the alcohol, aldehyde and acid groups have been well studied. Well it is clear that the cyano can be quickly converted into aldehyde group. The recovery agent, such as DIBALH in hexane, such as used in Weyerstahl, P.; Schlicht, V.; Liebigs Ann/Reel. 1997, 1, 175-177, or alternative catecholamin in THF, such as used in Cha, J.S.; Chang, S.W.; Kwon, O.O.; Kim, J.M.; Synlett. 1996, 2, 165-166, will quickly realize the specified transformation to obtain the intermediate compounds such as 44 (Scheme 16). Methods of synthesis of NITRILES below. Well it is clear that the protected alcohol, aldehyde and acid group may be present in the source azaindole and be carried through the synthesis of soedinenii formula I in protected form, until they are transformed into the desired substituent in positions from R1to R4. For example, benzyl alcohol can be protected as a benzyl ether or silloway ether, or other alcohol protecting group; an aldehyde can exist as acetal, and the acid may be protected as an ether or orthoevra until the removal of protection would be desirable and feasible using methods, Pref is effected in the prior art.

Stage G

Stage 1 scheme 17 discloses the recovery of nitro compounds 45 to the amino group of compound 46. Although it is shown in position 4 azaindole, this chemistry is also valid for other nitrosomonas. The procedure described in Ciurla, N.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371, uses hydrazine Nickel-Raney for recovery of nitro group to amine. Robinson, R.P.; DonahueO, K.M.; Son, P.S.; Wagy, S.D.; J. Hetrocycl. Chem. 1996, 33(2), 287-293 describes the application of the process of hydrogenation on Nickel-Raney for recovery of nitro group to amine. Similar conditions described by Nicolai, E.; Claude, S.; Teulon, J..; J. Hetrocycl. Chem. 1994, 31(1), 73-75 for the identical transformation. The following two links describe some trimethylsilyl based on sulphur or chlorine compounds which can be used to restore the nitro group to the amine. Hwu, J. R.; Wong, F.F.; Shiao, M.J.; J. Org. Chem. 1992, 57(19), 5254-5255; Shiao, M.J.; Lai, L.L.; Ku, W.S.; Lin, P.Y.; Hwu, J. R.; J. Org. Chem. 1993, 58(17), 4742-4744.

Stage 2 scheme 17 describes common ways of transforming the amino group of azaindole in other functional groups. Circuit 18 also illustrates the conversion of aminoethanol in various intermediate compounds and the compounds of formula I.

The amino group at any position of azaindole, such as 46 (Scheme 17)can be converted into a hydroxy group using sodium nitrite, sulfuric acid and water with the help of method, description of the frame at Klemm, L.H.; Zeil, R.; J. Hetrocycl. Chem. 1968, 5, 773. Bradsher, S. Kaliev; Brown, F..; Porter, H.K.; J. Am. Chem. Soc. 1954, 76, 2357, describing how the hydroxy-group can be alkylated under standard conditions or the conditions of the reaction Mitsunobu to form esters. The amino group can be converted directly into a methoxy group using the diazotization (sodium nitrite and acid) and trapping with methanol.

The amino azaindole, such as 46, may be converted into fluorine using the method described in Sanchez using HPF6, NaNO2and water, using the method described in Sanchez, J.P.; Gogliotti, R.D.; J. Hetrocycl. Chem. 1993, 30(4), 855-859. Other methods suitable for the conversion of the amino group in the fluorine described in Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18), 2937-2940 and Sanchez, J.P.; Rogowski, J.W.; J. Hetrocycl. Chem. 1987, 24, 215.

The amino azaindole, 46, can also be converted into chlorine through the reaction of diazotization and replacement of the chlorine, as described in Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371, or by using methods described in Raveglia, L.F.; Giardina, G.A.; Grugni, M.; Rigolio, R.; Farina, C.; J. Hetrocycl. Chem. 1997, 34(2), 557-559, or methods described in Matsumoto, J.I.; Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura, H.; J. Med. Chem. 1984, 27(3), 292; or as in Lee, T.C.; Salemnick, G.; J. Org. Chem. 1975, 24, 3608.

The amino azaindole, 46, can also be converted into a bromine using diazotization and replacement of the bromine, as described in Raveglia, L.F.; Giardina, G.A.; Grugni, M.; Rigolio, R.; Farina, C.; J. Hetrocycl Chem. 1997, 34(2, 557-559; Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293; and Abramovitch, R. A.; Saha, M.; Can. J. Chem. 1966, 44, 1765.

Getting 4-amino-4-azaindole and 7-methyl-4-azaindole described by Mahadevan, L; Rasmussen, M. J. Hetrocycl. Chem. 1992, 29(2), 359-67. The amino group of 4-amino-4-azaindole can be converted into a halogen, a hydroxy-group, a protected hydroxy-group, triplet, as described above in schemes 17-18 4-amino compounds, or using other methods known in this field of knowledge. Protection of the indole nitrogen of 7-methyl-4-azaindole through acetylation or other method, with subsequent oxidation of the 7-methyl group with potassium permanganate or chromic acid gives 7-acid /4-N-oxide. Recovery N-oxide, as described below, gives an intermediate compound, which introduce different substituents at position R4. Alternative precursor 4-azaindole, which is obtained as described in Mahadevan, L; Rasmussen, M. J. Hetrocycl. Chem. 1992, 29(2), 359-67, can be modified by nitrogen, to obtain 1-(2,2-diethylbutyl)azaindole, which can then be literowe using TMEDA /Deut. BuLi, as described in .Fukuda et. Al. Tetrahedron 1999, 55, 9151-9162; with the subsequent transformation of the ion balance in 7-carboxylic acid or 7-halogen, as described. Hydrolysis of N-amide using an aqueous solution of tert-butoxide in THF, regenerates the free NH group of the indole, which which can now be converted into compounds of formula I. Chemistry applied to the introduction of functional groups at position 7, may also be used according to the provisions of articles 5 and 6 of the indole.

Scheme 19 illustrates obtain 7-chloro-4-azaindole, 50, which may be converted into compounds of the formula I by means of chemical processes described previously, particularly catalyzed by palladium, based on the tin and boron of the condensation process described above. Nitrolingual, 49, is commercially available or obtained from 48 in accordance with the method Delarge, J.; Lapiere, .L. Pharm. Acta HeIv. 1975, 50(0), 188-91.

Scheme 20 below illustrates one way of synthesis for substituted 4-azaindole. 3-Aminopyrrolo, 51, reacts with the formation of pyrrolopyridine, 52, which will then restore to get hidroxizina, 53. Described pyrrolo[2,3-b]pyridine receive in accordance with the method disclosed in Britten, A.Z.; Griffiths, G.W.G. Chem. Ind. (London) 1973, 6, 278. Hidroxizina, 53 may then be converted into triflate derived and then, in the future, it reacts with the formation of compounds of formula I.

The following links describe the synthesis of 7-halo or 7 carboxyl or 7-aminopropionic 5-isoindoline, which can be used to form compounds of formula I. Bychikhina, N.N.; Azimov, VA; Yakhontov, L.N. Khim. Geterotskl. Soedin. 1983, 7, 58-62; Bychikhina, N.N.; Azimov, VA; Yakhontov, L.N. Khim. Geterotsikl. Soedin. 1982, 3, 356-60; Azimov, VA; Bychikhina, N.N.; Yakhontov, L.N. Khim. Geterotsikl. Soedin. 1981, 12, 1648-53; Spivey, A.C.; Fekner, T.; Spey, S.E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; Spivey, A.C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922. The methods described in Spivey et al. (the previous two references) to obtain 1-methyl-7-bromo-4-isoindoline, can be applied to obtain 1-benzyl-7-bromo-4-azaindole, 54, is shown below in scheme 21. It can be applied in the condensations on Still or Suzuki to get the connection 55, which removes the protection and digitalout to get the connection 56. Other suitable isoindoline intermediate compounds such as cyanoderivatives, 57 and 58, and aldehyde derivatives, 59 and 60, can be further transformed into compounds of formula I.

Alternative 7-functional 5-azaindole derivatives can be obtained by functionalization using techniques .Fukuda et. al. Tetrahedron 1999, 55, 9151, and M. Iwao et. Al. Heterocycles 1992, 34(5), 1031 described above for 4 or 6 azaindole. Position 4 or 6 5-azaindole can be functionalized by using an N-oxide azaindole.

The transformation of indoles in indoline well known in this field of knowledge and can be carried out, as shown in the diagram, or by using methods described in Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull. 1987, 35(8), 3146-54; Mao et. Al. Heterocycles 1992, 34(5), 1031; and Akagi, M.; Ozaki, K. Heterocycles 1987, 26(1), 61-4.

Getting anandalakshmi or oxopiperidine with carboxylic acids can be carried out on the basis of nitrile, aldehyde or anionic precursor via hydrolysis, oxidation or trapping CO2respectively. As shown in scheme 22, step 1, or the scheme below, stage and 12, one of the ways education nitrile intermediate, 62, is the replacement of the halogen cyanide in azaindole ring. Used cyanide reagent may be a cyanide or more preferably sodium cyanide or copper cyanide zinc. The reaction can be carried out in many solvents, which are well known in this field of knowledge. For example DMF used in the case of copper cyanide. Additional procedures suitable to perform the stage 1 scheme 24 disclosed in Yamaguchi, S.; Yoshida, M.; Miyajima, L; Araki, T.; Hirai, Y.; J. Hetrocycl. Chem. 1995, 32(5), 1517-1519, which uses copper cyanide; Yutilov, Y.M.; Svertilova, I.A.; Khim Geterotsiki Soedin 1994, 8, 1071-1075, which uses cyanide of potassium; and Prager, R.H.; Tsopelas, C.; Heisler, I.; Aust. J. Chem. 1991, 44 (2), 277-285, which uses copper cyanide in the presence of Meos web(O)2F. more preferably Chlorine or bromine on azaindole may be substituted with sodium cyanide in dioxane using the method described in Synlett. 199, 3, 243-244. Alternatively, the Nickel dibromide, zinc and triphenylphosphine can be used to activate aromatic and heteroaryl chlorides are replaced with potassium cyanide in THF or other suitable solvent, using a method described in Eur. Pat. Appl., 831083, 1998.

The conversion of cyanide intermediate compounds, 62, intermediate carboxylic acid, 63, depicted in stage 2, the circuit 22 or on the stage A12, scheme 23. Many ways of converting NITRILES to acids is well known in this field of knowledge and can be applied. Apply potassium hydroxide, water and aqueous alcohol, such as ethanol, discussed below, as appropriate conditions for phase 2 circuit 22, or conversion of intermediate compounds 65 in the intermediate connection 66. Usually, the reaction can be carried out by heating to boiling point over a period of one to 100 hours. Other methods of hydrolysis include those described in:

Shiotani, S.; Taniguchi, K.; J. Hetrocycl. Chem. 1997, 34(2), 493-499; Boogaard, A.T.; Pandit, U..; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560; Rivalle, S.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; Macor, J.E.; Post, R.; Ryan, K.; J. Hetrocycl Chem. 1992, 29(6), 1465-1467.

Acid intermediate compound 66 (scheme 23)may then be subjected to esterification, using conditions well known in this field of knowledge. For example, the reaction of the acid with diazomethane in an inert dissolve the barely, such as ether, dioxane or THF, can give the methyl ester. Intermediate compound 67 can then be converted into an intermediate connection 68 in accordance with the methodology described in scheme 2. The intermediate connection 68 may then be hydrolyzed to obtain the intermediate compound 69.

As shown in scheme 24, the stage A13, another way to get indeloxazine-7-carboxylic acid, 69, is carried out by oxidation of the corresponding 7-carboxaldehyde, 70. Many of auxilialy are suitable for the conversion of the aldehyde to the acid, and many of them are described in standard organic chemical reference books, such as: Larock, Richard C. total organic transformations: a guide to the introduction of functional groups 2nded. New York: Wiley-VCH, 1999. One preferred method of application of silver nitrate or silver oxide in a solvent such as aqueous or anhydrous methanol at a temperature of ˜25°or when such a high temperature as boiling. The reaction is usually carried out for from one to 48 hours, and usually followed by means of TLC or LC/MS until there is a complete transformation of the product from the source material. Alternatively, KMnO4or CrO3/N2SO4may be applied.

With the EMA 25 gives a specific example of the oxidation of the aldehyde intermediate compound, 70A, to obtain the intermediate carboxylic acid, 69A.

Alternatively, the intermediate compound 69 can be obtained by using a nitrile of the synthesis method, performed in an alternate order, as shown in scheme 26. Stage hydrolysis of the nitrile may be removed, and the nitrile may be carried through the synthesis to obtain the nitrile, which can be hydrolyzed in the end, to obtain the free acid, 69, as described above.

Stage N

Direct conversion of NITRILES, such as 72, to amides, such as 73, shown in scheme 27, step H, can be carried out using the conditions described in Shiotani, S.; Taniguchi, K.; J. Hetrocycl. Chem. 1996, 33(4), 1051-1056 (describes the use of aqueous solution of sulfuric acid); Memoli, K.A.; Tetrahedron Lett. 1996, 37(21), 3617-3618; Adolfsson, H.; Waemmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8), 2004-2009; and El Hadri, A.; Leclerc, G.; J. Hetrocycl. Chem. 1993, 30(3), 631-635.

Stage I for NH2

Shiotani, S.; Taniguchi, K.; J. Hetrocycl. Chem. 1997, 34(2), 493-499; Boogaard, A.T.; Pandit, U..; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560; Rivalle, S.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; Macor, J.E.; Post, R.; Ryan, K.; J. Hetrocycl Chem. 1992, 29(6), 1465-1467.

Stage J

The following diagram (28A) shows an example of retrieving 4-fluoro-7 substituted azaindole from known starting materials. References to the synthesis of indole p is Bartoli described earlier. Conditions for conversion to NITRILES, acids, aldehydes, heterocyclic compounds and amides have also been described for this application.

Stage A16, A17 and A18 cover reactions and formation conditions 1°, 2° and 3° amide bond, as shown in schemes 28 and 29 which lead to compounds such as the compounds of formula 73.

Reaction conditions for the formation of amide bonds, cover any reagents that form reaktsionnosposobnykh intermediate connection for the activation of carboxylic acids with amide formation, for example (but not limited to, Allgood, carbodiimide, salt acylamine, symmetrical anhydrides, mixed anhydrides (including phosphonic/phosphinic mixed anhydrides), active esters (including silloway ether, methyl ether and thioether), allcarbon, acylated, arylsulfonate, acyloxy TV-Fofanova salt. The reaction indolocarbazole acids with amines to form amides, can be initiated using standard amide formation conditions of communication described in this field of knowledge. Some examples of the formation of amide linkages are listed in the links 41-53, but this list is not limiting. Some agents condensation of carboxylic acids with amines, which are suitable, are EDC, disop percarbonate or other carbodiimide, Rover (benzothiazolylthio (dimethylamino) phosphonium hexaflurophosphate), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HBTU). A particularly suitable method of formation of an amide from isoindol-7-carboxylic acid is the use of carbonyldiimidazole as condensation reagent, as described in reference 53. The temperature of this reaction may be lower than in the reference from the 80°With (or possibly below) up to 150°C or higher. A more specific application is depicted in scheme 30.

The following four General methods give a more detailed description of the receiving indolocarbazole and these methods are used for the synthesis of compounds of formula I.

Method 1:

To a mixture of an acid intermediate, such as 69, (1 equiv., 0.48 mmol), the appropriate amine (4 equiv.) and DMAP (58 mg, 0.47 mmol)dissolved in CH2Cl2(1 ml), added EDC (90 mg, 0.47 mmol). The resulting mixture was shaken at room temperature for 12 hours and then evaporated in vacuum. The residue is dissolved in Meon and purified preparative HPLC with reversed phase.

Method 2:

To a mixture of the appropriate amine (4 equiv.) and NOT (16 mg, 0.12 mmol) in THF (0.5 ml) is added an acid intermediate connection, such as 69, (25 mg, 0.06 mmol) and NMM (50 μl, 0.45 mmol)and then EDC (23 mg, 0.12 mmol). The reaction mixture is shaken when the room is Noah temperature for 12 hours. Volatile matter is evaporated in vacuo; and the residue dissolved in Meon and purified using preparative HPLC with reversed phase.

Method 3:

To a mixture of an acid intermediate, such as 69, (0.047 mmol), amine (4 equiv.) and DEPBT (obtained in accordance with Li, H.; Jiang, X. Ye, Y.; Fan, C.; Todd, R.; Goodman, M. Organic Letters 1999, 1, 91; 21 mg, 0.071 mmol) in DMF (0.5 ml), add TEA (0.03 ml, 0.22 mmol). The resulting mixture was shaken at room temperature for 12 hours and then diluted with Meon (2 ml) and purified using preparative HPLC with reversed phase.

Method 4:

A mixture of an acid intermediate, such as 69, (0.047 mmol) and 8.5 mg (0.052 mmol) of 1,1-carbonyldiimidazole in anhydrous THF (2 ml) is heated to the boiling temperature under nitrogen atmosphere. After 2.5 hours add 0.052 mmol amine and heating continued. After another period of about 3-20 hours at boiling temperature under reflux, the reaction mixture was cooled and concentrated in vacuo. The residue purified via chromatography on silica gel to obtain compound of formula I.

In addition, the carboxylic acid may be converted into the acid chloride acid, using reagents such as thionyl chloride (by itself or in an inert solvent) or oxalicacid in a solvent such as benzene, toluene, THF or CH2Cl2. Amides can alternate is but to be obtained by the reaction of carboxylic acid with excess of ammonia, primary or secondary amine in an inert solvent, such as benzene, toluene, THF or CH2Cl2or with the stoichiometric quantity of an amine in the presence of a tertiary amine such as triethylamine, or bases, such as pyridine or 2,6-lutidine. Alternatively, the acid chloride of the acid can react with amines in alkaline conditions (usually sodium hydroxide or potassium hydroxide) in a solvent mixture containing water and possibly slavely the co-solvent, such as dioxane or THF. Scheme 25 illustrates typical conditions for obtaining the carboxylic acid and the modification process prior to the amide of formula I. in Addition, the carboxylic acid can be converted into an ester, preferably the methyl or ethyl ester, and then reacting with an amine. The ether can be formed through reaction with diazomethane or alternative with trimethylsilyldiazomethane using standard conditions, which are well known in this field of knowledge. Description and method to use this or any other reaction of the receipt of the broadcast can be found in the links 52 or 54.

Additional references describing the formation of amides from acids are: Norman, M.H.; Navas, F. III; Thompson, J.B.; Rigdon, G.C.; J. Med. Chem. 1996, 39(24), 4692-4703; Hong, F.; Pang, Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin TRANS 1 1997, 14, 2083-2088; Langry, K.C.; Org. Prep. Proc. Int. 1994, 26(4), 429-438; Romero, L.; Morge, R. A.; Biles, C.; Berios-Pena, N.; May, P.D.; Palmer, J.R.; Johnson, p; Smith, H.W.; Busso, M.; Tan, C.-K.; Yoorman, R.L.; Reusser, F.; Althaus, I.W.; Downey, K.M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014; Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect In 1994, 33(7), 679-682.

Scheme 31 shows the process of replacing chlorine in nitroethanol. Stage F-I circuit 31 can be carried out in accordance with the following methods:

Yamaguchi, S.; Yoshida, M.; Miyajima, I.; Araki, T.; Hirai, Y.; J. Hetrocycl. Chem. 1995, 32(5), 1517-1519;

Yutilov, Y.M.; Svertilova, I.A.; Khim Geterotsiki Soedin 1994, 8, 1071-1075; and Prager, R.H.; Tsopelas, C.; Heisler, I.; Aust. J. Chem. 1991, 44(2), 277-285. Stage F-2 Circuit 31 can be performed in accordance with the procedures set forth in: Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371; Robinson, R.P.; Donahue, K.M.; Son, P.S.; Wagy, S.D.; J. Heterocycl. Chem. 1996, 33(2), 287-293; Nicolai, E.; Claude, S.; Teuton, J.M.; J. Hetrocycl. Chem. 1994, 31(1), 73-75; Hwu, J. R.; Wong, F.F.; Shiao, M.-J.; J. Org. Chem. 1992, 57(19), 5254-5255; Shiao, M.-J.; Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J. R.; J. Org. Chem. 1993, 55(77), 4742-4744.

Introduction alkoxy or aryloxy Deputy in azaindole (stage G, the circuit 31, R2represents alkoxy or aryloxy) can be carried out using f of the techniques described in Klemm, L.H.; ZeIl, R.; J. Hetrocycl. Chem. 1968, 5, 773; Bradsher, S. Kaliev; Brown, F..; Porter, H.K.; J. Am. Chem. Soc. 1954, 76, 2357; and Hodgson, H.H.; Foster, S. Kaliev; J. Chem. Soc. 1942, 581.

The introduction of a substituent of fluorine in azaindole (stage G, scheme 31) can be performed in accordance with the techniques described in Sanchez, J.P.; Gogliotti, R.D.; J. Hetrocycl. Chem. 1993, 30(4), 855-859; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18), 2937-2940; the Sanchez, J.P.; Rogowski, J.W.; J. Hetrocycl. Chem. 1987, 24, 215.

The introduction of substituent chlorine in azaindole (stage G, scheme 31) can be performed in accordance with the techniques described in Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371; Raveglia, L.F.; Giardinal, G.A.M.; Grugni, M.; Rigolio, R.; Farina, C.; J. Hetrocycl. Chem. 1997, 34(2), 557-559; Matsumoto, J.I.; Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura, H.; J. Med. Chem. 1984, 27(3), 292; Lee, T.-C.; Salemnick, G.; J. Org. Chem. 1975, 24, 3608.

Introduction Deputy bromine in azaindole (stage G, scheme 31) can be performed in accordance with the techniques described in Raveglia, L.F.; Giardina, G.A.M.; Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997, 34(2). 557-559; Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293; Abramovitch, R. A.; Saha, M.; Can. J. Chem. 1966, 44, 1765.

It is well known in this field of knowledge, which heterocyclic ring can be obtained from an aldehyde, carboxylic acid, ester of carboxylic acid, carboxylic acid amide, gelegenheid carboxylic acid or cyanide derivative, or by attaching to another carbon atom substituted by bromine or another leaving group, such as triflate, mesilate, chlorine, iodine or fusional. Methods for such intermediate compounds of the typical intermediate compounds, such as carboxylic intermediate connection, 69, poslednee intermediate connection, 76, or aldehyde intermediate compound, 70 described above and well known to the average expert. The methods or the nature of heterocy the crystals, which can be entered as described in the prior art. The most characteristic finding of such heterocycles and their introduction are links 55 to 67, but they cannot be defined as limiting. However, the study of these references shows that many different methods available for the synthesis of variously substituted heterocycles, that is certainly known to experts in this field of knowledge, and this can be used to produce compounds of formula I. Specialist with experience in this field of knowledge, may at any time easily, quickly and as expected to find a variety of reactions to obtain heterocycles, amides, oximo or other substituents of the above starting compounds by examining reactions or techniques, using traditional electronic database, such as Scifinder (American Chemical Society), Crossfire (Beilstein), Theilheimer or Reaccs (MDS). Reaction conditions that are set by using such a search may then be applied, using the substrates described for this application to get all the connections are covered with the present invention. In the case of the amides can be applied in the synthesis of commercially available amines. Alternatively, the above program can be used to systematize the processes of obtaining, on the basis of literature data is izvestnyh amines or methods of synthesis of new amines. These techniques are then made by a specialist with knowledge in this area, to obtain the compounds of formula I for use as antiviral agents.

As shown below in scheme 32, step A13, the appropriate substituted azaindole, such as intermediate romasanta, 76, may be initiated by metal condensation with aryl group, heterocycle or vinylstyrene, to obtain the compounds of formula I, where R5represents, for example, aryl, heteroaryl or heteroalicyclic ring. Bromothiazole intermediate compounds, 76 (or asiandaily or iodides), can undergo condensation type condensation on Style with heteroresistance, as shown in scheme 32, step A13. Conditions for this reaction are well known in this field of knowledge and links 68-70 as well as the link 52, give many conditions in addition to the specific examples, privedennym in figure 14 and in specific embodiments. It should be recognized that undastandin can also join heterocyclic ring or arylhalides or triflate, to form compounds of formula I. the Combination Suzuki (reference 71) between poslednym intermediate connection 76, and a suitable boronate may also be applied, and some specific examples are available for this application.

As shown in scheme 34, step A14, the aldehyde intermediate compounds, 70, can be used to form a variety of compounds of formula I. the Aldehyde group can be a precursor for any of the substituents from R1for R5but conversion to R5for simplicity, the above. Aldehyde intermediate connection 70 may react to cause inclusion in the ring, as described

in the claims or be transformed into an acyclic group. Aldehyde, 70, may react with the reagent Cosmica (Tosmic)in order to establish the oksazolov (for example, the links 42 and 43). Aldehyde, 70, may react with the reagent Tomica and then an amine, to obtain the imidazoles, as in the link 72, or aldehyde intermediate compound, 70, may react with hydroxylamine to obtain the oxime, which is a compound of formula I, as described below. Oxidation of the oxime using NBS, tert-butylhypochlorite or other known reagents can give N-oxide, which reacts with alkynes or 3 alkoxyphenyl esters, to obtain isoxazoles with different substitution. The interaction of the intermediate aldehyde 70 with a known reagent, 77 (reference 70)shown below, and in alkaline conditions gives 4-amino ethyloxazole.

Removal of trityl gives 4-aminoanisole, which may be substituted with reactions acylation, reductive alkylation or alkylation or reactions for heterocycle. Trail can be replaced by an alternative protecting group, such as monoethoxylate, CBZ, benzyl or a suitable silyl group, if necessary. The link 73 discloses obtaining oksazolov containing triptorelin group, and conditions, demonstrating the synthesis oksazolov with fluorinated methyl groups attached to them.

The aldehyde can react with metal or a Grignard reagent (alkyl, aryl or heteroaryl)to form secondary alcohols. They are more efficient or can be oxidized to the ketone using TRAR, or MnO2, or PCC, for example, to obtain a ketone of the formula I, which can be used for processing or entering into the reaction with reagents of the metal to obtain tertiary alcohols, or alternatively converted into oximes using reaction with hydrochloride hydroxylamine in ethanol solvent. Alternative aldehyde can be converted into benzylamine using restorative animating. An example of the formation of oxazole using reagent Tomica shown below in scheme 35. The same reaction may raticate with aldehydes other terms and also in 5 - and 6-azaindole derivatives.

Diagram 36 shows on stage A15 cyanide intermediate connection, such as 62, which can be directly converted into the compounds of formula I using the heterocycle or by reaction with ORGANOMETALLIC reagents.

Scheme 37 illustrates a method of acylation of cyanoindole, intermediate compounds of formula 65, oxalicacid, which gives the acid chloride acid, 79, which can then be condensed with an appropriate amine in the presence of a base, to obtain 80.

Nitrile intermediate connection 80 may be turned into tetrazol formula 81, which can then be alkylated using trimethylsilyldiazomethane, to obtain the compound of formula 82 (Scheme 38).

Alkylation of tetrazole alkylhalides may be performed before the acylation of azaindole, as shown in scheme 39. The intermediate connection 65 may be turned into tetrazol, 83, which can be alkylated to obtain a connection 84. The intermediate connection 84 may then be allerban and hydrolyzed to obtain compound 85, which may be subject to action in the amide formation conditions to obtain a connection 86. Group, p is ukreplena to tetrazolo, can be completely different and yet to show significant potency.

Scheme 40 illustreret that oxadiazol, such as, 88, can be obtained by adding hydroxylamine to the nitrile, 80, with subsequent closure of the intermediate ring connection 87 with phosgene. Alkylation of oxadiazole, 88, with trimethylsilyldiazomethane leads to the compound of formula 89.

7-Cyanoindole, such as 80, can be efficiently converted into an intermediate ether in the usual reaction conditions of Pinner (Pinner), using 1,4-dioxane as solvent. The intermediate ester can react with nitrogen, oxygen or sulfur-containing nucleophiles to get a C7-substituted indoles, such as imidazoline, benzimidazole, azobenzenes, oxazoline, oxadiazole, thiazoline, triazoles, pyrimidines and amidine and so on. For example, the intermediate compound may react with acetylhydrazide with heating in not participating in the process solvent, such as, for example, dioxane, THF or benzene (water base or water base in an alcohol solvent may be needed in some cases to add it to effectively end dehydrating cyclization to form mailtrain. Can be applied to other hydrazines. Tr is atiny can also be introduced by condensation standincreasing 4, 5, 6 or 7-bromo or horizantally. References describing the examples of the formation of many of these heterocycles:

Links:

(1) Das, V.R.; Boykin, D.W. J. Med. Chem. 1977, 20, 531.

(2) Czarny, A.; Wilson, W.D.; Boykin, D.W. J. Hetrocyclic Chem. 1996, 33, 1393.

(3) Francesconi, I.; Wilson, W.D.; Tanious, F.A.; Hall, J.E.; Bender, B.C.; Tidwell, R.R.; McCurdy, D.; Boykin, D.W. J. Med. Chem. 1999, 42, 2260.

Scheme 41, illustrating the addition of either hydroxylamine or hydroxylamine acetic acid to intermediate aldehyde 90, can give oximes of formula 91.

Acid residue may be a precursor for the substituents from R1to R5when he occupies the corresponding position, such as R5as shown in scheme 42.

Acid, as an intermediate link, such as 69, can be applied as an alternating precursor to form many of the substituted compounds. The acid may be converted into hydrazonium, and then in the pyrazole as described in the link 74. One of the common methods heterocyclic synthesis can be transforming acid in alpha Bratton (reference 75) through the formation of carboxylic acid using standard methods, reaction with diazomethane, and finally reaction with NVG. Alpha Posledny ketone can be applied to obtain the aqueous various compounds of formula I, as it can be turned into many compounds, or other compounds of formula I. alpha aminoketone can be obtained by substitution of bromine on the amino group. Alternatively, alpha Posledny ketone can be applied to obtain the heterocycles that are not available directly from the aldehyde or acid. For example, using terms for Hilton (Hulton)disclosed in reference 76, reaction with alpha poslednym ketone will cause oksazolov. The reaction of the alpha bromoacetone with urea using the methods disclosed in reference 77, to give 2-aminoanisole. Alpha brooketon may also be applied to form furans using beta ketoesters (links 78-80) or other means, pyrrole (from beta dicarbonyl, as in the link 81, or by using the methods of Antica (Hantsch) (reference 82) thiazole, isoxazoles and imidazoles (reference 83), an example of the use of literary techniques. Condensation of the above-mentioned carboxylic acid with N-methyl-O-methylhydroxylamine have to give Amide Weinreb", which can be used in the reaction with alkyllithium or Grignard reagents to form ketones. Reaction of the anion Weinrebe with gianina hydroxylamine gives isoxazoles (reference 84). The reaction with acetylene lithium or other carbanion will lead to alkanolammonium. The reaction of this akinrinola intermediate soedineniya with diazomethane or other diazo compounds give the pyrazoles (reference 85). Reaction with azide or hydroxylamine gives heterocycles after elimination of water molecules. Nitrile oxides will react with alkynylamino to get isoxazoles (reference 86). The initial reaction of the acid to obtain the carboxylic acid using, for example, oxanilide, or thionyl chloride or triphenylphosphine/carbon tetrachloride gives useful intermediate compound, as described above. The reaction of carboxylic acids with alpha substituted isocyanide ether and the base is to give 2-substituted oksazolov (reference 87). They can be converted into amines, alcohols or halides, using standard conditions for the recovery or rearrangements Hoffman/Curtis.

Scheme 43 describes an alternative chemical process of introducing balance oxoazetidin in position 3 azaindole. Stage A"' scheme 43 illustrates the reaction with formaldehyde and dimethylamine using the conditions set out in Frydman, B.; Despuy, M.E.; Rapoport, N.; J. Am. Chem. Soc. 1965, 87, 3530, which can lead to dimethylaminomethylene.

Stage In"' illustrates the substitution of cyanide of potassium, leading to cyanoderivatives in accordance with the method described in Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.; Imanishi, T.; Chem. Pharm. Bull. 1997, 45(5), 932-935 or Kawase, M.; Sinhababu, A.K.; Borchardt, R.T.; Chem. Pharm. Bull 1990, 38(11), 2939-2946. The same transformation can also be carried out, the IP is using TMSCN and a source of fluoride, tetrabutylammonium, as in Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932. Sodium cyanide can also be used.

Stage With"' scheme 43 illustrates the hydrolysis of the nitrile with sodium hydroxide and methanol, which will lead to acid using, for example, the techniques described in Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932. Other bases used in the hydrolysis, are either NaOH or KOH, as described in Thesing, J.; et al.; Chem. Ber. 1955, 88, 1295 and Geissman, T.A.; Armen, A.; J. Am. Chem. Soc. 1952, 74, 3916. Application nitrilase enzyme to achieve the same transformation as described in Klempier N, de Raadt A, Griengl H, Heinisch G, J. Hetrocycl. Chem., 1992 29, 93 and can be applied.

Stage D' circuit 43 illustrates alpha hydroxylation, which may be performed using methods as described in Hanessian, S.; Wang, W.; Gai, Y.; Tetrahedron Lett. 1996, 37(42), 7477-7480; Robinson, R.A.; Clark, J.S.; Holmes, A.; J. Am. Chem. Soc. 1993, 115(22), 10400-10401 (KN(TMS)2and then camphorsulfonate or other oxaziridine; and Davis, F.A.; Reddy, R.T.; Reddy, R. E.; J. Org. Chem. 1992, 57(24), 6387-6389.

Stage E' scheme 43 illustrates the ways in which oxidation of the alpha hydroxyether to the ketone, which can be performed in accordance with methods described in Mohand, S.A.; Levina, A.; Muzart, J.; Synth. Comm. 1995, 25 (14), 2051-2059. The preferred method for stage E"' is that which is set out in MA, Z.; Bobbitt, J.M.; J. Org. Chem. 1991, 56(21), 6110-6114, which uses 4-(NH-Ac)-TAMRA in the solvent, t is lump as CH 2Cl2in the presence of para-toluensulfonate acid. The method described in Corson, B.B.; Dodge, R. A.; Harris, S.A.; Hazen, R.K.; Org. Synth. 1941, /, 241 for oxidation of alpha hydroxyether to ketone uses KMnO4as the oxidant. Another way of oxidation of the alpha hydroxyether to the ketone includes the one that is described in Hunaeus; Zincke; Ber. Dtsch Chem. Ges. 1877, 70, 1489; Acree; Am. Chem. 1913, 50, 391; and Claisen; Ber. Dtsch. Chem. Ges. 1877, 10, 846.

Stage F' scheme 43 illustrates the condensation reaction, which can be carried out as described previously in the application, and using your preferred method, which is described in Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93, and uses 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he (DEPBT); new reagent condensation with remarkable resistance to racemization.

Scheme 44 illustrates the formation of compounds of formula I using the condensation reaction HWC(O)a with acid, as described in stage F' scheme 43, with subsequent hydroxylation, as in stage D' Circuit 43, and oxidation, as described in stage E' scheme 43.

Scheme 45 illustrates a method of obtaining, which can be applied to obtain lidocaine formula I. stage G' represents the hydrolysis of the ester followed by amide formation (stage N', as described in stage F' scheme 43). Stage I' schema 45 illustri is the duty to regulate the obtaining N-oxide, which can be performed in accordance with procedures in Suzuki, N.; Iwata, S.; Sakurai, K.; Tokumoto, K.; Takahashi, N.; Hanada, M.; Yokoyama, Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172; and Ohmato, T.; Koike engineering Germany, K.; Sakamoto, Y.; Chem. Pharm. Bull. 1981, 29, 390. Cyanide N-oxide is shown in stage J' circuit 45, which may be made in accordance with the methods by Suzuki, N.; Iwata, S.; Sakurai, K.; Tokumoto, K.; Takahashi, N.; Hanada, M.; Yokoyama, Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606 and Suzuki, H.; Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172. Hydrolysis of the nitrile to the acid depicted at stage K' circuit 45 in accordance with techniques such as Shiotani, S.; Tanigucchi, K.; J. Hetrocycl. Chem. 1996, 33(4), 1051-1056; Memoli, K.A.; Tetrahedron Lett. 1996, 37(27; 3617-3618; Adolfsson, H.; Waemmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8), 2004-2009; and El Hadri, A.; Leclerc, G.; J. Hetrocycl. Chem. 1993, 30(3), 631-635. Stage L' scheme 45 illustrates a method that can be applied to obtain lidocaine formula I from cyanoderivatives, which can be performed in accordance with the techniques described in Shiotani, S.; Taniguchi, K.; J. Hetrocycl. Chem. 1997, 34(2), 493-499; Boogaard, A.T.; Pandit, U.K.; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560; Rivalle, S.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; and Macor, J.E.; Post, R.; Ryan, K.; J. Hetrocycl Chem. 1992, 29(6), 1465-1467. Stage M' of scheme 45 illustrates a method that can be applied to obtain lidocaine formula I derived from acid, which can be performed in accordance with the techniques described in Norman, M.H.; Navas, F. Ill; Thopson, J.B.; Rigdon, G.C.; J. Med. Chem. 1996, 39(24), 4692-4703; Hong, F.; Pang, Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 1 1997, 14, 2083-2088; Langry, K.S.; Org. Prep. Proced. Int. 1994, 26(4), 429-438; Romero, L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P.D.; Palmer, J.R.; Johnson, P.D.; Smith, H.W.; Busso, M.; Tan, C.-K.; Voorman, R.L.; Reusser, F.; Althaus, I.W.; Downey, K.M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014 and Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect In 1994, 33(7), 679-682.

Scheme 46 illustrates a method that can be applied for the synthesis of a derivative azaindolizines acid. Protection of the amino group can be effective with processing di-tert-BUTYLCARBAMATE to enter tert-butoxycarbonyl (BOC) group. Introduction oxalate residue can then be performed, as shown at the stage And circuit 46 in accordance with the techniques described in Hewawasam, P.; Meanwell, N.A.; Tetrahedron Lett. 1994, 35(40), 7303-7306 (using tert-Buli or s-buli, THF); or Stanetty, P.; Roller, H.; Mihovilovic, M.; J. Org. Chem. 1992, 57(25), 6833-6837 (using tert-Buli). The intermediate compound thus formed may then be subjected to cyclization to form azaindole, as shown in stage circuit 46 in accordance with the techniques described in Fuerstner, A.; Ernst, A.; Krause, H.; Ptock, A.; Tetrahedron 1996, 52(21), 7329-7344 (using TiCl3, Zn, DME); or Fuerstner, A.; Hupperts, A.; J. Am. Chem. Soc. 1995, 117(16), 4468-4475 (using Zn, excess Tms-Cl TiCl3(catalyst), MeCN).

Scheme 47 describes the alternative with ntis, which can be applied to derive azaindolizines acid. Stage With circuit 47 can be performed using the techniques described in Harden, F.A.; Quinn, R.J.; Scammells, P.J.; J. Med. Chem. 1991, 34(9), 2892-2898 [application 1. NaNO2, conc. HCI 2. SnCl2, conc. HCI (catalyst)]. Usually 10 equivalents NaNO2and 1.0 equivalent of the substrate is reacted at a temperature of 0°during the period from 0.25 hour to an hour and to this reaction mixture are added 3.5 equivalent SnCl2. Alternatively, it may be applied methodology is described in De Roos, K.B.; Salemink, C.A.; Reel. Trav. Chim. Pays-Bas 1971, 90, 1181 (use NaNO2, AcOH, H2O). The intermediate compound thus formed may further react and subjected to cyclization to obtain the derivative azaindolizines acid, as shown in stage D scheme 47 and in accordance with the techniques described in Atkinson, C. M.; Mattocks, A.R.; J. Chem. Soc. 1957, 3722; Ain Khan, M.; Ferreira Da Rocha, J.; Heterocycles 1978, 9, 1617; Fusco, R.; Sannicolo, F.; Tetrahedron 1980, 36, 161 [application of HCl (conc.)]; Abramovitch, R. A.; Spenser, I.D.; Adv. Hetrocycl. Chem. 1964, 3, 79 (application ZnCl2p-timal); and Clemo, G.R.; Holt, R.J.W.; J. Chem. Soc. 1953, 1313 (application ZnCl2Hcl , EtOH, sealed tube).

Scheme 48 illustrates other possible ways derivation azaindolizines acid. Stage F circuit 48 may be implemented as p is shown or in accordance with methods, such as those described in Yurovskaya, M.A.; Khamlova, I.G.; Nesterov, V.N.; Shishkin, O.V.; Struchkov, T.; Khim Geterotsikl Soedin 1995, 11, 1543-1550; Grzegozek, M.; Wozniak, M.; Baranski, A.; Van Der Plas, H.C.; J. Hetrocycl. Chem. 1991, 28(4), 1075-1077 (using NaOH, DMSO); Lawrence, N.J.; Liddle, J.; Jackson, D.A.; Tetrahedron Lett. 1995, 36(46), 8477-8480 (application NaH, DMSO); Haglund, O.; Nilsson, M.; Synthesis 1994, 3, 242-244; (application of 2.5 equiv. CuCl, 3.5 equiv. TBu-OK, DME, Py); Makosza, M.; Sienkiewicz, K.; Wojciechowski, K.; Synthesis 1990, 9, 850-852; (application KO-tBu, DMF); Makosza, M.; Nizamov, S.; Org. Prep. Proceed. Int. 1997, 29(6), 707-710; (application tBu-OK, THF). Stage F Circuit 48 illustrates the cyclization reaction, which gives the derivative azaindolizines acid. This reaction can be carried out in accordance with methods such as those described in Frydman, B.; Baldain, G.; Repetto, J..; J. Org. Chem. 1973, 35, 1824 (the use of N2Pd-C, EtOH); Bistryakova, I.D.; Smirnova, N.M.; Safonova, T.S.; Khim Geterotsikl Soedin 1993, 6, 800-803 (application of N2Pd-C (catalyst), Meon); Taga, M.; Ohtsuka, H.; Inoue, I.; Kawaguchi, T.; Nomura, S.; Yamada, K.; Date, T.; Hiramatsu, H.; Sato, Y.; Heterocycles 1996, 42(1), 251-263 (application SnCl2, HC;Et2O); Arcari, M.; Aveta, R.; Brandt, A.; Cecchetelli, L.; Corsi, G.B.; Dirella. M.; Gazz. Chim. Ital. 1991, 121(11), 499-504 [application NajSA, THF/EtOH/H2About (2:2:1)]; Moody, C. J.; Rahimtoola, K.F.; J. Chem. Soc., Perkin Trans 1 1990, 673 (application TiCl3, NH4Oac, acetone, N2O).

The circuit 49 is another way to intermediate compounds of azaindole, which can then be routed to obtain the compounds of formula I, such as shown aminopropane. One hundred is AI G" and H" circuit 49 can be carried out in accordance with methods, described in Takahashi, K.; Shibasaki, K.; Ogura, K.; lida, B.; Chem. Lett. 1983, 859; and Itoh, N.; Chem. Pharm. Bull. 1962, 10, 55. Processing of intermediate links in lidocaine formula I may be accomplished as previously described for stages I'-M' circuit 45.

Diagram 50 illustrates deriving asiandaily acid. The initial substance in the circuit 50 can be obtained in accordance with Tetrahedron Lett. 1995, 36, 2389-2392. Stages a', a', C' and D' Circuit 50 can be implemented in accordance with the methods described in Jones, R. A.; Pastor, J.; Siro, J.; Voro, T.N.; Tetrahedron 1997, 53(2), 479-486; and Singh, S.K.; Dekhane, M.; Le Hyaric, M.; Potier, P.; Dodd, R.H.; Heterocycles 1997, 44(1), 379-391. Stage E' Circuit 50 may be implemented in accordance with the techniques described in Suzuki, H.; Iwata, S.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.; Miyagi, C; Murakami, Y.; Chem. Pharm. Bull 1991, 39(8), 2170-2172; Hagen, T.J.; Narayanan, K.; Names, J.; Cook, J.M.; J. Org. Chem. 1989, 54, 2170; Murakami, Y.; Yokoyama, Y.; Watanabe, T.; Aoki, C.; et al.; Heterocycles 1987, 26, 875; and Hagen, T.J.; Cook, J.M.; Tetrahedron Lett. 1988, 29(20), 2421. Stage F' Diagram 50 illustrates the conversion of phenol in fluorine, chlorine or poslednee connection. The conversion of phenol in the fluoro-substituted compound can be carried out in accordance with the techniques described in Christe, K.O.; Pavlath, A.E.; J. Org. Chem. 1965, 30, 3170; Murakami, Y.; Aoyama, Y.; Nakanishi, S.; Chem. Lett. 1976, 857; Christe, C.O; Pavlath, A.E.; J. Org. Chem. 1965, 30, 4104; and Christe, K.O.; Pavlath, A.E.; J. Org. Chem. 1966, 31, 559. Turning penola chlorine substituted compound can be carried out in accordance with methods, described in Wright, S.W.; Org. Prep. Proc. Int. 1997, 29(1), 128-131; Hartmann, H.; Schulze, M.; Guenther, R.; Dyes Pigm 1991, 16(2), 119-136; Bay, E.; Bak, D. A.; Timony, P.E.; Leone-Bay, A.; J. Org. Chem. 1990, 55, 3415; Hoffmann, H.; et al.; Chem. Ber. 1962, 95, 523; and Vanallan, J.A.; Reynolds, G.A.; J. Org. Chem. 1963, 28, 1022. The conversion of phenol in poslednee connection can be carried out in accordance with the techniques described in Katritzky, A.R.; Li, J.; Stevens, C.V.; Ager, D.J.; Org. Prep. Proc. Int. 1994, 26(4), 439-444; Judice, J.K.; Keipert, S.J.; Cram, D.J.; J. Chem. Soc., Chem. Commun. 1993, 17, 1323-1325; Schaeffer, J.P.; Higgins, J.; J. Org. Chem. 1967, 32, 1607; Wiley, G.A.; Hershkowitz, R.L.; Rein, R.; Chung, B.C.; J. Am. Chem. Soc. 1964, 86, 964; and Tayaka, H.; Akutagawa, S.; Noyori, R.; Org. Syn. 1988, 67, 20.

Scheme 51 describes how to obtain derivatives azaindolizines acid using identical techniques used to obtain the derivatives of asiandaily acid, as shown and described in the diagram above 50. The original product used in scheme 51, can be obtained in accordance with J. Org. Chem. 1999, 64, 7788-7801. Stage A", B", C", D" and E" circuit 51 can be implemented in a similar manner as previously described for stages A', A', C', D' and E' scheme 50.

Other schemes provide an additional reference, examples and conditions for carrying out the present invention. Presents specific ways to obtain W and modification A. As shown in scheme 52, azaindole can be processed by oxalylamino or THF, or E. the Ira, in order to obtain the desired glyoxylide in accordance with literature methods (Lingens, F.; Lange, J. Justus Liebigs Ann. Chem. 1970, 738, 46-53). Intermediate glyoxylide you can condense with benzoylpiperazine (Desai, M.; Watthey, J.W. Org. Prep. Proc. Int. 1976, 8, 85-86) under alkaline conditions to obtain the compounds of formula I.

Alternatively, in scheme 52 processing azaindole-3-glyoxylide, (Scheme 52) tert-butyl-1-piperidinecarboxylate gives piperazinonyl product. It is undisputed in this field of knowledge that alternative Boc protected piperazine, which is synthesized as shown below, gives the compounds of formula I with alternative groups of the formula W. As discussed previously, other aminosidine groups, which do not require acid conditions, the removal of protection, can be used, if desirable. Removal of the Boc protection group is effective in the processing of 20% TFA/CH2Cl2that provides a free piperazine. This product is then condensed with a carboxylic acid in the presence of the polymer, which is applied as a substrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC), to obtain the products of formula I. This sequence reveals a common way of obtaining compounds with different values As in formula I.

Example obtain the compounds of formula I, which are the substituents in the A (or other parts of the molecule), which can be obtained in accordance with the standard reaction schemes of reactions shown in scheme 53. A derivative of piperazine (Scheme 53) is treated with a BOC-protected aminobenzoic acid in the presence of EDC to get piperidine. Part of the obtained product is separated and processed TFA to remove the Boc group, thereby obtaining derivatives.

Similarly deputies who have reaktsionnosposobnykh alcohol group can be introduced, as described below. A derivative of piperazine (Scheme 54) process acetoxybenzoic acid in the presence of EDC to obtain a derived piperazinediones. Part of the obtained product is separated and subjected to hydrolysis using LiOH, in order to remove the acetate group, thereby obtaining hydroxy.

Examples containing substituted piperazines, carried out using the General method indicated in the diagrams 55-38. Substituted piperazines are either commercially available from Aldrich, Co., or receive them in accordance with literature methods (Behun et al, Ref. 88(a), Scheme 31, EQ. 01). Hydrogenation of alkyl substituted pyrazino at a pressure of from 40 to 50 psi in EtOH gives C is displaced piperazines. When a Deputy is ether or amide group, pyrazinamide system can partially restore to tetrahydropyrazin (Rossen on et al. Link. 88(b), Scheme 55, ACV). Carbonization piperazines can be obtained in identical conditions described above using commercially available dibenzylpiperazine, Scheme 55, EQ. 03).

2-Triftorperasin (Jenneskens et al., Link. 88p) are obtained in four steps (Scheme 56). Using the Lewis acid TiCl4N,N'-dibenziletilendiaminom reacts with triftorperasin to get hemiacetal, which restores at room temperature with Et3SiH in TFA to obtain a lactam. Processing LiAlH4then recovery of lactam to 1,4-dibenzyl-2-cryptomaterial. Finally, hydrogenation of dibenzyl-2-cryptomaterial in the SPLA gives the desired product, 2-triftorperasin.

Monobenzone symmetrically substituted piperazines can be carried out using one of the following methods (Scheme 57). (a) Treatment of a solution of piperazine acetic acid acetylchloride gives desirable monumentalising piperazine (Desai et al. The link 27, the Circuit 57, EQ. 04). (b) Symmetric piperazines treated with 2 equivalents of n-utility, then add aout the benzoyl chloride at room temperature (Wang et al. A link 89, the Circuit 57, EQ. 05).

Monobenzone Asimmetrico substituted piperazines can be carried out using one of the following methods (Scheme 57), in which all methods are demonstrated using monoalkylammonium of piperazines. (a) Asymmetric piperazines treated with 2 equivalents of n-utility, then add benzoyl chloride at room temperature to obtain a mixture of two regioisomers, which can be separated by chromatography (Wang et al. The link 89 and 90(b), Scheme 58 EQ. 06); (b) Benzoic acid is converted into its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine gives monobenzylether with benzoline group with less spatial difficulty nitrogen (Adamczyk et al, the Link 90(a), Scheme 58, EQ. 07); (C) a Mixture of piperazine and methylbenzoate treated with dialkylamides aluminium chloride methylene within 2-4 days to get monobenzylether with benzoline group with less spatial difficulty nitrogen (Scheme 58 EQ. 08); (d) Asymmetric piperazines treated with 2 equivalents of n-utility, followed by the addition of triethylsilane and benzoyl chloride in THF at room temperature to obtain monobenzylether with benzoline group with more spatial zatrudneno the m nitrogen (Wang et al. The link 90(b), Scheme 58, EQ. 09). When the substituent in position 2 is the ether or amide group, monobenzone the benzoyl chloride is less spatial difficulties of nitrogen of the piperazine using triethylamine as base in THF (Scheme 58, EQ. 10).

In the case of tetrahydropyrazino (Scheme 59, EQ. 11), monobenzone is more spatial and rough nitrogen atom in similar conditions, as shown in equation 10 Circuit 58, by well-known methods (Rossen on et al, Reference 88(b)).

In addition, the ether group can be selectively recovered using NaBH4in the presence of benzamide (Masuzawa et al, Reference 91), as shown in scheme 60.

Ester group or as a binder for the piperazines or isoindoline nuclei can be hydrolyzed to the corresponding acid in basic conditions, such as K2CO3(Scheme 61, EQ. 13) or NaOMe (Scheme 61, EQ. 14) as the basis in the Meon and water.

The reaction azaindolizines substituted with benzoylpiperazine or tetrahydropyridine in CH2Cl2using I-Pr2Net as the base, gives the products of condensation as shown in scheme 62.

In the case of condensation reactions using 3-hydroxyethylpiperazine, hydroxyl group is temporarily protected as its TMS ether with BSTFA (N,O-bestemmelser)triptorelin (Furber et al, Reference 92). Unprotected nitrogen atom may then react with glyoxylide to form the desired diamide. During TMS protective group is removed to obtain the free hydroxyethylpiperazine, as shown in figure 63.

Pieperazinove intermediate gain, using standard chemical processes, as shown in scheme 64.

Scheme 65

Scheme 65 illustrates some of the more specific method for obtaining 5-asendulov for use in obtaining the claimed compounds. Some processes reductive cyclization include the use of Fe in acetic acid, chloride of tin II in aqueous HCl solution or powder of zinc in acetic acid. Can also be applied to the hydrogenation conditions or other terms used sequence of synthesis of the indole on Eigruber-Batch (LeimGruber-Batch). More specific way to obtain 5-azaindole:

X = chlorine or poslednee connection, or it can be converted into substituted connection, and then perform the network through a sequence.

The tautomers of nitrogen-containing heterocycles are included in the scope of this invention. For example, hydroxypyrazol also known as representing its corresponding tautomer, as well shown in scheme 66.

Schema 67-74 represent some non-limiting methods of obtaining substituted pyrazino that can be entered in the substituents of the compounds according to paragraph 1 of the claims, especially as part of R4. It should be noted that the nomenclature in these schemes does not match the claims, but rather illustrates examples of methods that can be applied to get the parts that form the connections for the claims. Thus, R1and R2these schemes have no relation to R1 and R2 in the formula of the invention, but, for example, are chemically compatible groups, which can be represented by professional chemists in this field and which can be used to obtain compounds according to the formula of the invention.

Throughout the chemical is Bardene were considered chemical transformations, which are well known in this field of knowledge. The average person skilled in the art knows well these transformations, and a complete list of suitable conditions for nearly all of the transformations is available for organic chemistry, and this list is contained in the link 52 created using Larock and United in its fullness for the synthesis of compounds of formula I.

Experimental part

Total

Additional descriptions of processes of production of starting compounds and intermediate compounds found in Wang et. al. PCT WO 01/62255, which is a reference.

Chemistry

All data is liquid chromatography (LC) were obtained on Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with data from mass spectrometry (MS), obtained using Micromassage platform for LC in the way electrospeed.

LC/MS Method (i.e., identification of connections)

Column A: YMC ODS-A S7 3.0×50 mm column

Column B: PHX-LUNA C18 4.6×30 mm column

Column: XTERRA ms 18 4.6×30 mm column

Column D: YMC ODS-A CIS 4.6×30 mm column

Column: YMC ODS-A C18 4.6×33 mm column

Column F: YMC C1 8 S5 4.6×50 mm column

Column G: XTERRA C18 S7 3.0×50 mm column

Gradient: 100% Solvent A / 0% Solvent to 0% Solvent A /100%

The solvent In

Solvent A = 10% Meon - 90% H2O - 0.1% TFA, Solvent B = 90% Meon -10% H2O - 0.% TFA; and R, in minutes

The gradient time: 2 minutes

Time saving: 1 minute

Flow rate: 5 ml/min

Detector wavelength: 220 nm

Solvent A: 10% Meon / 90% H2O /0.1% triperoxonane acid

Solvent A: 10% N2O / 90% Meon /0.1 % triperoxonane acid

Compounds purified using preparative HPLC, diluted in Meon (1.2 ml) and purified using the following methods on a Shimadzu LC-10A automatic preparative HPLC system or on a Shimadzu LC-8A automated preparative HPLC system with detector (SPD-IOAV UV-VIS) wavelength and solvent system (a and b), is identical to the above.

The way preparative HPLC (i.e., cleanup soedineniya)

Method of purification: the Initial gradient (40%, 60% And changes to the final gradient (100%, 0%) for 20 minutes, keeping the value within 3 minutes (100% B, 0% A)

Solvent A: 10% Meon / 90% H2O /0.1 % triperoxonane acid

Solvent A: 10% N2O / 90% Meon 70.1% triperoxonane acid

Column: YMC 18 S5 20×100 mm column

Detector wavelength: 220 nm

Typical methods and characteristics of selected Examples:

The Intermediate compounds:

The intermediate connection 1

4-Methoxyphenylalanine acid (24.54 g), hydrochloride 4-chloro-3-nitropyridine (26.24 g), Pd(Ph3R)4(4 g) and K2With the 3(111 g) are combined in DME (500 ml). The reaction mixture is heated to boiling point for 10 hours. The mixture is then cooled to room temperature, it was poured into a saturated aqueous solution of NH4OAc (500 ml ). The aqueous phase is extracted with EtOAc (3×200 ml). The combined extract was concentrated to obtain a residue, which was purified using chromatography on silica gel (10% to 30% EtOAc / PE)to obtain 10.6 g of the intermediate 1,3-Nitro-4-(4-methoxyphenyl)pyridine. MS m/e: (M+N)+calculated for: C12H11N2O3: 231.08; Found: 231.02. HPLC retention: 1.07 minutes (column B).

Intermediate compound 1a

An alternative way to 5-azaindole:

2-Methoxy-5-bromopyridin can be purchased from Aldrich (or other) or received. Oxidation 1.1 EQ. MSRWA in dichloromethane (20 ml, 10.6 mmol bromide) in the presence of anhydrous MgSO4(0.4 g per ml of dichloromethane with stirring in the temperature range from 0°C to ambient temperature for about 14 hours to give N-oxide, after you follow these steps and purification using flash chromatography on silica gel using 5% gradient mixture of EtOAc/Hexane, with an increase in EtOAc. N-Oxide (1.6 g) dissolved in 10 ml of 98% sulfuric acid and cooled to a temperature of 0°C. Add 10 ml of 69% nitric acid, and then give the possibility is ü the mixture to warm to ambient temperature with stirring. The reaction mixture was then heated and stirred at a temperature of 80°C for 14 hours and then poured on ice, extracted with dichloromethane, washed with water and concentrated to obtain a solid yellow color, which was purified using flash chromatography on silica gel using a mixture of 1:1 EtOAc/hexane and then a gradient to get kristallicheskoe solid yellow color.1H NMR (CDCl3) δ 8.50 (s, 1H), 7.59 (s, 1H), 4.12 (3H, s). LC-MS shows the desired M+N. N-oxide restore by dissolving the raw product in dichloromethane (M substrate) and cooled to a temperature of 0°C. Slowly add a solution of 1.2 EQ. PCl3(M) in dichloromethane, to maintain the reaction temperature 0°C. it is Then heated to ambient temperature and stirred for 72 hours. Water treatment and concentration gives a solid yellow color, which can be applied at a later stage or purified by chromatography. Note: this sequence can be applied with 2-methoxy-5-chloro-pyridine as the original product.

Intermediate compound 2A

Typical methods of obtaining azaindole from nitropyridine: Obtain 7-chloro-6-azaindole, intermediate 2A, represents the stage As in figure 1. 2 the PRS-3-nitropyridine (5.0 g, 31.5 mmol) dissolved in dry THF (200 ml). After that, the solution is cooled to a temperature of -78°and added dropwise vinylmania bromide (1.0M in THF, 100 ml). The reaction temperature equal support the following -78°within an hour, and then equal to -20°for a further 12 hours before quenching by the addition of 20% aqueous solution of NH4Cl (150 ml). The aqueous phase is extracted with EtOAc (3×150 ml). The combined organic layer is dried over MgSO4, filtered and the filtrate concentrated in vacuo to obtain a residue, which was purified by chromatographic column on silica gel (mixture of EtOAc / Hexane, 1/10)to obtain 1.5 g (31%) of 7-chloro-6-azaindole, the intermediate 2A.1H NMR (500 MHz, CD3OD) δ 7.84 (d, 1H, J=10.7 Hz), 7.55 (DD, 1H, J=10.9, 5.45 Hz), 6.62 (d, 1H, J=5.54 Hz), 4.89 (s, 1H). MS m/e: (M+H)+calculated for: C7H6ClN2: 153.02; Found: 152.93. HPLC retention: 0.43 minutes (column A).

Intermediate compound 2b

Intermediate compound 2b, 7-(4-methoxyphenyl)-4-azaindole, produced using the identical way, as an Intermediate compound 2A, starting from 3-nitro-4-(4-methoxyphenyl)pyridine, the intermediate 1. MS m/e: (M+N)+calculated for: C14H13N2O: 225.10; Found: 225.02. HPLC retention: 1.39 minutes (column B).

Intermediate compound 2C

Intermediate compound 2C, 4-bromo-7-chloro-6-azaindole, produced using the identical way, as an Intermediate compound 2A, starting from 2-chloro-3-nitro-5-bromopyridine (available from Aldrich, Co.). MS m/e: (M+N)+calculated for: C7H5BrClN2: 230.93; Found: 231.15. HPLC retention: 1.62 min (column C).

Intermediate compound 2d

Intermediate compound 2d, 4-fluoro-substituted-7-chloro-6-azaindole (see above)are in accordance with the following scheme:

A) fuming HNO3H2SO4,

B) POCl3/DMF, 110°C,

C) vinylmania bromide, THF, -78° ˜ -20°C.

It should be noted that 2-chloro-5-fluoro-3-nitropyridine, zz3', can be obtained using the method of example 5B, the reference Marfat, A. and Robinson, R.P.; "Azaoxindol Derivates US. 5,811,432, 1998. Obtaining below is some details that increase the outputs in accordance with this direction.

At the stage And the connection zz1' (1.2 g, 0.01 mol) is dissolved in sulfuric acid (2.7 ml) at room temperature. Pre-mixed fuming nitric acid (1 ml) and sulfuric acid is added dropwise at a temperature of 5-10°to a solution of compound zz1'. Then the reaction mixture is heated at a temperature of 85°C for one hour, then cooled to room tempera is URS and poured onto ice (20 g). The sediment of the yellow substance is collected by filtration, washed with water and dried in air to obtain 1.01 g of compound zz2'.

On stage In connection zz2' (500 mg, 3.16 mmol) was dissolved in phosphorus oxychloride (1.7 ml, 18.9 mmol) and dimethoxyethane at room temperature. The reaction mixture is heated to a temperature of 110°C for 5 hours. The excess phosphorus oxychloride is then removed by concentrating the reaction mixture under vacuum. Sediment chromatographic on silica gel, elute with chloroform (100%)to obtain 176 mg of the product zz3'.

On stage With the connection zz3' (140 mg, 0.79 mmol) dissolved in THF (5 ml) and cooled to a temperature of -78°C in nitrogen atmosphere. To this solution was added dropwise a solution of vinylmania bromide (1.2 mmol, 1.0 M in diethyl ether, 1.2 ml). Then the reaction mixture was left at -20°C for 15 hours. Then the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. Sediment chromatographic on silica gel, to obtain 130 mg of the intermediate 2i.1H NMR (500 MHz, CD3OD) δ 7.78 (s, 1H), 7.60 (d, 1H, J=3.0 Hz), 6.71 (d, 1H, J=3.05 Hz). MS m/e: (M+N)+calculated for: C7H5ClFN2: 171.10; Neid is but: 171.00. HPLC saving time: 1.22 minutes (column A).

Intermediate compound 2d, 4-fluoro-7-chloro-6-azaindole receive according to the method similar to the method for producing intermediate compounds 2A, starting from 2-chloro-3-nitro-5-herperidin, which is produced in accordance with methods specified above. Experimental details for this process to obtain, see Wang et. al. PCT WO 01/62255.1H NMR (500 MHz, CD3OD) δ 7.78 (s, 1H), 7.60 (d, 1H, J=3.0 Hz), 6.71 (d, 1H, J=3.05 Hz). MS m/e: (M+H)+calculated for: C7H5ClFN2: 171.10; Found: 171.00. HPLC saving time: 1.22 minutes (column A).

Intermediate compound 2E

Intermediate compound 2E get by using any of the methods a or b, below.

Method a: a Mixture of 4-bromo-7-chloro-6-azaindole (1 g), Cul (0.65 g) and NaOMe (4 ml, 25% in methanol) in the Meon (16 ml) is heated at a temperature of 110-120°C for 16 hours in a sealed tube. After cooling to room temperature the reaction mixture was neutralized with 1N HCl to pH 7. The aqueous solution is extracted with EtOAc (3×30 ml)then the combined organic layer is dried over MgSO4, filtered and the filtrate concentrated in vacuo to obtain a residue, which was purified using chromatography on silica gel to obtain 0.3 g of 4-methoxy-7-chloro-6-azaindole, intermediate compounds 2E. MS m/e: (M+N)+ 8H8ClN2O: 183.03; Found: 183.09. HPLC retention: 1.02 minutes (column B).

Method: a Mixture of 4-bromo-7-chloro-6-azaindole (6 g), CuBr (3.7 g) and NaOMe (30 ml, 5% in the Meon) is heated at a temperature of 110°C for 24 hours in a sealed tube. After cooling to room temperature the reaction mixture was added to saturated aqueous solution of NH4Cl. The resulting aqueous solution extracted with EtOAc (3×30 ml). The combined organic layer is dried over MgSO4, filtered and the filtrate concentrated in vacuo to obtain a residue, which was purified using chromatography on silica gel to obtain 1.8 g of 4-methoxy-7-chloro-6-azaindole, the intermediate 2A.

Intermediate compound 2f

Intermediate compound 2f, 7-bromo-6-azaindole receive according to the method similar to the method for producing the intermediate compound 2A from 2-bromo-3-nitropyridine (available from Aldrich, Co.). MS m/e: (M+N)+calculated for: C7H6BrN2: 197.97; Found: 197.01. HPLC retention: 0.50 minutes (column A).

The intermediate connection 2g

The intermediate connection 2g, 7-chloro-4-azaindole receive according to the method similar to the method for producing intermediate compounds 2A, on the basis of 4-chloro-3-nitro-pyridine (HCl salt, available from Austin Chemical Company, Inc.). MS m/e: M+H) +calculated for: C7H6ClN2: 153.02; Found: 152.90. HPLC retention: 0.45 minutes (column A).

Intermediate compound 2h

Intermediate compound 2h, 5-chloro-7-methyl-4-azaindole receive according to the method similar to the method for producing the intermediate compound 2A from 2-chloro-4-methyl-5-nitropyridine (available from Aldrich, Co.). MS m/e: (M+N)+calculated for: C8H8ClN2: 167.04; Found: 166.99. HPLC saving time: 1.22 minutes (column B).

Example 2i

Intermediate compound 2j, 4-fluoro-7-bromo-6-azaindole receive according to the method similar to the method for producing intermediate compounds 2E, using POBr3in stage instead of POCl3. MS m/e: (M+N)+calculated for: C7H5BrFN2: 214.96; Found: 214.97. HPLC retention: 1.28 minutes (column G).

Intermediate compound 2j

To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42 mmol) in 1,4-dioxane (100 ml) was added pyrazole (5.8 g, 85 mmol). The resulting mixture is stirred at a temperature of 120°for 26.5 hours and then evaporated after cooling to room temperature. The crude product is purified using flash chromatography (0 to 5% mixture of EtOAc/Hexane)to obtain the desired product 5-bromo-3-nitro-2-pyrazole-1-yl-pyridine.1 H NMR: (CD3OD) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.73 (s, 1H), 6.57 (s, 1H); LC/MS: (ES+) m/e; (M+H)+= 269, 271, HPLC Rf=1.223.

A round bottom flask of 250 ml fill in 5-bromo-3-nitro-2-pyrazole-1-yl-pyridine (1.02 g, 3.8 mmol) and THF (30 ml). The mixture is then cooled to a temperature of -78°and add a solution vinylmania bromide in THF (23 ml, 18.4 mmol, 0.8 M). After three minutes the reaction mixture is heated to a temperature of -45°and left to mix for one hour. The reaction mixture was then quenched with ammonium chloride and the mixture extracted with EtOAc. The combined extracts are evaporated in vacuo and the residue purified using flash chromatography column (5% mixture EtAOc/Hexane)to obtain compound 2 (using HPLC contains about 50% by-product, presumably 3-vinylamine connection 1);1H NMR: (CDCl3) δ 10.75 (b s,1H), 8.73 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 6.67 (s, 1H), 6.53 (s, 1H); LC/MS: (ES+) m/e (M+N)+= 262, 264; HPLC Rf= 1.670.

Intermediate compound 2k

To a solution of 2-bromo-5-chloro-3-nitropyridine 5 (20 g, 84 mmol, obtained in stage 2 of 2-amino-5-chloropyridine, as described in WO 9622990) in THF (300 ml) at a temperature of -78°add a solution vinylmania bromide in THF (280 ml, 252 mmol, 0.9 M). The resulting mixture is stirred at a temperature of -78°within an hour, and then spend scholar is of an aqueous solution of ammonium chloride (500 ml, saturated) and extracted with EtOAc (5×500 ml). The combined organic extracts washed with an aqueous solution of ammonium chloride (2×500 ml, saturated) and water (3×500 ml), dried (MgSO4) and evaporated to obtain a brown residue. The crude product is pulverized into powder with CH2Cl2and the formed solid was filtered to obtain compound 6 in a solid yellow color (8.0 g, 41%);1H NMR: (DMSO-d6) 12.30 (broadened s, 1H), 7.99 (s, 1H), 7.80 (d, J=3.0, 1H), 6.71 (d, J=3.0, 1H); LC/MS: (ES+) m/e (M+N)+= 231, 233, 235; HPLC Rf= 1.833.

The intermediate connection 2m

4-Fluoro-7-bromo-6-azaindole (500 mg, 1.74 mmol) dissolved in THF (5 ml) and cooled to a temperature of -78°and then added dropwise n-BuLi (2.5 M, 2.1 ml). The reaction mixture is stirred at a temperature of -78°C for 15 min, and then stirred at a temperature of 0°C for 30 minutes the Reaction mixture is again cooled to a temperature of -78°and add DMF (0.7 ml, 8.7 mmol). After stirring for 30 minutes, water is added to quench the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer is dried over MgSO4filter, concentrate and chromatographic to obtain 208 mg of the intermediate connection 2m. LC/MS: (ES+) m/e (M+N)+= 164.98. Rf=0.44 min

Split timing the e connection 2n

A mixture of intermediate compound 2 (50 mg, 0.30 mmol), potassium carbonate (42 mg, 0.30 mmol) and dosimeter of isocyanide (60 mg, 0.30 mmol) in Meon (3 ml) is heated to boiling point for about 2 hours. The solvent is removed in vacuum and the residue is treated with ice water and extracted with ether. The organic layer was washed with aqueous HCl solution (2%), water and dried over magnesium sulfate. After filtration and evaporation of the solvent the residue purified on silica gel to obtain the titled compound (60 mg). LC/MS: (ES+) m/e (M+N)+= 204. Rf= 0.77 min

The intermediate connection 2O

4-Fluoro-7-bromo-6-azaindole (510 mg, 2.39 mmol) in anhydrous DMF (5 ml) is treated with copper cyanide (430 mg, 4.8 mmol) at a temperature of 150°in a sealed tube for one hour. Then add an aqueous solution of NH4OH (10 ml) and the reaction mass is extracted with diethyl ether (2×50 ml) and ethyl acetate (2×50 ml). The combined organic phases are dried over sodium sulfate, filtered, concentrated in vacuo and chromatographic on silica gel (gradient elution of a mixture of AcOEt/Hexane 0-30%)to obtain the titled compound as a brownish solid (255 mg, 66%) LC/MS: (ES+) m/e (M+N)+= 162.

The intermediate connection 2P

Intermediate compound 2 (82 mg, 0.51 mmol) dissolved in absolute ethanol (200%, 5 ml) and treated with hydroxylamine hydrochloride (53 mg, 0.76 mmol) and triethylamine (140 μl, 1.0 mmol) and the reaction mixture is heated to a temperature of 80°in a sealed tube for 2 hours. The solvent is removed in vacuum and the solid residue pale yellow washed with water to obtain the titled compound. LC/MS: (ES+) m/e (M+N)+= 195. This connection is used in the next stage without further purification.

The intermediate connection 2q

The intermediate connection 2P dissolved in triethylorthoformate (1 ml) and heated at a temperature of 85°in a sealed tube for one hour and then cooled to room temperature, the solvent is removed in vacuum and the residue chromatographic on silica gel (AcOEt/Hexane, gradient elution 10-60%)to obtain the titled compound (54 mg, LC/MS: (ES+) m/e (M+N)+= 205).

The intermediate connection 2r

The intermediate connection 2q (100 mg, 0.62 mmol, crude product) in ethanol (5 ml) is treated with an aqueous solution of sodium hydroxide (50%, 2 ml) and the reaction mixture is heated to a temperature of 110°C overnight in a sealed tube. The pH value was adjusted to 2 with HCl (6N) and the precipitated brown svetocheloveka. The solution is concentrated to dryness to obtain the titled compound in the form of a solid pale yellow color LC/MS: (ES+) m/e (M+N)+= 181. This compound is used without further purification.

The intermediate connection 2s

The intermediate connection 2r (0.62 mmol) dissolved in DMF (1 ml) and treated with 3-aminopyridine (58.3 mg, 0.62 mmol), DEBT (185 mg, 0.62) and the base Janiga (216 μl, 1.26 mmol), and then the reaction mixture was stirred at room temperature for 18 hours. Then water is added and the reaction mass is extracted with AcOEt (2×25 ml) and CHCl3(2×25 ml), dried over sodium sulfate, concentrated and chromatographic on silica gel (AcOEt/Hexane gradient elution 0-50%)to obtain the titled compound in the form of a solid brown color LC/MS: (ES*) rn/z (M+H)+= 257.

The intermediate connection 2s

Intermediate compound 2h, 4-methoxy-7-bromo-5-azaindole receive according to the method similar to the method for producing intermediate compounds 2A, on the basis of 2-methoxy-5-bromo-4-nitropyridine (intermediate compound 1a).1H NMR (CDCl3) δ 8.52 (s, 1H), 7.84 (s, 1H), 7.12 (t, 1H), 6.68 (d, 1H), 3.99 (s, 3H). LC-MS shows the desired M+N.

The intermediate connection 2t

The mixture is intermediate the first aldehyde 2m (150 mg, 0.91 mmol), sodium cyanide (44 mg, 0.091 mmol) and dosimeter of isocyanide (177 mg, 0.91 mmol) in EtOH (3 ml) was stirred at room temperature for 30 minutes and then filtered and the crystals washed with a mixture of ether-hexane (1:1) and dried. The obtained crystals and a saturated solution of ammonia in dry methanol (8 ml) is heated to between 100-110°C for 16 hours. The mixture of concentrate and chromatographic to obtain 20 mg of intermediate 2. LC/MS: (ES+) m/e (M+N)+= 203. Rf= 0.64 min

Intermediate compound 3A

A typical method for acylation of azaindole: Obtain methyl (7-chloro-6-azaindole-3-yl)-oxoacetate, intermediate compounds 3A, which is an example of a stage In scheme 1. 7-Chloro-6-azaindole, intermediate compound 2A (0.5 g, 3.3 mmol) are added to suspensive AlCl3(2.2 g, 16.3 mmol) in CH2Cl2(100 ml). Stirring is continued at room temperature for 10 minutes before adding dropwise methyl chlorocatechol (2.0 g, 16.3 mmol). The reaction mass is stirred for 8 hours. The reaction is quenched with ice-cold aqueous solution of NH4OAc (10%, 200 ml). The aqueous phase is extracted with CH2Cl2(3×100 ml). The combined organic layer is dried over MgSO4, filtered and the filtrate concentrated in vacuo to obtain a residue, which which is transferred to the next stage without further purification. Intermediate compound 2, methyl (7-chloro-6-azaindole-3-yl)-oxoacetate: MS m/e: (M+N)+calculated for: C10H8ClN2O3: 239.02; Found: 238.97. HPLC retention: 1.07 minutes (column A).

Intermediate compound 3b

Intermediate compound 3b, methyl (6-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of 6-azaindole. MS m/e: (M+N)+calculated for: C10H9N2O3: 205.06; Found: 205.14. HPLC retention: 0.49 minutes (column A).

Intermediate compound 3C

Intermediate compound 3C, methyl (7-(4-methoxyphenyl)-4-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of 7-(4-methoxyphenyl)-4-azaindole (intermediate compound 2b). MS m/e: (M+N)+calculated for: C17H15N2C4311.10; Found: 311.04. HPLC retention: 1.15 minutes (column A).

Intermediate compound 3d

Intermediate compound 3d, methyl (7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of intermediate compounds 2E, 4-methoxy-7-chloro-6-azaindole. MS m/e: (M+H)+you is isleno to: 12H12ClN2O4: 283.05; Found: 283.22. HPLC retention: 1.37 minutes (column B).

Intermediate compound 3E

Intermediate compound 3E, methyl (7-chloro-4-fluoro-6-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of the intermediate 2d, 4-fluoro-substituted-7-chloro-6-azaindole.1H NMR (500 MHz, CD3OD) δ 8.63 (s, 1H), 8.00 (s, 1H), 3.95 (s, 3H). MS m/e: (M+H)+calculated for: C10H7ClFN2About3: 257.01; Found: 257.00. HPLC saving time: 1.26 minutes (column A).

Intermediate compound 3f

Intermediate compound 3f, methyl (7-chloro-4-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of intermediate compounds 2g, 7-chloro-4-azaindole. MS m/e: (M+N)+calculated for: C10H8ClN2O3: 239.02; Found: 238.97. HPLC retention: 0.60 minutes (column A).

The intermediate connection 3g

The intermediate connection 3g, methyl (5-chloro-7-methyl-4-azaindole-3-yl)-oxoacetate receive according to the method similar to the method for producing intermediate compounds 3A, on the basis of the intermediate 2h, 5-chloro-7-methyl-4-azaindole. MS m/e: (M+N)+you is isleno to: 11H10ClN2About3: 253.04; Found: 252.97. HPLC retention: 1.48 minutes (column B).

Intermediate compound 4A

A typical method of ester hydrolysis: Obtaining (7-chloro-6-azaindole-3-yl)-oxoacetate potassium, intermediate compounds 4A, which represents the sample stage With scheme 1. The crude product methyl (7-chloro-6-azaindole-3-yl)-oxoacetate, intermediate compound 3A, and excessive amounts of K2CO3(2 g) dissolved in Meon (20 ml) and N2O (20 ml). After 8 hours the solution is concentrated and the residue purified by chromatographic column on silica gel to obtain 200 mg of (7-chloro-6-azaindole-3-yl)-oxoacetate potassium. MS m/e: (M+N)+see the corresponding acid. Calculated for C9H6ClN2O3: 225.01; Found: 225.05. HPLC retention: 0.83 minutes (column A).

Intermediate compound 4b

(6-Azaindole-3-yl)oxoacetate potassium intermediate compound 4b, get the technique similar to the technique of intermediate compounds 4A, from methyl (6-azaindole-3-yl)oxoacetate, the intermediate 3b. MS m/e: (M+N)+see the appropriate acid. Calculated for C9H7N2O3: 191.05; Found: 190.99. HPLC retention: 0.12 minutes (column A).

The intermediate compounds is of 4C

Intermediate compound 4C, (7-(4-methoxyphenyl)-4-azaindole-3-yl)-oxoacetate potassium receive according to the method similar to the method for producing intermediate compounds 4A, from methyl (7-(4-methoxyphenyl)-4-azaindole-3-yl)-oxoacetate, the intermediate 3C. MS m/e: (M-K+H)+calculated for: C16H13N2O4: 297.07; Found: 297.04. HPLC retention: 1.00 min (column A).

Intermediate compound 4d

Intermediate compound 4d (7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacetate potassium receive according to the method similar to the method for producing intermediate compounds 4A, from methyl (7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacetate, the intermediate 3d. MS m/e: (M+N)+the corresponding acid of compound 4d (M-K+N)+calculated for: C10H8ClN2O4: 255.02; Found: 255.07. HPLC retention: 0.74 minutes (column A).

Intermediate compound 4E

Intermediate compound 4E, (7-chloro-4-azaindole-3-yl)-oxoacetate potassium receive according to the method similar to the method for producing intermediate compounds 4A, from methyl (7-chloro-4-azaindole-3-yl)-oxoacetate, intermediate compound 3f. MS m/e: (M+H)+the corresponding acid of compound 4E (M-K+H)+calculated for: H6ClN2O3: 225.01; Found: 225.27. HPLC retention: 0.33 minutes (column A).

Intermediate compound 4f

Intermediate compound 4f, (5-chloro-7-methyl-4-azaindole-3-yl)-oxoacetate potassium receive according to the method similar to the method for producing intermediate compounds 4A, on the basis of methyl (5-chloro-7-methyl-4-azaindole-3-yl)-oxoacetate, intermediate 3g connection. MS m/e: (M+N)+the corresponding acid of compound 4f (M-K+H)+calculated for: C10H8ClN2About3: 239.02; Found: 238.94. HPLC retention: 1.24 minutes (column B).

Intermediate compound 4g

Intermediate compound 4g (7-bromo-6-azaindole-3-yl)-oxoacetate potassium receive according to the method similar to the method for producing intermediate compounds 4A, from methyl (7-bromo-6-azaindole-3-yl)-oxoacetate (obtained in accordance with the method for intermediate compounds 3A of 7-bromo-6-azaindole, the intermediate 2f).1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.16 (d, 1H, J=5.3 Hz), 8.08 (d, 1H, J=5.45 Hz);13With NMR (125 MHz, DMSO-d6) δ 180.5, 164.0, 141.6, 140.4, 132.4, 125.3, 115.5, 113.0.

Intermediate compound 4h

Intermediate compound 4h, (7-bromo-4-fluoro-6-azaindole-3-yl)-oxoacetate potassium receive according to the method, a similar method is ke obtain the intermediate compounds 4A, from methyl (7-poslednee-4-fluoro-substituted-6-azaindole-3-yl)-oxoacetate (obtained in accordance with the method for intermediate compounds 3A 7-poslednego-4-fluoro-6-azaindole, the intermediate 2i). MS m/e: (M+N)+the corresponding acid of compound 4g (M-K+H)+calculated for: C9H5BrFN2O3: 286.95; Found: 286.94. HPLC retention: 0.94 minutes (column A).

Intermediate compound 4I

1-Ethyl-3-methylimidazolium chloride (0.172 g, 1.1 mmol) is added to aluminum chloride (0.560 g, 4.2 mmol) and the mixture vigorously stirred. After the formation of the liquid add the intermediate connection 2j, then add utilisateur (0.12 ml, 1.1 mmol). The mixture should be allowed the opportunity to mix at room temperature for 16 hours, after which additional add chlorocatechol (0.12 ml, 1.1 mmol). Then the reaction mass additionally give you the opportunity to mix at room temperature for another 24 hours. The flask is cooled to a temperature of 0°and then water is added, whereupon a precipitate. The obtained solid is filtered, washed with water and methanol, and then dried in high vacuum to obtain compound 3; LC/MS: (ES+) m/e (M+N) = 334, 336; HPLC Rf= 1.390.

Intermediate compound 4j

1-ethyl-3-methylimidazolium chloride (2.54 g, 17.3 mmol) is added aluminum chloride (6.91 g, 51.8 mmol). The mixture is vigorously stirred at ambient temperature for 10 minutes. To the obtained liquid yellow add intermediate compound 2k (2.0 g, 8.64 mmol) and utilisateur (2.0 ml, 17.3 mmol)and then stirred at ambient temperature for 16 hours. Then to the reaction mixture is added ice water (300 ml)to obtain a precipitate, which is filtered and washed with water to obtain the titled compound in the form of a solid yellow (1.98 g). The aqueous solution is extracted with EtOAc (3×300 ml) and the extracts evaporated in vacuo to obtain a second batch of compound 8 in the form of a solid yellow (439 mg, total yield 92%);1H NMR: (DMSO-d6) 14.25 (broadened s, 1H), 13.37 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H); LC/MS: (ES+) m/e (M+H)+303, 305, 307; HPLC Rf=1.360.

The intermediate connection 4k

1-Ethyl-3-methylimidazolium chloride (82 mg, 0.56 mmol) is added to the flask, which contains the intermediate connection 2n (56 mg, 0.28 mmol) and the mixture is cooled to a temperature of 0°C. Then added aluminium chloride (336 mg, 2.52 mmol) in one portion, and then ClCOCOOEt (58 μl, 0.56 mmol) and the reaction mixture was stirred at room temperature for 2 days. Add ice water, the button to quench the reaction. The reaction mixture is filtered. The solid is washed with water and diethyl ether and dried in air to obtain the titled compound (58 mg). LC/MS: (ES+) m/e (M+N)+= 276. Rf=0.8 minutes

The intermediate connection 4m

1-Ethyl-3-methylimidazolium chloride (73 mg, 0.52 mmol) and aluminium chloride (198 mg, 1.56 mmol) are stirred together under nitrogen atmosphere for one hour. To this solution was added intermediate connection 2q (54 mg, 0.26 mmol) and ETHYLACETYLENE (58 μl, 0.52 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction is quenched with water and the mixture is stirred for 15 minutes, the Solid is collected by filtration and washed with water and diethyl ether. LC/MS (ES+) m/e (M+N)+= 276. This compound is used without further purification.

Intermediate compound 4n

1-Ethyl-3-methylimidazolium chloride (26 mg, 0.18 mmol) is added to the flask, which contains the intermediate connection 2t (18 mg, 0.09 mmol) and the mixture is cooled to a temperature of 0°C. Then added aluminium chloride (92 mg, 0.54 mmol) in one portion, and then ClCOCOOEt (20 μl, 0.18 mmol) and the reaction mixture was stirred at room temperature for 2 days. Add ice water to quench the reaction. The reaction mixture is filtered. Solid the second substance is washed with water and diethyl ether and dried in air, to obtain compound D (18 mg). LC/MS: (ES+) m/e (m+H)+= 275. Rf=0.49 min

Intermediate compound 5A

A typical method of condensing a derivative of piperazine and azaindole acid: Obtain 1-benzoyl-3-(R)-methyl-4-[(7-chloro-6-azaindole-3-yl)-oxoacyl]piperazine intermediate compound 5, which is an example of stage D scheme 1. 7-Chloro-6-azaindole 3-glyoxylate, being potassium intermediate compound 4A (100 mg, 0.44 mmol), 3-(R)-methyl-1-benzoylpiperazine (107 mg, 0.44 mol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he (DEPBT) (101 mg, 0.44 mol) and base Janiga (diisopropylethylamine, 0.5 ml) are combined in 5 ml of DMF. The mixture is stirred at room temperature for 8 hours. DMF is removed by evaporation under reduced pressure and the residue purified using automated preparative HPLC system Shimadzu, to obtain 1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindole-3-yl)-oxoacyl]-piperazine (70 mg, 39%). MS m/e: (M+N)+Calculated for C21H20ClN4O3: 411.12; Found: 411.06. HPLC retention: 1.32 minutes (column A).

Intermediate compound 5b

Intermediate compound 5b, 1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, ex the Dublin core (7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacetate potassium, intermediate compounds 4d, and 1-benzoylpiperazine. MS m/e: (M+N)+Calculated for C21H20ClN4O4: 427.12; Found: 427.12. HPLC retention: 1.28 minutes (column A).

Intermediate compound 5C

Intermediate compound 5C, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-chloro-4-methoxy-6-azaindole-3-yl)-oxoacetate potassium, intermediate compounds 4d, and 1-benzoylpiperazine.1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.72 (s, 1H), 7.40 (s, 5H), 3.89 (s, 3H), 3.71-3.40 (m, 8H). MS m/e: (M+N)+Calculated for C22H22ClN4O4: 441.13; Found: 441.17. HPLC retention: 1.33 minutes (column A).

Intermediate compound 5d

Intermediate compound 5d, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-chloro-4-azaindole-3-yl)-oxoacetate potassium, intermediate compounds 4E, and 1-benzoyl-3-(R)-methylpiperazine. MS m/e: (M+N)+Calculated for C21H20ClN4O3411.12; Found: 411.04. HPLC retention: 1.10 minutes (column A).

Intermediate compound 5e

Intermediate compound 5e, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (5-chloro-7-methyl-4-azaindole-3-yl)-oxoacetate potassium, intermediate compounds 4f and 1-benzoyl-3-(R)-methylpiperazine. MS m/e: (M+H)+Calculated for C22H22ClN4O3425.24; Found: 425.04. HPLC retention: 1.72 minutes (column B).

Intermediate compound 5f

Intermediate compound 5f, 1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, based on the potassium salt of (7-bromo-6-azaindole-3-yl)-octoxynol acid, intermediate compounds 4g, and 1-benzoyl-3-(R)-methylpiperazine. MS m/e: (M+N)+Calculated for C21H20BrN4O3: 455.07; Found: 455.14. HPLC retention: 1.45 minutes (column B).

Intermediate compound 5g

Intermediate compound 5g, 1-benzoyl-4-[(7-bromo-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, based on the potassium salt of (7-poslednee-6-azaindole-3-yl)-octoxynol acid, intermediate compounds 4g, and 1-benzoylpiperazine. MS is/e: (M+N) +Calculated for C20H18BrN4O3: 441.06; Found: 441.07. HPLC retention: 1.43 minutes (column B).

The intermediate connection 5h

Intermediate compound 5h, 1-benzoyl-3-(R)-methyl-4-[(6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (6-azaindole-3-yl)oxoacetate potassium, intermediate compounds 4b, and 1-benzoyl-3-(R)-methylpiperazin. MS m/e: (M+N)+Calculated for C21H21N4O3: 377.16; Found: 377.10. HPLC retention: 0.88 minutes (column A).

The intermediate connection 5i

Added to a solution of aluminum trichloride in dichloromethane intermediate compound 2d was stirred at ambient temperature and then 30 minutes later mix with chlorochilon or chlorethoxyfos (in accordance with the method described for intermediate compounds 3A), receiving or methyl or ethyl ester, respectively. Hydrolysis with KOH (as in the standard method of hydrolysis described for intermediate compounds 4A) gives (7-chloro-4-fluoro-6-azaindole-3-yl)oxoacetate potassium. Then (7-chloro-4-fluoro-substituted-6-azaindole-3-yl)oxoacetate potassium reacts with 1-benzoylpiperazine in the presence of DEPBT in standard conditions (as described for itocnode compounds 5A), to obtain 1-benzoyl-4-[(4-fluoro-7-chloro-6-azaindole-3-yl)-oxoacyl) piperazine, the intermediate connection 5i.1H NMR (500 MHz, CD3OD) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.46 (broadened s, 5H), 3.80-3.50 (m, 8H); LC/MS (ES+) m/e (M+N)+415 observed value; time saving 1.247 minutes; LC/MS method: YMC ODS-A C18 S7 3.0×50 mm column; Start %B=0, End %B=100, Gradient time = 2 min; flow Rate = 5 ml/min; detector wavelength = 220 nm.

The intermediate connection 5i

1-Benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindole-3-yl)-oxoacyl]-piperazine are obtained by reaction of a combination of (7-chloro-4-fluoro-6-azaindole-3-yl)oxoacetate potassium, obtained as described above for intermediate compounds 5i, 1-benzoyl-3-(R)-methylpiperazine, in the presence of DEPBT in standard conditions (as described for intermediate compounds 5A), to obtain 1-benzoyl-3-(R)-methyl-4-[(4-fluoro-substituted-7-chloro-6-azaindole-3-yl)-oxoacyl]piperazine intermediate compound 5j.1H NMR (500 MHz, CD3OD) δ 8.42, 8.37 (s, 1H), 8.03 (s, 1H), 7.71-7.45 (m, 5H), 4.72-3.05 (m, 7H), 1.45-1.28 (m, 3H); LC/MS (ES+) m/e (M+H)+429 observed value; time saving 1.297 minutes; LC/MS method: YMC ODS-A C18 S7 3.0×50 mm column; Start %B=0, End %B=100, Gradient time = 2 min; flow Rate = 5 ml/min; detector wavelength = 220 nm.

Intermediate compound 5k

Intermediate compound 5k, 1-benzoyl-4-[(7-chloro-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, based on the potassium salt of (7-chloro-6-azaindole-3-yl)-octoxynol acid, intermediate compounds 4A and 1-benzoylpiperazine. MS m/e: (M+N)+Calculated for C20H18ClN4About3: 397.11; Found: 396.97. HPLC retention: 2.37 minutes (column F, gradient time = 3 min, flow rate = 4 ml/min).

The intermediate connection 5l

The intermediate connection 5l, 1-pikolinos-4-[(4-methoxy-7-chloro-6-azaindole-3-yl)-oxoacyl]piperazine get by the method similar to the method for producing intermediate compounds 5A, on the basis of (4-methoxy-7-chloro-6-azaindole-3-yl)oxoacetate potassium, intermediate compounds 4d and picolylamine.1H NMR (500 MHz, DMSO-d6) δ 8.63-7.45 (m, 7 H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/e: (M+N)+Calculated for C20H19ClN5O4: 428.11; Found: 428.11. HPLC retention: 1.09 minutes (column A).

The intermediate connection 5m

The intermediate connection 5m, (R)-1-pikolinos-3-methyl-4-[(7-bromo-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-bromo-6-asand the l-3-yl)oxoacetate potassium, intermediate compounds 4g, and (R)-3-methyl-1-picolylamine. MS m/e: (M+N)+Calculated for C20H19BrN5O3: 456.07; Found: 456.11. HPLC retention: 1.12 minutes (column A).

The intermediate connection 5n

The intermediate connection 5n, (S)-1-pikolinos-3 - methyl-4-[(7-bromo-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-poslednee-6-azaindole-3-yl)oxoacetate potassium, intermediate, 4g connectivity, and (S)-3-methyl-1-pikolinos-piperazine.1HNMR (500 MHz, CDCl3) δ 8.63-7.36 (m, 7H), 5.02-3.06 (m, 7H), 1.42-1.26 (m, 3H).

The intermediate compound 5 °

Intermediate compound 5o, (R)-1-pikolinos-3-methyl-4-[(7-bromo-4-fluoro-6-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-bromo-4-fluoro-6-azaindole-3-yl)oxoacetate potassium, intermediate compounds 4h, and (R)-3-methyl-1 picolylamine.1H NMR (500 MHz, CD3OD) δ 8.68-7.52 (m, 6N), 4.94-2.69 (m, 7H), 1.48-1.24 (m, 3H). MS m/e: (M+H)+Calculated for C20H18BrFN5O3: 474.06; Found: 474.23. HPLC retention: 1.20 minutes (column A).

The intermediate connection 5P

The intermediate link is 5P, 1-benzoyl-4-[(7-chloro-4-azaindole-3-yl)-oxoacyl]piperazine, get the technique similar to the technique of intermediate compounds 5A, on the basis of (7-chloro-4-fluoro-4-azaindole-3-yl)oxoacetate potassium, intermediate compounds 4E, and 1-benzoylpiperazine.1H NMR (500 MHz, CD3OD) δ 8.83 (s, 1H), 8.63 (d, 1H, J=5.35 Hz), 7.91 (d, 1H, J=5.75 Hz), 7.47 (m, 5H), 3.80-3.30 (m, 3H). MS m/e: (M+N)+Calculated for C20H18ClN4O3: 397.11; Found: 397.02. HPLC retention: 1.20 minutes (column A).

Intermediate compound 5q

Intermediate compound 5q, 1-(4-benzylpiperazine-1-yl)-2-(7-bromo-4-chloro-1H-pyrrolo[2,3-C]pyridine-3-yl)-ethane-1,2-dione.

To a solution of the acid intermediate compound 4j (2.4 g, 7.9 mmol) in DMF (40 ml) is added 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he (DEPBT, 5.96 g, 19.9 mmol), hydrochloride benzoylpiperazine (2.71 g, 11.9 mmol) and N,N-diisopropylethylamine (14 ml, 80.4 mmol). The mixture was stirred at ambient temperature for 16 hours. Then to the reaction mixture are added water (400 ml) and extracted with EtOAc (4×300 ml). The combined extracts evaporated in vacuo to obtain a residue of a brownish color, which is crushed into a powder with Meon, to obtain the titled compound in the form of a solid white color (2.8 g, 74%);1H NMR: (DMSO-d6) 13.41 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.45 (ush is provided with, 5H), 3.80-3.35 (extended m, 8H); LC/MS: (ES+) m/e (M+N)+= 475, 477, 479; HPLC Rf=1.953.

The intermediate compound 5 was produced using the techniques used for 5q using mono N-Boc - piperazine.1H NMR: (CDCl3) δ 8.26 (s, 1H), 8.19 (s, 1H), 3.71 (broadened s, 2H), 3.53 (extended m, 6N), 1.48 (s, N); LC/MS: (ES+) m/e (M+N)+=471, 473, 475; HPLC Rf=1.543.

The intermediate compound 6

A typical method of obtaining N-Oxide: Obtain 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindole-3-yl)-oxoacyl]piperazine intermediate compound 6. 20 mg of 1-benzoyl-3-(R)-methyl-4-[(6-azaindole-3-yl)-oxoacyl]piperazine intermediate compound 5h, (0.053 mmol) was dissolved in CH2Cl2(2 ml). Then to the solution was added 18 mg of mCPBA (0.11 mmol) and the reaction mass is stirred for 12 hours at room temperature. Remove the CH2Cl2by evaporation under reduced pressure and the residue purified using automated preparative HPLC system Shimadzu, to obtain the compound shown above (5.4 mg, 26%). MS m/e: (M+N)+Calculated for C21H21N4O4: 393.16; Found: 393.11. HPLC retention: 0.90 minutes (column A).

Intermediate compound 7

Getting 1-benzoyl-3-(R)-methyl-4-[(6-methyl-7-azaindole-3-yl)-oxoacyl]-piperazine or 1-be who zoilus-3-(R)-methyl-4-[(4-methyl-7-azaindole-3-yl)-oxoacyl]-piperazine. Excessive amounts of MeMgI (3M in THF, 0.21 ml, 0.63 mmol) are added to a solution of 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindole-3-yl)-oxoacyl]piperazine intermediate compound 6, (25 mg, 0.064 mmol). The reaction mixture was stirred at room temperature, and then quenched with Meon. The solvents are removed in vacuo, the residue diluted with Meon and purified using automated preparative HPLC system Shimadzu, to obtain the compound shown above, which is one of the isomers, but his regieme finally determined, (6.7 mg, 27%). MS m/e: (M+H)+Calculated for C22H23N4O3: 391.18; Found: 391.17. HPLC saving time: 1.35 minutes (column B).

Intermediate compound 8

1-Benzoyl-3-(R)-methyl-4-[(6-phenyl-7-azaindole-3-yl)-oxoacyl]piperazine or 1-benzoyl-3-(R)-methyl-4-[(4-phenyl-7-azaindole-3-yl)-oxoacyl]piperazine (regieme has not been finally determined) obtained using the method described for Example 7, from 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindole-3-yl)-oxoacyl]piperazine intermediate compounds 6 and fenermine bromide (phenyl Grignard reagent). MS m/e: (M+N)+Calculated for C27H25N4About3: 453.19; Found: 454.20. HPLC retention: 1.46 minutes (column B).

Intermediate compound 9

+Calculated for C21H21N4O3391.18 found 391.15. HPLC retention: 1.15 minutes (column A).

Intermediate compounds 10 and 11

Obtaining an intermediate compound 10, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine and intermediate compounds 11, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine: a Mixture of 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindole-3-yl)-oxoacyl]piperazine (1.78 g) and SeO2(4.7 g) in dioxane/water (100: 1) is heated to the boiling temperature under reflux for 10 hours. After cooling to room temperature the mixture was concentrated in vacuo to obtain a residue. The residue purified via chromatography on silica gel with EtOAc and the Meon as an eluting solvent to obtain an intermediate compound 10 (350 mg) and intermediate with the unity 11 (410 mg).

Intermediate compound 10, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine: MS m/e: (M+H)+Calculated for C22H20ClN4O4: 439.12 found: 439.01. HPLC retention: 1.37 minutes (column A).

Intermediate compound 11, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine: MS m/e: (M+N)+Calculated for C22H20ClN4O5: 455.11 found: 455.10. HPLC saving time: 1.44 minutes (column A).

Intermediate compounds 12 and 13

Intermediate compound 12, 1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine and an intermediate connection 13, 1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine prepared according to a similar method of obtaining intermediates 10 and 11, using the intermediate compound 9 as the original product. Intermediate compound 12, 1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine: MS m/z: (M+N)+Calculated for C22H21N4O4: 405.16 found: 405.14. HPLC retention: 0.91 minutes (column A); the Intermediate connection 13, 1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindole-3-yl)-oxoacyl]-piperazine: MS m/z: (M+N)+Calculated for C22H21N4O5: 421.15 found: 21.09. HPLC retention: 1.02 minutes (column A).

Intermediate compounds 14a-1 to 14a-21

The following agents tin and boron agents can be obtained from commercial sources and used without any further processing (table 1).

Table 1
The number of Intermediate connectionsThe structural formulaCompany
14a-1Frontier Scientific, Inc.
14a-2Maybndge Chem. Co.
14a-3Frontier Scientific, Inc.
14a-4Matrix Scientific
14a-5Matrix Scientific
14a-6Aldrich, Co.
14a-7Aldrich, Co.
14a-8Aldrich, Co.
14a-9Aldrich, Co.
14a-10 Aldrich, Co.
14a-11Lancaster
14a-12Aldrich, Co.
14a-13Aldrich, Co.
14a-14Frontier Scientific, Inc.
14a-15Matrix Scientific
14a-16Frontier Scientific, Inc.
14a-17Kiedel-de Haen ACi
14a-18Lancaster
14a-19Lancaster
14a-20Aldrich, Co.
14a-21Frontier Scientific, Inc.

Receiving Agents Tin:

The intermediate 14-1-14-65

The following well-known agents of tin and boron agents can be obtained in accordance with the described methods without any modification (table 2):

Table 2
The number of Intermediate connectionsThe structural formulaLink
14-1Dondom, A., et al Synthesis, 1987, 693
14-2Aldous, D. J., etal US-5, 453, 433
14-3Sandosham, J., et al Tetrahedron 1994, 50, 275.
14-4Lehn, L. M., et al. Chem. Eur.J.2000, 6, 4133.
14-5Jutzi, F., et al, J. Organometallic Chem. 1983, 246, 163.
14-6Jutzi, P., et al, J. Organometallic Chem. 1983, 246, 163.
14-7Graybill, I. L., et al Bioorg. Med. Chem. Lett. 1995, 5 (4), 387.
14-8Heldmann, U. K., et al Tetrahedron Lett. 1997, 38,5791.
14-9Kennedy, j., et al Tetrahedron Lett. 1996, 37, 7611.
14-10Kondo, Y., et al Tetrahedron Lett. 1989, 30, 4249
14-11Kondo, Y., et al Tetrahedron Lett. 1989, 30, 249
14-12Ur, Y. b., et al US-6, 054, 435
14-13Ur, Y. S., et al US-6, 054, 435
14-14Okada, T., et al WO-0123383
14-15Okada, T., et al WO-0123383
14-15Sandosham, J., et al Tetrahedron 1989, 50, 275
14-17Sandosham, J., et al Acta Chem. Scand. 1989, 43, 684.
14-18Nicolaou, K. C., et al WO-9967252
14-19Nicolaou, K. C., et al WO-9967252
14-20Nicolaou, K. J., et al WO-9967252
14-21Benheda, K..