Quinazoline derivatives inhibiting egfr activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

 

Cross-reference to related applications

This application claims priority based on U.S. patent No. 12/164610, filed June 30, 2008, Its content is incorporated into this description by reference in its entirety.

Background of invention

Binding epidermal growth factor (EGF) receptor, epidermal growth factor (EGFR) activates the tyrosine kinase activity and thereby triggers reactions that lead to cell proliferation. Overexpression and hyperactivity of EGFR can lead to uncontrolled cell division - a predisposition to cancer. See, for example, Science, 2004, 304:1497-1500.

Accordingly, compounds that will ingibiruet the overexpression and hyperactivity of EGFR, are potential candidates for cancer treatment.

Summary of the invention

This invention is based on the discovery of the fact that a number khinazolinov compounds inhibits the activity of EGFR.

In one aspect this invention relates to a compound of the following formula:

where each of R1, R2and R5independently, represents H, halogen, nitro, amino, cyano, hydroxy, alkyl, alkenyl, quinil, aryl, cycloalkyl, heteroseksualci, heteroaryl, alkoxy, alkylthio, alkylsulphonyl, carboxy, alkoxycarbonyl, carbon is laminitis, sulfonylamino, aminocarbonyl or aminosulfonyl; one of R3and R4represents a

where n represents 1, 2, 3, 4, or 5; each of Ra, Rband Rcindependently, represents H, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl, or RbandRctogether with the nitrogen atom to which they are attached, form a 3-12 membered saturated, unsaturated or aromatic ring containing 1-3 heteroatoms selected from N, O and S; and each of Rdand Reindependently, represents H, alkyl, alkenyl or quinil; or Rdand Retogether with the nitrogen to which they are attached, form a 3-12 membered saturated, unsaturated or aromatic ring containing 1-3 heteroatoms selected from N, O and S; and the other of R3and R4represents H, halogen, nitro, amino, cyano, hydroxy, alkyl, alkenyl, quinil, aryl, cycloalkyl, heteroseksualci, heteroaryl, alkoxy, alkylthio, alkylsulphonyl, carboxy, alkoxycarbonyl, carbylamine, sulfonylamino, aminocarbonyl or aminosulfonyl; X represents O, S, or NRfwhere Rfrepresents H, alkyl, alkenyl, quinil, aryl, cycloalkyl, heteroseksualci, heteroaryl, alkylaryl, alkoxycarbonyl, aminocarbonyl or aminosulfonyl; Y represents a phenyl, neoba is consequently substituted with halogen, nitro, cyano, alkyl, alkenyl or quinil, or optionally is condensed with another 3-8 membered ring; or Y represents alkyl substituted by phenyl, which optionally is substituted with halogen, nitro, cyano, alkyl, alkenyl or quinil, or optionally is condensed with another 3-8 membered ring; and Z represents N or C-CN.

Referring to the above formula, one group of compounds characterized by the fact that one of R3and R4represents a

,

where n is 1, and each of Ra, Rband Rcindependently, represents H, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl.

Another subgroup of compounds is characterized by the fact that one of R3and R4represents a

,

where n represents 1 or 2; Rarepresents H, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl; and Rband Rctogether with the nitrogen atom to which they are attached, form a 3-12 membered saturated, unsaturated or aromatic ring containing 1-3 heteroatoms selected from N, O and S. In some compounds, Rband Rctogether with the nitrogen atom to which they are attached, form a bicyclic ring next f is rmula:

where each of m1, m2, m3and m4independently, represents 0, 1, 2 or 3; A represents N or CR; B is NR or CRR', each R and R', independently, represents H, alkyl or halogen; and each of Ri, Rii, Riii, Riv, Rv, Rvi, Rviiand Rviii, independently, represents H, alkyl or halogen.

Another subgroup of compounds is characterized by the fact that one of R3and R4represents a

,

where Rarepresents H, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl.

Another subgroup of compounds is characterized by the fact that one of R3and R4represents a

where Rarepresents H, alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl; and each of Rdand Reindependently, represents H, alkyl, alkenyl or quinil; or Rarepresents H, alkyl, alkenyl or quinil; and Rdand Retogether with the nitrogen to which they are connected form a 3-12 membered saturated, unsaturated or aromatic ring containing 1-3 heteroatoms selected from N, O and S.

Next, another group of compounds characterized by the fact that X is the Wallpaper O NH or N-CH3; Z represents N; or Y is a

.

The term "alkyl" herein refers to linear or branched hydrocarbon containing 1-10 carbon atoms. Examples of alkyl groups include, but are not limited to specified, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. The term "alkoxy" refers to-O-alkyl.

The term "alkenyl" in this description refers to C2-10linear or branched hydrocarbon containing one or more C=C double bonds. Examples alkenyl groups include, but are not limited to specified, vinyl, 2-propenyl and 2-butenyl.

The term "quinil" in this description refers to C2-10linear or branched hydrocarbon containing one or more C≡C triple bonds. Examples etkinlik groups include, but are not limited to specified, ethinyl, 2-PROPYNYL and 2-butynyl.

The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system, where each ring can have 1-4 substituent. Examples of aryl groups include, but are not limited to specified, phenyl, naphthyl and anthracene.

The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon group having 3-12 carbons. An example is cycloalkyl groups include, but are not limited to specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N or S). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, chinoline, indolyl and thiazolyl. The term "heteroalkyl" refers to an alkyl group, substituted heteroaryl group.

The term "heteroseksualci" refers to nonaromatic 3-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N or S). Examples geterotsiklicheskikh groups include, but are not limited to specified, piperazinil, pyrrolidinyl, dioxane, morpholinyl and tetrahydropyranyl. Heteroseksualci can be sahariano ring, for example, glucosyl.

Referred to in the present description, the alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl and alkoxy include both substituted and unsubstituted fragments. Examples of substituents include, but are not limited to specified, halogen, hydroxyl, amino, cyano, nitro, measures the Aptian, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylsulphonyl, urea, carbamyl, carboxyl, touraid, thiocyanato, sulfonamide, alkyl, alkenyl, quinil, alkyloxy, aryl, heteroaryl, cycloalkyl, heteroseksualci, in which alkyl, alkenyl, quinil, alkyloxy, aryl, heteroaryl, cycloalkyl, and heteroseksualci may be optionally substituted.

The above hintline compounds include their pharmaceutically acceptable salts, MES and prolekarstva, if applicable.

Examples of compounds according to this invention is shown below:

Another aspect of this invention relates to a method of treatment of cancer. The method comprises the administration to a subject suffering from cancer, an effective amount of one or more khinazolinov compounds according to this invention. Examples of cancer that is targeted for treatment include, but are not limited to specified, lung cancer, head and neck cancer, colorectal cancer, cancer of POG lodochnoy gland, cancer of the colon, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, bone cancer and leukemia.

Also in the scope of the present invention includes (1) a composition comprising one or more of the above described khinazolinov compounds and pharmaceutically acceptable carrier, for use in the treatment of cancer and (2) applying one or more khinazolinov compounds to obtain drugs for cancer treatment. The details of one or more embodiments of the present invention are given in the following description. Other distinctive features, objectives and advantages of this invention will be clear from the description and claims.

Detailed description of the invention

Hintline compounds according to this invention can be synthesized from commercially available starting materials by methods well known in the field. For example, as shown in the diagram below, you can associate a suitable derivative of 4-chlorination with benzene compound to obtain a compound according to this invention.

,

Z represents N or C-CN

X represents O, S, NH or NCH3.

Thus obtained compound can be further modified by peripheral position is to obtain other compounds of this invention. Synthetic chemical transformations that can be used in the synthesis of the target khinazolinov compounds described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser''s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

Before use, the compounds may be purified column chromatography, high performance liquid chromatography, crystallization, and other appropriate methods. Hintline compounds according to this invention in contact with EGFR inhibit the activity of these receptors. An effective amount of one or more data connections, respectively, can be used to treat various types of cancer associated with the overexpression and EGFR activity.

The term "effective amount" refers to the number chineselanguage connection that is required in order to cause the intended effect in the subject. Effective amounts may vary, as it is clear to experts in this field, depending on the route of administration, use of excipient and the possibility of co-usage with other agents. The term "treatment" refers to the introduction of one or more of the above khinazolinov is soedinenii subject who has cancer or symptoms of cancer, or has a predisposition to cancer with the purpose to cure, heal, alleviate, reduce the severity, changes, feleciana, improvement, help, or effects on cancer, symptoms of cancer or predisposition to cancer.

For the practical implementation of this method, a composition comprising one or more khinazolinov compounds according to this invention, can be administered orally, parenterally or by inhalation spray, or via an implanted reservoir. The term "parenteral"as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, nutritionally, vnutrenniy, vnutriobolochechnoe, inside the affected organ, intracranial methods of injection or infusion.

The oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. The tablets also usually add lubricants such as magnesium stearate. For oral administration in the form of capsules used diluents include lactose and dried cook Rosny starch. When orally administered aqueous suspension and emulsion, the active ingredient may be suspended or dissolved in the oil phase in combination with emulsifying or suspendresume agents. If desired, can be added to some sweeteners, flavors or dyes.

A sterile composition for injection (for example, aqueous or oily suspension) can be obtained in accordance with methods known in this field, using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspendida agents. Sterile injectable drugs may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. To an acceptable vehicles and solvents that can be used include lures, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or suspendida environment (such as synthetic mono or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives, can be used to obtain injectable drugs, as well as natural pharmaceutically-acceptable oils, such as olive oil or Castoro the second oil especially in their polyoxyethylene options. Such oil solution and suspensions can also contain a long-chain alcohol diluent or dispersant agent, or carboxymethyl cellulose or similar dispersing agents.

Composition for inhalation can be obtained in accordance with methods well known in the field of pharmaceutical preparations, and can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, promoters suction to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in this field.

The composition for external use can be obtained in the form of oil, cream, lotion, ointment and the like. Suitable carrier materials for the composition include vegetable and mineral oils, white petrolatum (colorless soft paraffin), branched fats and oils, animal fats and high molecular weight alcohols (greater than C12). The preferred carriers are those in which soluble active ingredient. It may also include emulsifiers, stabilizers, moisturizers and antioxidants, and optionally agents, which impart color and flavor. In addition, such external preparations optionally, you can use amplifiers cresko the Noah permeability. Examples of such amplifiers permeability can be found in U.S. patent 3989816 and 4444762. Creams are preferably prepared from a mixture of mineral oil, savemarriage beeswax and water, this mixture is mixed active ingredient, dissolved in a small amount of oil, such as almond oil. An example of such a cream is a cream that includes about 40 parts of water, about 20 parts beeswax, about 40 parts of mineral oil and about 1 part almond oil. Ointments can be obtained by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm paraffin and cooling the mixture. An example of such ointment is an ointment, which includes about 30% by weight of almond oil and about 70% by weight colorless soft paraffin.

The carrier in the pharmaceutical composition must be "acceptable" in the sense that it is compatible with the active ingredients of the drug (and preferably, capable of stabilizing) and is not harmful to the subject being treated. For example, solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with one or more active hinazolinam compounds of the extract) can be used as pharmaceutical former is Ipatov for delivery of active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C yellow No. 10.

Suitable in vitro can be used for a preliminary assessment of the effectiveness of the above compounds hintline as inhibitors of EGFR activity. It may be additionally investigated the effectiveness of the compounds in the treatment of cancer in vivo analyses. For example, the compounds can be introduced to an animal (e.g., a mouse model)having cancer, and then evaluate its therapeutic effect. On the basis of these results can also be determined from the appropriate dosage and route of administration.

Without further elaboration, it is assumed that the above description makes one fit adequately the present invention. Accordingly, the following specific examples should be considered only as illustrative and not restrictive, the remaining part of the invention in any way.

Example 1:

Synthesis of 1-(3-terbisil)-3-(4-(3-ethynylphenyl)hinzelin-6-yl)-1-metalmachine (Compound 1)

The way of synthesis of compound 1 shown below:

To a solution of 5-nitroanthranilic (1,00 g, 6,13 mmol) in dioxane (25 ml) was added dimethylacetal of dimethylformamide (0.88 g, 7.36 mmol). After stirring at 100aboutWith over 2 hours of reaction the second mixture was cooled to room temperature and placed in the refrigerator. The precipitate was filtered, washed several times with cold ether and dried in vacuum, obtaining of 1.30 g (97%) of product (E)-N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine, in a solid yellow color.

A mixture of (E)-N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1,00 g, 4,58 mmol) and 3-aminophenylacetylene (0.64 g, 5,49 mmol) in HOAc (15 ml) was stirred at 100°C for 3 hours. The resulting mixture was cooled to room temperature. The precipitate was filtered off, washed with simple ether and dried in vacuum, obtaining of 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine in the form of a solid yellow color.

A mixture of N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine (1,00 g of 3.45 mmol) and SnCl2·2H2O (3,10 g of 13.8 mmol) in ethyl acetate (35 ml) was heated at the boil under reflux for 2 hours and then cooled to room temperature. After the pH of the mixture was Dowden to 9-10 using 5% aqueous NaHCO3the mixture was subjected to extraction with EtOAc. The combined organic layers were washed with saturated salt solution and H2O and dried. The solvent was removed under reduced pressure, getting 0,79 g (89%) of N4-(3-ethynylphenyl)hinzelin-4,6-diamine in the form of a solid yellow color.

To a solution of N4-(3-ethynylphenyl)hinzelin-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 ml)containing pyridine (37 μl, 0.46 mmol), was added phenylcarbamate (49 μl, 0,38 shall mol) dropwise at room temperature. After 10 minutes was added (3-terbisil)methylamine (52,9 mg, 0.38 mmol) and the reaction mixture was heated at 80°C for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were concentrated and purified on a column of silica gel, receiving compound 1 in solid yellow with 86% yield.

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), 8,89 (s, 1H), 8,55 (d, J=8 Hz, 2H), 8,04 (s, 1H), 7,79 (DD, J=2,4 Hz, 2.0 Hz, 1H), 7,79 (DD, J=2.0 Hz, 2.4 Hz, 1H), 7,74 (d, J=2.0 Hz, 1H), 7,41-7,37 (m, 3H), 7,13-7,10 (m, 3H), with 4.64 (s, 2H), 4,20 (s, 1H), 3,03 (s, 3H); Mass spectrum (m/e): 426 (M+1).

Examples 2-59: Synthesis of compounds 2-59

Connection 2-59 got a way similar to that described in example 1.

Connection 2:

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), 8,88 (s, 1H), 8,79 (s, 1H) 8,43 (d, J=8 Hz, 2H), 8,10 (s, 1H), 7,94 (t, J=2.4 Hz, 1H), 7,82 (t, J=2.0 Hz, 1H), 7,80 (d, J=2.0 Hz, 1H), 7,42~of 7.36 (m, 3H), 7,09-7,06 (m, 3H), 4,48 (s, 2H), 3,53 (s, 1H); Mass spectrum (m/e): 412 (M+1).

3 connection:

1H NMR (DMSO-d6, 400 MHz): δ 9,42 (s, 1H), 8,93 (s, 1H), 8,63 (s, 1H), 8,53 (s, 1H), 8,44 (d, J=3.2 Hz, 2H), 8,21 (s, 1H), 7,35 (t, J=2.4 Hz, 1H), 7,32~to 6.88 (m, 5H), to 6.80 (d, J=2.0 Hz, 1H), of 6.68 (d, J=2.4 Hz, 1H), 6,65 (, 1H), of 4.44 (s, 2H), Android 4.04 (s, 1H); Mass spectrum (m/e): 395 (M+1).

Compound 4:

1H NMR (DMSO-d6, 400 MHz): δ 9,68 (s, 1H), 9,14 (s, 1H), 8,51 (s, 1H), 8,51 (d, J=2.0 Hz, 1H), 8,11 (s, 1H), 7,89 (t, J=2.0 Hz,2H), 7,72 (d, J=8 Hz, 1H), 7,40 (t, J=3,6 Hz, 1H), 7,21 (d,J=4 Hz, 1H), 4,24 (s, 1H), of 3.46 (s, 4H), of 1.53 (s, 6H); Mass JV the crown-rump length (m/e): 372 (M+1).

Connection 5:

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), 8,88 (s, 1H), 8,79 (s, 1H), 8,43 (d, J=8 Hz, 2H), 8,10 (s, 1H), 7,94 (t, J=2.4 Hz, 1H), 7,82 (t, J=2.0 Hz, 1H), 7,80 (d, J=2.0 Hz, 1H), 7,42~of 7.36 (m, 3H), 7,09-7,06 (m, 3H), 4,48 (s, 2H), 3,53 (s, 1H); Mass spectrum (m/e): 412 (M+1).

Compound 6:

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), 8,87 (d, 1H), 8,79 (s, 1H) 8,43 (d, J=8 Hz, 2H), 8,10 (s, 1H), 7,94 (t, J=2.4 Hz, 1H), 7,80 (d, J=2.0 Hz, 1H), 7,42~of 7.36 (m, 3H), 7,09-7,06 (m, 3H), 4,48 (s, 2H), 3,53 (s, 1H); Mass spectrum (m/e): 430 (M+1).

Compound 7:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), to 8.57 (d, J=10,8 Hz, 1H), and 8.50 (s, 1H), 8,04 (s, 1H), of 7.96 (d, J=2 Hz, 1H), 7,89 (d, J=8 Hz, 1H), 7,69 (d, J=20 Hz, 1H), 7,35 (t, J=8.0 Hz, 1H), 4,20(s, 1H), 2.49 USD (C, 4H), to 1.86 (s, 4H); Mass spectrum (m/e): 358 (M+1).

Compound 8:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), of 9.02 (s, 1H), 8,53 (s, 1H), 8,5l (d, J=2 Hz, 1H), with 8.05 (s, 1H), 7,88 (t, J=8 Hz, 2H), 7,72 (d, J=8 Hz, 1H), 7,38 (d, J=8 Hz, 1H), 7,20 (d, J=7.2 Hz, 1H), 4,18 (s, 1H), the 3.65 (t, J=4.4 Hz, 4H), 3,51 (t, J=4.8 Hz, 4H); Mass spectrum (m/e): 374 (M+1).

Compound 9:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), 8,99 (s, 1H), charged 8.52 (s, 2H), with 8.05 (s, 1H), to 7.93 (m, 2H), 7,69 (d, J=8,8 Hz, 1H), 7,38 (t, J=8 Hz, 1H), 7,19 (d, J=8 Hz, 1H), 4,23 (s, 1H), 2,23-of 0.91 (m, 8H), of 0.91 (m, J=2,8 Hz, 6H); Mass spectrum (m/e): 400 (M+1).

The connection 10:

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), up 8.75 (s, 1H), charged 8.52 (s, 1H), 8,44 (s, 1H), of 7.90 (m, 2H), 7,71 (d, J=8,4 Hz, 2H), 7,39 (t, J=8 Hz, 1H), 7,20 (d, J=8 Hz, 1H), 4,20 (s, 1H)and 3.59 (s, 4H), 3,53 (s, 4H), 3,53 (s, 6H); Mass spectrum (m/e): 420 (M+1).

The connection 11:

1H NMR (DMSO-d6, 400 MHz): δ 8,5 (1H), of 8.06 (s, 1H), with 8.05 (s, 1H), 7.68 per-7,80 (d, J=9,2 Hz, 3H) 7,39-7,42 (t, J=8.0 Hz, 1H), 7,29-7,31 (d, J=3.2 Hz, 1H), 7,20-7,20 (d, J=0.4 Hz, 1H), 4,08-4,12 (t, J=8.0 Hz, 2H), 3,67-to 3.73 (m, 4H), 3,21-of 3.25 (m, 6H), 1,65-of 1.85 (m, 6H); Mass spectrum (m/e): 459,3 (M+1).

The connection 13:

1H NMR (DMSO-d6, 400 MHz): δ 9,81 (s, 1H), 8,63 (s, 1H), 8,54 (s, 1H), 8,49 (s, 1H), 8,51 (s, 1H), with 8.05 (s, 1H), 7,92 (m, 2H), of 7.70 (d, J=12 Hz, 1H), 7,37 (t, J=2.4 Hz, 1H), 7,19 (d, J=4 Hz, 1H), 4,17 (s, 1H), 3,71(m, 2H), 3,76 (m, 2H), and 3.16 (m, 1H), 2,70 (m, 1H), 2,18-2,07 (m, 8H), at 1.73 (m, 1H), 1,31 (m, 1H); Mass spectrum (m/e): 441 (M+1).

The connection 14:

1H NMR (DMSO-d6, 400 MHz): δ 9,76 (s, 1H), 8,97 (s, 1H), 8,51 (d, J=8,8, 2H), with 8.05 (s, 1H), 7,89 (t, J=8,8 Hz, 2H), 7,71(d, J=8,8 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,20 (d, J=8 Hz, 1H), 4,19 (s, 1H), 3,54 (s, 4H), of 2.26 (t, J=2 Hz, 2H), 0,87 (d, J=4 Hz, 1H), 0,49 (d, J=8 Hz, 2H), 0,1l (s, 2H); Mass spectrum (m/e): 427 (M+1).

The connection 15:

1H NMR (DMSO-d6, 400 MHz): δ 9,95 (s, 1H), 8,87 (s, 1H), 8,51 (s, 1H), of 8.47 (s, 1H), 8,03 (s, 1H), a 7.85 (m, 2H), 7,69 (d, J=8,8 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,19 (d, J=8 Hz, 1H), to 4.41 (s, 1H), 4,08 (s, 1H), 4,05 (s, 1H), equal to 2.94 (t, J=10,8 Hz, 2H), 2,17 (t, J=4 Hz, 1H), 1,86 (t, J=6 Hz, 2H), of 1.66 (s, 4H), of 1.33 (m, 2H); Mass spectrum (m/e): 401 (M+1).

The connection 17:

1H NMR (DMSO-d6, 400 MHz): δ 9,96 (s, 1H), 9,44 (s, 1H), and 8.50 (s, 1H), 8,45 (s, 1H), 8,00 (s, 1H), 7,88 (t, J=2,8 Hz, 1H), of 7.70 (d, J=8,8 Hz, 1H), was 7.36 (t, J=8.0 Hz, 1H), 7,19 (d, J=7,6 Hz, 1H), 6,85 (d, J=6 Hz, 1H), 4,19 (s, 1H), 3.33 and (m, 4H), up 3.22 (s, 3H); Mass spectrum (m/e): 362 (M+1).

The connection 18:

1H NMR (DMSO-d6, 400 MHz): δ 8,51 (s, 1H), of 8.47-8,46 (d, J=2.4 Hz, 1H), of 7.97 (s, 1H), 7,93-to $ 7.91 (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,83-7,81 (DD, J=1,6 Hz and 8.4 Hz, 1H), to 7.77-7,74 (d,J=8,8 Hz, 1H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,28-7,26 (DD, J=1.2 Hz, 8 Hz, 1H), 3,78-7,74 (t, J=6.4 Hz, 2H), 3,52 (s, 1H), 2,93-2,90 (m, H), 2,86-2,82 (t, J=6.0 Hz, 2H), 1,13-1,10 (m, 2H), 0,97-of 0.95 (m, 2H); Mass spectrum (m/e): 397,4 (M+1).

The connection 19:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), of 8.90 (s, 1H), 8,55-8,55 (d, J=2 Hz, 1H), 8,44 (s, 1H), 8,18-8,17 (d, J=1.2 Hz, 1H), 8,07 (s, 1H), 7,94-to $ 7.91 (DD, J=2 Hz and 9.2 Hz, 1H), 7,70-the 7.65 (m, 2H), 7,56-rate of 7.54 (d, J=8,8 Hz, 1H), 7,43-7,40 (m, 1H), 7,17-to 7.09 (m, 3H), with 4.64 (s, 2H), 3,03 (s, 3H); Mass spectrum (m/e): 417,5 (M+1).

The connection 20:

1H NMR (DMSO-d6, 400 MHz): δ 9,78 (s, 1H), 8,71 (s, 1H), 8,54 are 8.53 (d, J=1.6 Hz, 1H), charged 8.52 (s, 1H), of 8.06 (s, 1H), of 7.96-of 7.90 (m, 2H), 7,71-of 7.69 (d, J=9,2 Hz, 1H), 7,40 and 7.36 (t, J=8 Hz, 1H), 7,20-7,19 (d, J=7.2 Hz, 1H), 4,20 (s, 1H), 3.43 points-to 3.41 (m, 2H), 2,99 (s, 3H), 1,13-of 1.09 (t, J=7.2 Hz, 3H); Mass spectrum (m/e): 346,4 (M+1).

The connection 22:

1H NMR (CD3OD, 400 MHz): δ 8,49 (s, 1H), 8,40-8,39 (d, J=2.4 Hz, 1H), to 7.99 (s, 1H), 7,94 (s, 1H), 7,80-to 7.77 (d, J=8,8 Hz, 1H), 7,74-7,72 (d, J=8,8 Hz, 1H), 7,62-EUR 7.57 (m, 1H), 7,39-to 7.35 (t, J=7,6 Hz, 1H), 7,28-7,26 (d, J=7,6 Hz, 1H), 3,55 (s, 1H), 3,56-to 3.49 (m, 4H), 2,85-2,78 (m, 6H), 1,28-1,25 (t, J=6.8 Hz, 3H), 1,19-of 1.15 (t, J=6.8 Hz, 6H); Mass spectrum (m/e): 431,5 (M+1).

The connection 23:

1H NMR (CD3OD, 400 MHz): δ 8,51 (s, 1H), 8,39-8,39 (d, J=2.4 Hz, 1H), 7,98 (s, 1H), 7,83 (s, 1H), 7,81 for 7.78 (DD, J=2 Hz, 9.6 Hz, 1H), 7,75-7,73 (d, J=9.4 Hz, 1H), 7,41-7,37 (t, J=8 Hz, 1H), 7,30-7,27 (m, 1H), 3,53 (s, 1H), 3.46 in-of 3.43 (t, J=7.2 Hz, 4H), 1,68-of 1.65 (m, 4H), 1,45-of 1.40 (m, 4H), 1,03 is 0.99 (t, J=7.2 Hz, 6H); Mass spectrum (m/e): 416,5 (M+1).

Compound 24:

1H NMR (CD3OD, 400 MHz): δ of 8.50 (s, 1H), 8,40-8,39 (d, J=2.0 Hz, 1H), of 7.97 (s, 1H), 7,83-7,81 (d, J=8,4 Hz, 1H), 7,75-to 7.68 (m, 2H), 7,41-7,37 (t, J=8,4 Hz, 1H), 7,29-7,27 (m, 1H), 3,61-to 3.58 (t, J=6.0 Hz, 2H), 3,53 (s, 1H), 3,12 (s, 1H), 2,72-2,69 (t, J=6.0 Hz, 2H), 2,45 (s, 6H); Mass spectrum (m/e): to 389.5 (M+1).

Compound 25:

1 H NMR (CD3OD, 400 MHz): δ 8,51 (s, 1H), 8,40-8,39 (d, J=2 Hz, 1H), 7,98 (s, 1H), 7,83-7,80 (DD, J=2,4 Hz and 9.2 Hz, 1H), 7,75-7,73 (d, J=9,2 Hz, 1H), 7,41-7,27 (t, J=8 Hz, 1H), 7,29-7,27 (d, J=7,6 Hz, 1H), 3,53 (s, 1H), 3,53-of 3.48 (t, J=7,6 Hz, 2H), 3,39-to 3.36 (t, J=6,8 Hz, 2H), 1.77 in-1,71 (m, 2H), 1,15-to 1.14 (m, 1H), 1,02-and 0.98 (t, J=7.2 Hz, 3H), 0,62 is 0.58 (m, 2H), 0.37 to 0.34 in (m, 2H); Mass spectrum (m/e): 400,5 (M+1).

Compound 26:

1H NMR (CD3OD, 400 MHz): δ is 8.75 (s, 1H), 8,73-8,72 (d, J=2 Hz, 1H), 8,08-with 8.05 (DD, J=2,4 Hz and 9.2 Hz, 1H), 7,92-a 7.92 (d, J=1.2 Hz, 1H), 7,83 (s, 1H), 7,81 (s, 1H), 7,78 to 7.75 (m, 1H), 7,50-7,47 (m, 2H), 3,80-of 3.77 (t, J=6,4 Hz, 2H), 3,63 (s, 1H), 3,24 (s, 3H), 2,86-and 2.83 (t, J=6.4 Hz, 2H); Mass spectrum (m/e): 371,4 (M+1).

Compound 27:

1H NMR (CD3OD, 400 MHz): δ of 8.50 (s, 1H), 8,40-8,39 (d, J=2.4 Hz, 1H), 7,79 (s, 1H), 7,82-7,79 (DD, J=2.0 Hz, 8,8 Hz, 2H), 7,73-7,71 (d, J=8,8 Hz, 1H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,28-7,26 (d, J=8,4 Hz, 1H), 3,53 (s, 1H), 3,51-3,4 (kV, J=7.2 Hz, 2H), 3.46 in-of 3.42 (t, J=7,6 Hz, 2H), 1,68-of 1.64 (m, 2H), 1,45-of 1.40 (m, 2H), 1,28-1,25 (t, J=7.2 Hz, 3H), 1,02 is 0.99 (t, J=7,6 Hz, 3H); Mass spectrum (m/e): 388,5 (M+1)

Compound 28:

1H NMR (DMSO-d6, 400 MHz): δ 9,76 (s, 1H), 8,91 (s, 1H), 8,53 (s, 1H), 8,49 (s, 1H), 8,04 (s, 1H), of 7.90 (d, J=8 Hz, 1H), of 7.75 (d, J=8,8 Hz, 1H), 7,39 (t, J=8.0 Hz, 1H), 7,20 (d, J=7,6 Hz, 1H), 4,19 (s, 1H), 3,50 (s, 8H), 2,43 (s, 4H), of 2.16 (s, 6H); Mass spectrum (m/e): 444 (M+1).

Compound 29:

1H NMR (DMSO-d6, 400 MHz): δ 9,78 (s, 1H), 9,11 (s, 1H), charged 8.52 (s, 2H), 8,04 (s, 1H), to $ 7.91 (d, J=8 Hz, 2H), 7,69 (t, J=8.0 Hz, 1H), 7,37 (d, J=7,6 Hz, 1H), 7,18 (d, J=7,6 Hz, 1H), 4,19 (s, 1H), 3,65 is 3.23 (m, 12H), 3,14 (s, 3H); Mass spectrum (m/e): 431 (M+1).

Compound 30:

1H NMR (DMSO-d6, 400 MHz): δ 9,78 (s, 1H), 9.15, with (s, 1H), and 8.50 (s, 1H), to 8.41 (s, 1H), 8,03 (s, 1H), 7,88 (d, J=8 Hz, 1H), to 7.84 (d, J=8,8 Hz, 1H), of 7.70 (d, J=8,8 Hz, 1H), 7,38 (t,J=8.0 Hz, 1H), 7,20 (d, J=7,6 Hz, 1H), 6,45 (t, J=2.4 Hz, 1H), 4,19 (s, 1H), of 2.38 (t, J=6.4 Hz, 6H), of 1.52 (m, J=5,2, 4H), of 1.40 (m, 2H), 1,23 (s, 2H); Mass spectrum (m/e): 415 (M+1).

Compound 32:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), 9,01 (s, 1H), and 8.50 (s, 1H), 8,40 (s, 1H), 8,02 (s, 1H), 7,85 (t, J=8.0 Hz, 2H), 7,71 (d, J=8,8 Hz, 1H), 7,39 (t, J=8.0 Hz, 1H), 7,20 (d, J=6,8 Hz, 1H), 6,44 (t, J=2.4 Hz, 1H), 4,19 (s, 1H), 3.27 to (m, 4H), of 2.54 (m, 4H), to 1.70 (s, 4H); Mass spectrum (m/e): 401 (M+1).

Compound 33:

1H NMR (DMSO-d6, 400 MHz): δ 9,46 (s, 1H), 8,87 (s, 1H), and 8.50 (s, 1H), 8,44 (s, 1H), 8,03 (s, 1H), 7,88 (d, J=8 Hz, 2H), of 7.70 (d, J=5,2 Hz, 1H), 7,38 (t, J=8.0 Hz, 2H), 7,20 (d, J=8 Hz, 2H), 4,21 (s, 1H), 3,20 (m, 2H), 2.95 and (m, 2H); Mass spectrum (m/e): 398 (M+1).

Compound 34:

1H NMR (CDCl3, 400 MHz): δ 9,79 (s, 1H), and 8.50 (s, 1H), 8,45-at 8.36 (m, 2H), with 8.05 (s, 1H), 7,97-of 7.95 (d, J=8,4 Hz, 1H), 7,92-of 7.90 (d, J=8,4 Hz, 1H), 7.68 per-the 7.65 (d, J=8,8 Hz, 1H), 7,38-7,34 (t, J=7,6 Hz, 1H), 7,19-7,17 (d, J=and 7.6 Hz, 1H), 4,19 (s, 1H), to 3.58 of 3.56 (m, 2H), 1,74 is 1.60 (m, 4H), 1,26 is 1.23 (m, 6H), 0,91 is 0.86 (m, 6H); Mass spectrum (m/e): 416,5 (M+1).

Compound 35:

1H NMR (CDCl3, 400 MHz): δ 9,86 (s, 1H), 9,20 (s, 1H), 8,56-8,56 (d, J=2 Hz, 1H), 8,53 (s, 1H), of 8.06 (s, 1H), 7,98-of 7.95 (DD, J=2 Hz and 8.8 Hz, 1H), 7,93-to $ 7.91 (d, J=8,4 Hz, 1H), 7,73-of 7.70 (d, J=8,8 Hz, 1H), 7,39-to 7.35 (t, J=7.2 Hz, 1H), 7,20-to 7.18 (d, J=7,6, 1H), 4,20 (s, 1H), 3,79 of 3.75 (t, J=6,8 Hz, 4H), 2,85-2,82 (t, J =6,8 Hz, 4H); Mass spectrum (m/e): 410,4 (M+1).

The connection 36:

1H NMR (CDCl3, 400 MHz): δ 9,77 (s, 1H), 8,69 (s, 1H), 8,53-8,51 (m, 2H), with 8.05 (s, 1H), 7.95 is-7,89 (m, 2H), 7,69-to 7.67 (d, J=8,8, 1H), 7,39-to 7.35 (t, J=7.2 Hz, 1H), 7,19-7,17 (d, J=7.2 Hz, 1H), 4,19 (s, 1H), 2,98 (s, 3H), 1,51 of 1.50 (m, 2H), 1.26 in a 1.25 (m, 6H), is 0.84 (s, 3H); Mass spectrum (m/e): 402,5 (M+1).

Connect the tion 37:

1H NMR (CD3OD, 400 MHz): δ of 8.50 (s, 1H), 8,40-to 8.40(d, J=2.0 Hz, 1H), of 7.97 (s, 1H), 7,80-to 7.77 (m, 2H), 7,74-7,71 (d, J=9,2 Hz, 1H), 7,38 and 7.36 (t, J=238,0 Hz, 1H), 7,28-7,27 (d, J=7,6 Hz, 1H), 4,29-the 4.29 (d, J=2.4 Hz, 2H), of 3.53 (s, 1H), 3,18 (s, 3H), 2,75-by 2.73 (t, J=2.4 Hz, 1H); Mass spectrum (m/e): 356,4 (M+1).

Compound 38:

1H NMR (DMSO-d6, 400 MHz): δ 8,51 (s, 1H), 8,49 (s, 1H), 7,94 (s, 1H), to $ 7.91-7,88 (DD, J=1,6 Hz and 9.2 Hz, 1H), 7,80 for 7.78 (d, J=8,8 Hz, 1H), 7,76-7,76 (d, J=0.8 Hz, 1H), 7,46-7,44 (t, J=8,8 Hz, 1H), 7,38 and 7.36 (t, J=7,6 Hz, 1H), 7,29-7,28 (m, 1H), 7,27-7,24 (t, J=8,4 Hz, 1H), 4,60 (s, 4H), 3,51 (s, 1H); Mass spectrum (m/e): 382,4 (M+1)

Compound 39:

1H NMR (CDCl3, 400 MHz): δ 9,78 (s, 1H), 8,77 (s, 1H), 8,53-charged 8.52 (d, J=2 Hz, 1H), 8,51 (s, 1H), 8,04 (s, 1H), 7,94-7,88 (m, 2H), 7,70-to 7.68 (d, J=8,8 Hz, 1H), 7,39-7,353 (t, J=8 Hz, 1H), 7,19-7,17 (d, J=7,6 Hz, 1H), of 5.84-5,79 (m, 1H), 5,22-5,16 (m, 2H), 4,19 (s, 1H), was 4.02-4,01 (d, J=4,8 Hz, 2H), 2,97 (s, 1H); Mass spectrum (m/e): 357,4 (M+1).

The connection 40:

1H NMR (DMSO-d6, 400 MHz): δ 9,81 (s, 1H), 9,23 (s, 1H), charged 8.52 (s, 2H), 8,49 (s, 1H), 8,04 (s, 1H), of 7.90 (m, 2H), of 7.70 (d, J=8,8 Hz, 1H), 7,37 (t, J=7,6 Hz, 1H), 7,18 (d, J=7,6 Hz, 1H), 4,19 (s, 1H), a 3.87 (t, J=8 Hz, 2H)and 3.59 (s, 2H), 2.06 to (m, 2H) 1,72 (s, 2H); Mass spectrum (m/e): 408 (M+1).

Compound 41:

1H NMR (DMSO-d6, 400 MHz): δ 9,78 (s, 1H), 9,11 (s, 1H), 8,51 (s, 2H), 8,04 (s, 1H), of 7.90 (d, J=8,8 Hz, 2H), 7,69 (d, J=8,8 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,18 (d, J=8,8 Hz, 1H), 4,19 (s, 1H), 3,68(m, 4H), 2,59 (m, 6H), of 1.07 (m, 3H); Mass spectrum (m/e): 401 (M+1).

The connection 42:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), 9,13 (s, 1H), 8,51 (s, 2H), 8,04 (s, 1H), 7,92 (t, J=7,6 Hz, 2H), 7,69 (d, J=8,8 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,18 (d, J=6.0 Hz, 1H), 4,19 (s, 1H), 3,88 (s, 4H)and 3.59 (t, J=5.2 Hz, 4H), 1,64 (t, J=5,2 Hz, 4H); Mass spectrum (m/e): 430 (M+1).

Compound 43:

1H NMR (DMSO-d6, 400 MHz): δ 9,76 (s, 1H), 9,92 (s, 1H), 8,51 (s, 2H), 8,04 (s, 1H), of 7.90 (d, J=8 Hz, 2H), 7,68 (d, J=8,8 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,17 (d, J=8,8 Hz, 1H), 4,19 (s, 1H), was 2.76 (t, J=12 Hz, 1H)that is 2.41 (t, J=10,8 Hz, 6H), 1,66-of 1.42 (m, 6H), 1,22-of 1.07 (m, 8H); Mass spectrum (m/e): 428 (M+1).

Compound 44:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), of 8.90 (s, 1H), 8,51 (d, J=6,8, 2H), 8,03 (s, 1H), 7,87(t, J=8,8 Hz, 2H), 7,71 (d, J=8,8 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,18 (d, J=8 Hz, 1H), 4,18(s, 1H), to 3.67 (m, 8H), to 1.15 (d, J=2.0 Hz, 1H), 0,79 (m, 4H); Mass spectrum (m/e): 441 (M+1).

Compound 45:

1H NMR (DMSO-d6, 400 MHz): δ 9,79 (s, 1H), 9,18 (s, 1H), 8,54 (d, J=4.4 Hz, 2H), with 8.05 (s, 1H), 7,89 (m, 2H), 7,74-7,71 (d, J=8,8 Hz, 1H), 7,41-7,37 (t, J=8.0 Hz, 1H), 7,21-7,19 (d, J=7,6 Hz, 1H), 4,20 (s, 1H), 3,65 (Sirs, 4H), 3,18 (Sirs, 4H), to 2.94 (s, 3H); Mass spectrum (m/e): of 451.5 (M+1).

The connection 46:

1H NMR (CD3OD, 400 MHz): δ 8,51 (1H), of 8.06 (1H), with 8.05 (s, 1H), 7.68 per-7,80 (d, J=9,2 Hz, 3H), 7,39-7,42 (t, J=8.0 Hz, 1H), 7,29-7,31 (d, J=3.2 Hz, 1H), 7,20-7,20 (d, J=0.4 Hz, 1H), 4,08-4,12 (t, J=8.0 Hz, 2H), 3,67-to 3.73 (t, J=8.0 Hz, 2H); Mass spectrum (m/e): 348,1 (M+1).

Compound 47:

1H NMR (DMSO-d6, 400 MHz): δ 9,82 (s, 1H), 8,93 (s, 1H), charged 8.52-8,46 (m, 4H), 8,03 (s, 1H), of 7.90-7,88 (m, 2H), 7,72-of 7.70 (m, 2H), 7,37 (s, 2H), 7,19-to 7.18 (m, 1H), 4,74 (s, 2H), 4,20 (s, 1H), 3.33 and-to 3.35 (m, 2H), 1,07-of 1.05 (m, 1H), 0,42-0,41 (m, 2H), of 0.23 to 0.19 (m, 2H); Mass spectrum (m/e): 449,5 (M+1).

The connection 48:

1H NMR (CDCl3, 400 MHz): δ 9,78 (s, 1H), to 8.70 (s, 1H), 8,53-8,48 (m, 4H), 8,02-of 7.97 (m, 2H), 7,88-to 7.84 (m, 1H), 7,74-the 7.65 (m, 2H), 7,32 (s, 2H), 7,19 (s, 1H), of 4.54 (s, 2H), 4,19 (s, 1H), 2,65-of 2.58 (m, 1H), 0,96-0,89 (m, 2H,), from 0.76 to 0.75 (m, 2H); Mass spectrum (m/e): 35,5 (M+1).

Compound 49:

1H NMR (DMSO-d6, 400 MHz): δ 9,79 (s, 1H), 9,04 (s, 1H), and 8.50 (s, 1H), to 8.41 (s, 1H), 8,03 (s, 1H), of 7.90-to 7.84 (m, 2H), 7,71-of 7.69 (d, J=8,8 Hz, 1H), 7,41-7,37 (t, J=8.0 Hz, 1H), 7,21-7,19 (d, J=7,6 Hz, 1H), 6,82-to 6.80 (d, J=8.0 Hz, 1H), 4,20 (s, 1H), a 3.87-3,82 (m, 2H), 3.75 to to 3.73 (Sirs, 1H), 3.43 points-to 3.38 (t, J=9,2 Hz, 2H), 1.85 to is 1.81 (d, J=5.6 Hz, 2H), 1,44-of 1.40 (m, 2H); Mass spectrum (m/e): of 388.4 (M+1).

Compound 50:

1H NMR (DMSO-d6, 400 MHz): δ 9,79 (s, 1H), which is 9.09-9,05 (m, 1H), and 8.50 (s, 1H), to 8.41 (s, 1H), 8,03 (s, 1H), 7,89-to 7.84 (m, 2H), 7,72-of 7.70 (d, J=9,2 Hz, 1H), 7,41-7,37 (t, J=8.0 Hz, 1H), 7,21-7,19 (d, J=7.2 Hz, 1H), 6,69-of 6.65 (m, 1H), 4,20 (s, 1H), to 3.73 is 3.40 (t, J=7.2 Hz, 2H), 2,62 at 2.59 (t, J=7.2 Hz, 2H), 2,10 (s, 3H); Mass spectrum (m/e): 378,4 (M+1).

The connection 51:

1H NMR (DMSO-d6, 400 MHz): δ 9,79 (s, 1H), of 9.02 (s, 1H), and 8.50 (s, 1H), to 8.41 (s, 1H), 8,03 (s, 1H), 7,89-to 7.84 (m, 2H), 7,71-of 7.69 (d, J=8,8 Hz, 1H), 7,41-7,37 (t, J=8,8 Hz, 1H), 7,21-7,19 (d, J=7.2 Hz, 1H), 6,69 (m, 1H), 4,20 (s, 1H), 3,24-3,20 (t, J=6,8 Hz, 2H), 2,55 of $ 2.53 (t, J=7.2 Hz, 2H), 2.06 to (s, 3H), 2,55-2,53 (TT, J=6,8 Hz, 7.2 Hz, 2H); Mass spectrum (m/e): 392,5 (M+1).

The connection 52:

1H NMR (DMSO-d6, 400 MHz): δ 9,83 (s, 1H), 9,37 (s, 1H), 8,54 (d, J=8,8, 2H), 8,08 (s, 1H), to 7.93 (t, J=8,8 Hz, 2H), 7,74 (d, J=9,2 Hz, 1H), 7,39 (t, J=8.0 Hz, 1H), 7,20 (d, J=7,6 Hz, 1H), 4,23 (s, 1H), 3,55 (m, 8H); Mass spectrum (m/e): 469(M+1).

Compound 53:

1H NMR (DMSO-d6, 400 MHz): δ 9,77 (s, 1H), 9,01 (s, 1H), charged 8.52 (d, J=6,8, 2H), with 8.05 (s, 1H), 7,88 (m, 2H), 7,72 (d, J=7.2 Hz, 1H), 7,39 (t, J=8,4 Hz, 1H), 7,20 (d, J=7,6 Hz, 1H), 4,20 (s, 1H), 3,66 (d, J=6,4 Hz, 2H), of 3.54 (t, J=5.2 Hz, 4H), to 2.66 (t, J=4.8 Hz, 4H); Mass spectrum (m/e): 455(M+1).

The connection 54:

1H NMR (CD3OD, 400 MHz): δ 8,49 (s, 1H), of 8.37 (s, 1H), of 7.96 (s, 1H), 7,81-7,79 (d, J=7.2 Hz, 1H),7,74-7,73 (m, 2H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,27-of 7.25 (d, J=7.2 Hz, 1H), 3,64-3,62 (Sirs, 4H), 3,52 (s, 1H), 2,53 is 2.51 (Sirs, 4H), to 2.35 (s, 3H); Mass spectrum (m/e): 387,5 (M+1).

Compound 55:

1H NMR (CD3OD, 400 MHz): δ 8,48 (s, 1H), of 8.37 (s, 1H), of 7.96 (s, 1H), 7,81-7,79 (d, J=7.2 Hz, 1H), 7,74-7,73 (m, 2H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,27-of 7.25 (d, J=7.2 Hz, 1H), 3,64-3,61 (Sirs, 4H), 3,52 (s, 1H), 2.77-to 2,74 (m, 1H), 2,64-2,62 (Sirs, 4H), 1,12-1,10 (d, J=6.4 Hz, 3H); Mass spectrum (m/e): 415,5 (M+1).

The connection 56:

1H NMR (CD3OD, 400 MHz): δ 8,48 (s, 1H), of 8.37 (s, 1H), of 7.96 (s, 1H), 7,81-7,79 (d, J=7.2 Hz, 1H), 7,74-7,73 (m, 2H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,27-of 7.25 (d, J=7.2 Hz, 1H), 4,34-or 4.31 (d, J=13,6 Hz, 2H), 3,51 (s, 1H), 2,97-only 2.91 (t, J=12,4 Hz, 2H), 2,52-2,48 (m, 1H), 2,33 (s, 6H), 2.00 in of 1.97 (d, J=11,6 Hz, 2H), 1,49-of 1.45 (m, 2H); Mass spectrum (m/e): 415,5 (M+1).

Compound 57:

1H NMR (CD3OD, 400 MHz): δ 8,48 (s, 1H), of 8.37 (s, 1H), of 7.96 (s, 1H), 7,81-7,79 (d, J=7.2 Hz, 1H), 7,74-7,73 (m, 2H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,27-of 7.25 (d, J=7.2 Hz, 1H), 4,34-or 4.31 (d, J=13,6 Hz, 2H), 3,51 (s, 1H), 2,98-only 2.91 (t, J=13,2 Hz, 3H), by 2.73 (m, 4H), 1,96-of 1.93 (d, J=12,4 Hz, 2H), 1.56 to 1,53 (m, 2H), 1,14-1,10 (t, J=7,6 Hz, 6H); Mass spectrum (m/e): 443,5 (M+1).

The connection 58:

Mass spectrum (m/e): 443 (M+1).

Compound 59:

Mass spectrum (m/e): 45,2 (M+1).

Example 60: Synthesis of N-(4-(3-ethynylphenyl)-7-florinopolis-6-yl)piperidine-1-carboxamide (Compound 60)

The way of synthesis of compound 60 is shown below:

2-Amino-4-fermenting acid (1.55 g, 10 mmol) in formamide (5 ml) was heated at 150°C for 6 hours. The mixture was cooled to room temperature under stirring. Sediment tfilter ivali and washed with ethyl ether, obtaining 1.3 g of 7-florinopolis-4-ol (78%).

7-Florinopolis-4-ol (1 g, 6.0 mmol) was dissolved in concentrated H2SO4(3 ml) at 0°C. was Added dropwise under stirring within 15 minutes of concentrated HNO3(3 ml). The mixture was heated at 100°C for 3 hours, and poured into a mixture of ice-water with stirring after cooling to room temperature. The precipitate was filtered and recrystallized from HOAc, receiving of 0.60 g of 7-fluoro-6-nitroquinazoline-4-ol (38%).

7-Fluoro-6-nitroquinazoline-4-ol (518 mg, 2 mmol) was dissolved in chloride tionale (3 ml)containing 2 drops of DMF. The solution was heated at the boil under reflux for 3 hours and then the solvent was removed under reduced pressure. The residue, 4-chloro-7-fluoro-6-nitroquinazoline, used directly in the next stage without purification.

4-Chloro-7-fluoro-6-nitroquinazoline and 3-ethynylbenzoate (234 mg, 2 mmol) was dissolved in isopropanol (5 ml) and was heated at the boil under reflux for 3 hours. After cooling to room temperature, the precipitate was filtered and washed with water, getting a 0.59 g of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazoline-4-amine (95%).

A mixture of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazoline-4-amine (310 mg, 1 mmol) and SnCl2-2H2O (171 mg, 4.5 mmol) in ethyl acetate (35 ml) was heated at the boil under reflux for 2 hours. After cooling the Oia to room temperature, the mixture was treated with 5% aqueous solution of NaHCO3to bring its pH to 9-10. Then the mixture was extracted with EtOAc. The combined organic layers were washed with saturated salt solution and H2O and dried. The solvent was removed under reduced pressure, receiving 225 mg (81%) of N4-(3-ethynylphenyl)-7-florinopolis-4,6-diamine in the form of a solid yellow color.

N4-(3-ethynylphenyl)-7-florinopolis-4,6-diamine (100 mg, 0.36 mmol) was dissolved in DMF (3 ml)containing pyridine (35 μl, 0,432 mmol). Phenylcarbamate (46 μl, 0.36 mmol) was bury to the mixture at room temperature and was heated at 70°C for 1 hour, receiving phenyl 4-(3-ethynylphenyl)-7-florinopolis-6-ylcarbamate. The compound obtained was used directly in the next stage without purification. Then was added the amine (0.36 mmol) and stirred at 70°C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were concentrated and purified on a column of silica gel, receiving the connection 60 (105 mg, 75% yield).

1H NMR (DMSO-d6, 400 MHz): δ 10,22 (s, 1H), to 8.70 (s, 1H), 8,66 (s, 1H), 8,63 (1H), 8,02 (s, 1H), of 7.90 (d, J=8 Hz, 1H), 7.62mm (d, J=12 Hz, 1H), 7,42 (t, J=8,4 Hz, 1H), 7,25 (d, J=7,6 Hz, 1H), 4,23 (s, 1H), 3,49 (m, 4H), of 1.53 (m, 6H); Mass spectrum (m/e): 390 (M+1).

Examples 61-65: Synthesis of compounds 61-65

Connection 61-65 got way analogion the m described in example 60.

Compound 61:

1H NMR (DMSO-d6, 400 MHz): δ 9,88(s, 1H), 8,71 (s, 1H), 8,59(d, J =6,4 Hz, 2H), with 8.05(1H), of 7.90 (d, J=9,2 Hz, 1H), to 7.61 (d, J=7,6 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7,24(d, J=8,8 Hz, 1H), 4,22 (s, 1H), the 3.65 (m, 4H), to 3.49 (m, 6H); Mass spectrum (m/e): 392 (M+1).

Compound 62:

1H NMR (DMSO-d6, 400 MHz): δ 10,04 (s, 1H), 8,79 (s, 1H), 8,67 (d, J=0.4 Hz, 1H), 8,56 (s, 1H), 8,07 (s, 1H), 7,92 (d, J=8,8 Hz, 1H), 7,60 (d, J=10,8 Hz, H), 7,41 (m, 2H), 7.23 percent (d, J=7,6 Hz, 1H), 7,12 (m, 3H), to 4.62 (s, 1H), 4,23 (s, 1H), 3,01 (s, 1H); Mass spectrum (m/e): 444 (M+1).

Compound 63:

1H NMR (DMSO-d6, 400 MHz): δ 10,00 (s, 1H), 8,83 (s, 1H), 8,73 (d, J=4 Hz, 1H), 8,56 (s, 1H), 8,00 (s, 1H), 7,78 (d, J=8 Hz, 1H), to 7.61 (d, J=12 Hz, 1H), 7,40 (m, J=7,6 Hz, 1H), 7.23 percent (d, J=7.2 Hz, 1H), 4,22 (s, 1H), of 3.57 (s, 8H), 3,37 (s, 6H); Mass spectrum (m/e): 438(M+1).

Compound 64:

1H NMR (DMSO-d6, 400 MHz): δ 9,96 (s, 1H), 8,67 (s, 1H), 8,59 (s, 1H), at 8.60 (s, 1H), 8,39 (s, 1H), with 8.05 (d, J=8,4 Hz, 1H), to $ 7.91 (d, J=8,8 Hz, 1H), to 7.59 (d, J=10,8 Hz, 1H), 7,39 (d, J=7,6 Hz, 1H), 7,22 (d, J=6 Hz, 1H), 7,13 (d, J=2.0 Hz, 1H), 4,22 (s, 1H), 3,68 (m, 4H), 2,22 (s, 6H), of 1.80 (m, 2H); Mass spectrum (m/e): 419 (M+1).

Compound 65:

1H NMR (DMSO-d6, 400 MHz): δ to 9.93 (s, 1H), 8,73 (s, 1H), 8,58 (s,2H), of 8.06 (s, 1H), to $ 7.91 (d, J=8.0 Hz, 1H), 7,58 (d, J=8,8 Hz, 1H), 7,40 (t, J=6,8 Hz, 1H), 7.23 percent (d, J=8 Hz, 1H), 4,22 (s, 1H), 2,92 (t, J=5,2 Hz, 2H), of 2.51 (m, 4H), 1,99 is 1.91 (m, 4H), 1,72-of 1.42 (m, 4H), 1,23-of 1.16 (m, 4H); Mass spectrum (m/e): 459(M+1).

Example 66: Synthesis of N-(4-(3-ethynylphenyl)-7-methoxyquinazoline-6-yl)piperidine-1-carboxamide (Compound 66)

The way of synthesis of compound 62 to the following:

Sodium (92 mg, 4 mmol) Rast is oral in methanol (4 ml) under nitrogen atmosphere at 0°C. Added 7-fluoro-6-nitroquinazoline-4-ol (418 mg, 2 mmol). The mixture was heated at the boil under reflux for 3 hours and then cooled to room temperature and was treated with 2N HCl to bring its pH to 3-4. The solution was concentrated, and the residue was diluted with ethyl acetate, and washed with water twice. The organic solution was concentrated, obtaining 7-methoxy-6-nitroquinazoline-4-ol (405 mg, yield: 92%).

7-Methoxy-6-nitroquinazoline-4-ol was converted into compound 66 in a manner analogous to the one described in example 60.

1H NMR (DMSO-d6, 400 MHz): δ 9,81 (s, 1H), 8,59 (s, 1H), 8,53 (s, 1H), 8,02 (s, 1H), 7,98 (s, 1H), 7,89 (d, J=8,8 Hz, 1H), 7,38 (t, J=8 Hz, 1H), 7,25 (s, 1H), 7,19 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 3,98 (s, 3H), 3,53-3,5l (m, 4H), 1.60-to of 1.53 (s, 6H); Mass spectrum (m/e): 402 (M+1).

Examples 67-84: Synthesis of compounds 67-84

Connection 67-84 got a way similar to that described in example 66.

Compound 67:

1H NMR (DMSO-d6, 400 MHz): δ RS 9.69 (s, 1H), 8,58 (s, 1H), 8,54 (s, 1H), 8,10 (s, 1H), 8,04 (s, 1H), of 7.90 (d, J=8,8 Hz, 1H), 7,38 (t, J=8 Hz, 1H), 7,26 (s, 1H), 7,19 (d, J=7.2 Hz, 1H), 4,19 (s, 1H), 3,99 (s, 3H), 3,64 (t, J=4.8 Hz, 4H), 3,49 (s, J=4,8 Hz, 4H); Mass spectrum (m/e): 404 (M+1).

Compound 68:

1H NMR (DMSO-d6, 400 MHz): δ 9,71 (s, 1H), to 8.57 (s, 1H), charged 8.52 (s, 1H), 8,07 (s, 1H), 8,04 (s, 1H), to $ 7.91 (d, J=8,8 Hz, 1H), 7,37 (t, J=6,4 Hz, 1H), 7,24 (s, 1H), 7,18 (d, J=5,2 Hz, 1H), 4,19(s, 1H), 3,98 (s, 3H), 3,50 (m, 4H), 2,48 (m, 6H), was 1.04 (s, 3H); Mass spectrum (m/e): 431 (M+1).

Compound 69:

1H NMR (DMSO-d6, 400 MHz): δ 9,65 (s, 1H), 8,73 (s, 1H), 857 (s, 1H), 8,49 (s, 1H), 8,00 (s, 1H), 7,87 (d, J=7,6 Hz, 1H), 7,37 (t, J=8 Hz, 1H), 7,24 (s, 1H), 7,17 (d, J=7,6 Hz, 1H), 4,19 (s, 1H), 4,01 (s, 3H), of 3.56 (s, 8H), to 3.36 (s, 6H); Mass spectrum (m/e): 450 (M+1).

Compound 70:

1H NMR (DMSO-d6, 400 MHz): δ 9,73 (s, 1H), 8,66 (s, 1H), 8,53 (s, 1H), 8,49 (s, 1H), 8,03 (s, 1H), 7,98 (s, 1H), 7,89 (d, J=7.2 Hz, 1H), 7,46 and 7.36 (m, 3H), 7,25-7,13 (m, 6H), 4,63 (s, 2H), 4,19 (s, 1H), 3,98 (s, 3H), 3.04 from (s, 3H); Mass spectrum (m/e): 456 (M+1).

Compound 71:

1H NMR (DMSO-d6, 400 MHz): δ to 9.66 (s, 1H), 8,88 (s, 1H), 8,48(s, 1H), to 8.41 (s, 1H), 7,98 (s, 1H), a 7.85 (d, J=8.0 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,12 (s, 1H), 7,15 (d, J=7.2 Hz, 1H), 4,18 (s, 1H), a 4.03 (s, 3H), 3,43-3,30 (m, 7H); Mass spectrum (m/e): 392 (M+1).

Compound 72:

1H NMR (DMSO-d6, 400 MHz): δ 9,76 (s, 1H), to 8.62 (s, 1H), 8,5l (s, 1H), at 8.36 (s, 1H), 8,00 (s, 1H), 7,87 (d, J=7,6 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,26 (s, 1H), 7,18 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 4,01 (s, 3H), of 3.54 (DD, J=4.0 Hz, 4.0 Hz, 4H), 3.46 in (s, 3H), and 3.16 (s, 3H); Mass spectrum (m/e): 406 (M+1).

Compound 73:

1H NMR (DMSO-d6, 400 MHz): δ 9,68 (s, 1H), to 8.57 (s, 1H), and 8.50 (s, 1H), 8,04 (s, 1H), 8,00 (s, 1H), 7,89 (d, J=7,6 Hz, 1H), 7,35 (t, J=8.0 Hz, 1H), 7,24 (s, 1H), 7,17 (d, J=7,6 Hz, 1H), 4,20 (s, 1H), 3,98 (s, 3H), 3,42-3,40 (m, 2H), 2,99 (s, 3H), 2,80-to 2.74 (m, 6H), of 1.09 (m, 6H); Mass spectrum (m/e): 447 (M+1).

Compound 74:

1H NMR (DMSO-d6, 400 MHz): δ RS 9.69 (s, 1H), 8,56 (s, 1H), 8,53 (s, 1H), with 8.05 (s, 1H), 8,04 (s, 1H), of 7.90 (d, J=7,6 Hz, 1H), 7,38 (t, J=8 Hz, 1H), 7,26 (s, 1H), 7,19 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 3,99 (s, 3H), to 3.58 (m, 4H), of 2.36 (m, 4H), of 2.23 (s, 3H); Mass spectrum (m/e): 417 (M+1).

Compound 76:

1H NMR (DMSO-d6, 400 MHz): δ to 9.70 (s, 1H), to 8.57 (s, 1H), 8,53 (s, 1H), 8,04 (s, 2H), of 7.90 (d, J=8.0 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), of 7.25 (s, 1H), 7,19 (d, J=8.0 Hz, 1H), 4,21 (s, 1H), 3,99 (s, 3H), 3,50 (m, 4H), 2.49 USD (m, 4H), 2,24 (m, 2H), 0,85-0,11 (m, 5H); Mass spectrum (m/e): 457 (M+1).

Compound 77:

1H NMR (DMSO-d6, 400 MHz): δ RS 9.69 (s, 1H), 8,56 (s, 1H), 8,53 (s, 1H), 8,04 (s, 2H), of 7.90 (d,J=8.0 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,25 (s, 1H), 7,19 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 4,11 (m, 2H), a 4.03 (s, 3H), 2,95 (m, 2H), by 2.73 (m, 4H), of 2.21 (m, 1H), of 1.88 (m, 2H), 1,71 (m, 4H), of 1.41 (m, 2H); Mass spectrum (m/e): 458 (M+1).

Compound 79:

1H NMR (DMSO-d6, 400 MHz): δ RS 9.69 (s, 1H), 8,56 (s, 1H), 8,53 (s, 1H), 8,04 (s, 2H), of 7.90 (d, J=7,6 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,25 (s, 1H), 7,19 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 4,14 (m, 2H), 3,99 (s, 3H), 2,86 (m, 2H), measuring 2.20 (s, 6H), of 1.78 (m, 2H), 1,35 (m, 2H), 1,24 (m, 1H); Mass spectrum (m/e): 445 (M+1).

Compound 80:

1H NMR (DMSO-d6, 400 MHz): δ to 9.66 (s, 1H), 8,61 (s, 1H), charged 8.52 (s, 2H), 8,04 (s, 1H), to $ 7.91 (d, J=7.2 Hz, 1H), 7,38 (t, J =8.0 Hz, 1H), 7,22 (s, 1H), 7,21 (d, J=7.2 Hz, 1H), 4.26 deaths (m, 2H), 4,18 (s, 1H), 3,50 (m, 4H), of 2.51 (m, 2H), 2,41 (m, 4H), for 1.49 (m, 3H), 1.04 million (m, 3H); Mass spectrum (m/e): 445 (M+1).

Compound 81:

1H NMR (DMSO-d6, 400 MHz): δ 8,53 (s, 1H), 8.34 per-8,31 (m, 3H), 7,83 (DD, J=2.0 Hz, J=1.6 Hz, 1H), 7,60 (d, J=9,2 Hz, 1H), 7,47 (s, 1H), 7,7,45 (s, 1H), 7,31 (t, J=7,6 Hz, 2H), 7,21 (t, J=7.2 Hz, 1H), 5,61-to 5.58 (m,1H), 3,79-of 3.77 (m, 1H), 3,66-to 3.64 (m, 1H), 3,39-3,37 (m, 2H), 3,18-3,17 (m, 2H), 2.40 a (s, 6H), 2,25-of 2.24 (m, 1H), 1,58 (d, J=7,6 Hz, 3H); Mass spectrum (m/e): 405 (M+1).

Compound 82:

1H NMR (DMSO-d6, 400 MHz): δ charged 8.52 (s, 1H), 8,28 (s, 2H), 7,63 (s, 1H), of 7.48 (d, J=7,6 Hz, 2H), 7.24 to 7,14 (m, 4H), 5,80 is 5.77 (m, 1H), 3,99 (s, 3H), 3,78-to 3.89 (m, 4H), 3,29-up 3.22 (m, 2H), 2,33 (s, 6H), 2,25-of 2.24 (m, 1H), and 1.56 (d, J=7.2 Hz, 3H); Mass spectrum (m/e): 453 (M+1).

Compound 83:

1H NMR (DMSO-d , 400 MHz): δ total of 8.74 (s, 1H), 8,48 (s, 1H), 8,29 (s, 1H), 7,56 (s, 1H), 7.23 percent-to 7.15 (m, 6H), of 3.96 (s, 3H), 3.72 points is 3.57 (m, 3H), 3,32 be 3.29 (m, 2H), 2,82-2,78 (m, 2H), of 2.23 (s, 6H), of 1.34 (s, 4H); Mass spectrum (m/e): 447 (M+1).

Compound 84:

1H NMR (DMSO-d6, 400 MHz): δ 9,54 (s, 1H), 8,61 (s, 1H), 8,44 (s, 1H), 7,69 (s, 2H), of 7.48 (d, J=8.0 Hz, 2H), 7.23 percent-7,19 (m, 3H), 3,99 (s, 3H), 3,80-3,66 (m, 2H), 3.45 points is 3.40 (m, 2H), 3,18-of 3.06 (m, 3H), 2,90-and 2.83 (m, 6H), 2,08-a 2.01 (m, 3H), 1,24-of 1.18 (m, 3H); Mass spectrum (m/e): 447 (M+1).

Example 85: Synthesis of 1-(2-(dimethylamino)ethyl)-3-(4-(3-ethynylphenyl)hinzelin-7-yl)-1-metalmachine (Compound 85)

The way of synthesis of compound 85 is shown below:

To a solution of 2-amino-4-nitrobenzoic acid (6,00 g, 32,94 mmol) in ethanol (40 ml) was added formamidine (6,80 g, 65,32 mmol). The reaction mixture was heated at the boil under reflux for 5 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The precipitate was filtered, washed with several portions of cold ethanol and then dried in vacuum, obtaining the ceiling of 5.60 g (89%) of 7-nitroquinazoline-4-ol in the form of a solid yellow color.

A mixture of 7-nitroquinazoline-4-ol (3.4 g, 17,79 mmol), chloride taanila (20 ml) and DMF (0.5 ml) was heated at the boil under reflux for 48 hours. After cooling the mixture the excess chloride tiomila was removed by evaporation and the residue was subjected to the azeotropic distillation with toluene, getting 2,61 g (70%) 4-chloro-7-nitro is natalina in a solid yellow color.

A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9,54 mmol), isopropanol (30 ml) and 3-ethynylbenzene (1.2 g, 10,00 mmol) was heated at the boil under reflux for 5 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The solid was filtered, washed several times with cold isopropanol and dried in vacuum, obtaining 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazoline-4-amine in the form of a solid yellow color.

A mixture of N-(3-ethynylphenyl)-7-nitroquinazoline-4-amine (2.0 g, 6,89 mmol), SnCl2(5.0 g, 26,37 mmol) and ethyl acetate (50 ml) was heated at the boil under reflux for 3 hours, and then was extracted twice with ethyl acetate (20 ml). The combined organic layers washed twice with saturated salt solution (20 ml), dried over Na2SO4and concentrated in vacuum, obtaining 1.6 g (86%) of N4-(3-ethynylphenyl)hinzelin-4,7-diamine in the form of a solid yellow color.

A mixture of N4-(3-ethynylphenyl)hinzelin-4,7-diamine (48 mg, 0.18 mmol), phenylcarbonylamino of 25.2 μl), pyridine (32 μl) and DMF (2 ml) was stirred at room temperature for 1.5 hours. Was added N,N,N-trimethylated-1,2-diamine (20 mg, 0,19 mmol). The mixture was stirred at 80aboutC for 3 hours. Then the resulting solution was poured into water and was extracted 3 times with ethyl acetate (20 ml). The combined organic layers dailypaul saturated salt solution (10 ml), dried over Na2SO4and concentrated in vacuum, obtaining 55 mg (78%) of compound 85 in a solid yellow color.

1H NMR (DMSO-d6, 400 MHz): δ 9,92 (s, 1H), to 9.66 (s, 1H), 8,69-8,58 (d, J=8,8 Hz, 1H), charged 8.52 (s, 1H), 8,15 (s, 1H), 8,00-7,98 (DD, J=0.8 Hz, 8,8 Hz, 1H), 7,92-to $ 7.91 (d, J=1.6 Hz, 1H), 7,72-of 7.70 (d, J=9,2 Hz, 1H), 7,39-to 7.35 (t, J=7,6 Hz, 1H), 7,19-7,17 (d, J=7,6 Hz, 1H), 4,20 (s, 1H), 3,48 is-3.45 (m, 2H), 3.00 and (s, 3H), 2,53-2,48 (m, 2H), 2,28 (s, 6H); Mass spectrum (m/e): to 389.5 (M+1).

Examples 86-90: Synthesis of compounds 86-90

Connection 86-90 got a way similar to that described in example 85.

Compound 86:

1H NMR (DMSO-d6, 400 MHz): δ 9,85 (s,1H), 8,56-8,54 (d, J=9,2, 1H), charged 8.52 (s, 1H), 8,13 (s, 1H), 7,98-of 7.96 (d, J=8,8 Hz, 1H), to 7.84 (s, 1H), 7,69-7,66 (d, J=9.6 Hz, 1H), 7,40 and 7.36 (t, J=7,6 Hz, 1H), 7,20-to 7.18 (d, J=7.5 Hz, 1H), 4,20 (s, 1H), 2,99 (s, 3H), 2,87-to 2.85 (m, 2H), 2,66-of 2.56 (m, 6H), 1,03 is 0.99 (t, J=7.2 Hz, 6H); Mass spectrum (m/e): 417,5 (M+1).

Compound 87:

1H NMR (DMSO-d6, 400 MHz): δ 9,90 (s, 1H), 8,97 (s, 1H), 8,59-8,457 (d, J=9,2 Hz, 1H), 8,53 (s, 1H), 8,15 (s, 1H), 8,02-8,02 (d,J=1.6 Hz, 1H), 8,00-7,98 (d, J=7,6 Hz, 1H), 7,85-7,83 (DD, J=1,6 Hz and 8.8 Hz, 1H), 7,39-to 7.35 (t, J=8.0 Hz, 1H), 7,20-to 7.18 (d,J=7,6 Hz, 1H), 5,88-5,79 (m, 1H), to 5.21-5,16 (m, 2H), 4,20 (s, 1H), 4,03-was 4.02 (d,J=5,2 Hz, 2H), 3.15 in (s, 3H); Mass spectrum (m/e): 358,4 (M+1).

Compound 88:

1H NMR (DMSO-d6, 400 MHz): δ 10,13 (s, 1H), 9,86 (s, 1H), 8,56-8,54 (d, J=9,2 Hz, 1H), charged 8.52 (s, 1H), 8,12 (s, 1H), of 7.97 (s, 1H), 7,95 (s, 1H), 7,58-7,56 (d, J=9,2 Hz, 1H), 7,49-7,46 (t, J=6,4 Hz, 1H), 7,39-7,33 (m, 5H), 7,27-of 7.23 (m, 1H), 7,20-to 7.18 (d, J=12 Hz, 1H), 4,36-4,34 (d, J=6.0 Hz, 2H), 4,21 (s, 1H); Mass spectrum (m/e): 394,4 (M+1).

Compound 89:

1H NMR (who MCO-d 6, 400 MHz): δ to 9.91 (s, 1H), 8,59-to 8.57 (d, J=9,2 Hz, 1H), 8,53 (s, 1H), 8,14 (s, 1H), 8,02 shed 8.01 (d, J=2.0 Hz, 1H), 7,99-7,98 (d, J=7,6 Hz, 1H), 7,85-of 7.82 (DD, J=1,6 Hz and 8.8 Hz, 1H), 7,39-to 7.35 (t, J=8 Hz, 1H), 7,20-to 7.18 (d, J=8 Hz, 1H), 4,21 (s, 1H), 3,64-3,62 (m, 4H), 3,54-to 3.52 (m, 4H); Mass spectrum (m/e): 374,4 (M+1).

Compound 90:

1H NMR (DMSO-d6, 400 MHz): δ 9,73 (s, 1H), 8,79 (s, 1H), 8,54 (s, 1H), 8,46-8,44 (d, J=9.6 Hz, 1H), 8,11 (s, 1H), of 7.96 (s, 1H), 7.95 is-to 7.93 (d, J=8 Hz, 1H), 7,80-to 7.77 (t, J=1.2 Hz, 9,2), 7,41-7,37 (t,J=15.2 Hz, 1H), 7,21-7,19 (d, J=8 Hz, 1H), 4,21 (s, 1H), 3,55-3,51 (m, 2H), 3,30 (s, 1H), 3.04 from (s, 1H); Mass spectrum (m/e): 376,4 (M+1).

Example 91: Synthesis of N-(4-(3-ethynylphenyl)hinzelin-6-yl)-2-(4-methylpiperazin-1-yl)ndimethylacetamide (Compound 91)

The way of synthesis of compound 91 is shown below:

To a solution of 5-nitroanthranilic (1,00 g, 6,13 mmol) in dioxane (25 ml) was added dimethylacetal of dimethylformamide (0.88 g, 7.36 mmol). The reaction mixture was stirred at 100°C for 2 hours and then cooled to room temperature and placed in the refrigerator. The precipitate was filtered, washed several times with cold simple ether and then dried in vacuum, obtaining of 1.30 g (97%) of (E)-N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in a solid yellow color.

(E)-N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamide (1,00 g, 4,58 mmol) and 3-aminophenylacetylene (0.64 g, 5,49 mmol) was dissolved in HOAc (15 ml). After stirring at 100°C for 3 hours, the mixture was cooled to room temperature. About the ADOC was filtered, washed a simple ether and dried in vacuum, obtaining of 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine in the form of a solid yellow color.

A mixture of N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine (1,00 g of 3.45 mmol) and SnCl2·2H2O (3,10 g of 13.8 mmol) in ethyl acetate (35 ml) was heated at the boil under reflux for 2 hours and then cooled to room temperature. the pH was brought to 9-10 using processing 5% aqueous solution of NaHCO3. The mixture was extracted with EtOAc. The combined organic layers were washed with saturated salt solution and H2O and dried. The solvent was removed under reduced pressure, getting 0,79 g (89%) of N4-(3-ethynylphenyl)hinzelin-4,6-diamine in the form of a solid yellow color.

To a solution of N4-(3-ethynylphenyl)hinzelin-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 ml)containing N,N-diisopropylethylamine (124 μl, from 0.76 mmol) was added chlorocatechol (32 μl, 0.38 mmol) at room temperature. After 10 minutes, was added 1-methylpiperazine (209 μl, 1,90 mmol) and the reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated and the residue was purified using the PT-LC (preparative liquid chromatography)to give compound 91 in the form of a solid yellow color with a 94% yield.

1H NMR (CD3OD, 400 MHz): δ 8,65 (s, 1H), 8,54 (s, 1H), 7,99-of 7.97 (m, 2H), 7,84-7,79 (m, 2H), 7,43-7,39 (t, J=8.0 Hz, 1H), 7,31-7,29 (d, J=8.0 Hz, 1H), to 4.62 (s, 2H, of 3.54 (s, 1H), 2,75-2,67 (Sirs, 8H), is 2.41 (s, 3H); Mass spectrum (m/e): is 401.5 (M+1).

Examples 92-125: Synthesis of compounds 92-125

Connection 92-125 got a way similar to that described in example 91.

Compound 92:

1H NMR (CD3OD, 400 MHz): δ 8,59 (d, J=2.0 Hz, 1H), of 8.37 (s, 1H), to 7.93 (DD, J=2.4 Hz, J=2.4 Hz, 1H), 7,72 (d, J=8,8 Hz, 1H), 7,47 (t, J=6,8 Hz, 1H), 7,28-7,25 (m, 1H), 7,11 (kV, 1H), by 5.87 of 5.84 (m, 1H), 3,38 (s, 2H), 3.04 from (m, 4H), of 2.86 (m, 4H), to 2.66 (s, 3H), 1,71 (d, J=7.2 Hz, 3H); Mass spectrum (m/e): 423 (M+1).

Compound 93:

1H NMR (DMSO-d6, 400 MHz): δ 9,99 (s, 1H), 9,88 (s, 1H), 8,66 (s, 1H), to 8.57 (s, 1H), of 8.06 (d, J=9,2 Hz, 1H), 8,03 (s, 1H), 7,89 (d, J=8.0 Hz, 1H), 7,78 (d, J =8,8 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (d, J=7.2 Hz, 1H), to 4.23 (s, 1H), 3,20 (d, 2H), 3,17 (d, J=4.4 Hz, 1H), 2,60 (m, 8H), and 2.6 (m, 8H), 2,35 (t, J=6.8 Hz, 3H); Mass spectrum (m/e): 415 (M+1).

Compound 94:

1H NMR (DMSO-d6, 400 MHz): δ becomes 9.97 (s, 1H), 9,88 (s, 1H), 8,66 (d, J=1.6 Hz, 1H), to 8.57 (s, 1H), of 8.06 (d, J=9,2 Hz, 1H), 8,03 (s, 1H), 7,89 (d, J=8.0 Hz, 1H), 7,78 (d, J=9,2 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 4,23 (s, 1H), 3,19 (d, 2H), and 2.6 (m, 8H), 0,99 (d, J=6.8 Hz, 6H); Mass spectrum (m/e): 429 (M+1).

Compound 95:

1H NMR (DMSO-d6, 400 MHz): δ 9,96 (s, 1H), 8,79 (s, 1H), 8,58 (s, 1H), 8,12 (d, J=8,8 Hz, 1H), 8,07 (s, 1H), 7,92 (d, J=7,6 Hz, 1H), 7,80 (d, J=8,4 Hz, 1H), 7,40 (t, J=7.2 Hz, 1H), 7,22 (d, J=7.2 Hz, 1H), 4,23 (s, 1H), 3,39 (s, 2H), 2,98 (m, 8H), of 1.13 (s, 6H); Mass spectrum (m/e): 417 (M+1).

Compound 96:

1H NMR (DMSO-d6, 400 MHz): δ 9,94 (s, 1H), 8,73 (s, 1H), to 8.57 (s, 1H), 8,11 (d, J=6,4 Hz, 1H), with 8.05 (s, 1H), of 7.90 (d, J=8.0 Hz, 1H), 7,79 (d, J=9,2 Hz, 1H), 7,39 (t, J=7,6 Hz, 1H), 7,21 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 3,39 (s, 2H), 3,34 (m, 4H), and 2.79 (s, H); Mass spectrum (m/e): 389 (M+1).

Compound 97:

Mass spectrum (m/e): 413,2 (M+1)

Compound 98:

1H NMR (DMSO-d6, 400 MHz): δ of 10.09 (s, 1H), 9,92 (s, 1H), to 8.62 (s, 1H), to 8.57 (s, 1H), 8,10 (d, J=8,8 Hz, 1H), 8,02 (s, 1H), to 7.99 (d, J=8.0 Hz, 1H), 7,81 (d, J=8,8 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7,22 (d, J=7,6 Hz, 1H)that is 4.21 (s, 1H), 3,47 (t, J=4,2 Hz, 4H), 3,39 (s, 2H), 3,26 (s, 6H), 2,85 (t, J=3,9 Hz, 4H); Mass spectrum (m/e): 434 (M+1).

Compound 99:

1H NMR (DMSO-d6, 400 MHz): δ 9,98 (s, 1H), 9,85 (s, 1H), to 8.62 (d, J=2.0 Hz, 1H), to 8.57 (s, 1H), 8,10 (DD, J=8,8, 2.0 Hz, 1H), 8,03 (s, 1H), 7,88 (DD, J=8,4, 1.2 Hz 1H), 7,78 (d, J=9,2 Hz, 1H), 7,41 (t, J=7,6 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 4,23 (s, 1H), 3,18 (s, 2H), 2,90 (d, J=12.0 Hz, 2H), 2,48 (s, 3H), 2,22 (t, J=11.2 Hz, 2H), 1,97 (t, J=9.6 Hz, 1H), 1,85 (d, J=12.0 Hz, 2H), 1,67 (d, 4H), of 1.55 (m, 2H); Mass spectrum (m/e): 455 (M+1).

Compound 100:

1H NMR (DMSO-d6, 400 MHz): δ 9,98 (s, 1H), 9,86 (s, 1H), 8,64 (d, J =1.6 Hz, 1H), to 8.57 (s, 1H), with 8.05 (DD, J=8,8, 2.0 Hz, 1H), 8,03 (s, 1H), 7,89 (DD, J=8,4, 1.2 Hz 1H), 7,78 (d, J=9,2 Hz, 1H), 7,41 (t,J=8.0 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 4,23 (s, 1H), 3,20 (s, 2H), has 2.56 (m, 8H), is 2.37 (m, 4H), and 2.14 (s, 6H); Mass spectrum (m/e): 458 (M+1).

Compound 102:

Mass spectrum (m/e): 475 (M+1).

Compound 103:

1H NMR (DMSO-d6, 400 MHz): δ becomes 9.97 (s, 1H), 9,86 (s, 1H), 8,64 (d, J=1.6 Hz, 1H), to 8.57 (s, 1H), of 8.06 (DD, J=9,2, 2.0 Hz, 1H), 8,03 (s, 1H), 7,89 (DD, J=8,4, 1.2 Hz, 1H), 7,78 (d, J=8,4 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (l, J=7,6 Hz, 1H), 4,23 (s, 1H), 3,21 (s, 2H), has 2.56 (m, 8H), 2,20 (d, J=6,4 Hz, 2H), 1,24 (s, 1H), or 0.83 (m, 1H), and 0.46 (m, 2H), 0,80 (m, 2H); Mass spectrum (m/e): 441 (M+1).

Compound 104:

1H NMR (DMSO-d6, 400 MHz): δ 9,99 (s, 1H), 9,86 (s, 1H), 8,65 (d, J=1.2 Hz, 1H), to 8.57 (s, 1H), of 8.06 (DD, J=8,8, ,0 Hz, 1H), 8,03 (s, 1H), 7,89 (DD, J=8,4, 1.2 Hz 1H), 7,79 (d, J=9,2 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (d,J=7,6 Hz, 1H), 4,23 (s, 1H), 3,38 (s, 2H), 3,17 (d, J=5,2 Hz, 1H), 2,86 (t, J=5.6 Hz, 4H), 2,62 (d, J=a 4.8 Hz, 4H) 2,31 (s, 3H), of 1.80 (m, 2H), 1,24 (s, 1H); Mass spectrum (m/e): 415 (M+1).

Compound 105:

Mass spectrum (m/e): 431 (M+1).

Compound 106:

Mass spectrum (m/e): 427,2 (M+1).

Compound 107:

1H NMR (DMSO-d6, 400 MHz): δ 9,94 (s, 1H), 9,84 (s, 1H), 8,63 (s, 1H), 8,55 (s, 1H), 8,03 (m, 2H), 7,88 (d, J=8.0 Hz, 1H), to 7.77 (d, J=9,2 Hz, 1H), 7,37 (t, J=8.0 Hz, 1H), 7,20 (d, J=7,6 Hz, 1H), 4,20 (s, 1H), and 3.16 (s, 2H), 2.95 points (d, J=11.2 Hz, 2H), 2,39 (m, 5H), 2,17 (t, J=8,8 Hz, 2H), 1,62 (m, 4H), of 1.35 (m, 4H), or 0.83 (t, J=7,6 Hz, 6H); Mass spectrum (m/e): 485,3 (M+1).

Compound 108:

1H NMR (DMSO-d6, 400 MHz): δ of 10.09 (s, 1H), 9,86 (s, 1H), 8,68 (s, 1H), to 8.57 (s, 1H), 8,02 (m, 2H), 7,88 (d, J=8.0 Hz, 1H), 7,79 (d, J=9,2 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (d, J=7,6 Hz, 1H), 4,20 (s, 1H), 3,78 (s, 2H), to 3.58 (s, 2H), or 3.28 (s, 2H), 2.63 in (s, 2H), of 2.51 (s, 2H), 1,99 (s, 1H), 0,73 (m, 4H); Mass spectrum (m/e): to 455.2 (M+1).

Compound 109:

1H NMR (DMSO-d6, 400 MHz): δ 9,96 (s, 1H), 9,84 (s, 1H), to 8.62 (s, 1H), to 8.57 (s, 1H), of 8.09 (d, J=8,8 Hz, 1H), 8,02 (s, 1H), 7,88 (d, J=8.0 Hz, 1H), 7,79 (t, J=8,8 Hz, 1H), 7,41 (t, J=8.0 Hz, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 4,22 (s, 1H), only 3.57 (m, 1H), 3,17 (s, 2H), 2,80 (m, 2H), 2,30 (m, 2H), 1,78 (m, 2H), and 1.54 (m, 2H); Mass spectrum (m/e): 402,1 (M+1).

Compound 110:

1H NMR (DMSO-d6, 400 MHz): δ 9,95 (s, 1H), 9,84 (s, 1H), 8,61 (s, 1H), 8,55 (s, 1H), 8,09 (m, 2H), 7,86 (d, J=8,8 Hz, 1H), 7,76 (d, J=9,2 Hz, 1H), 7,79 (t, J=8.0 Hz, 1H), 7,21 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 3,42 (t, J=6.0 Hz, 2H), up 3.22 (s, 3H), 3,17 (s, 2H), 2.49 USD (m, 10H); Mass spectrum (m/e): 445,2 (M+1).

Compound 111:

1H NMR (DMSO-d6 , 400 MHz): δ 9,95 (s, 1H), 9,84 (s, 1H), 8,64 (s, 1H), to 8.57 (s, 1H), 8,08 (d, J=8,8 Hz, 1H), 8,03 (s, 1H), 7,89 (d, J=8,1 Hz, 1H), 7,78 (d, J=9,2 Hz, 1H), 7,40 (t, J=8,4 Hz, 1H), 7.23 percent (d, J=7,6 Hz, 1H)that is 4.21 (s, 1H), 3,18 (s, 2H), 2,95 (d, J=10,8 Hz, 2H), 2.40 a (s, 3H), 2,30 (m, 4H), to 2.18 (m, 7H), to 1.76 (m, 2H), and 1.56 (m, 2H); Mass spectrum (m/e): 484,0 (M+1).

Compound 112:

1H NMR (CD3OD, 400 MHz): δ 8,69 (s, 1H), 8,51 (s, 1H), 7,94 (s, 1H), 7,81 to 7.75 (m, 3H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,28-7,26 (d, J=8.0 Hz, 1H), 3,51 (s, 1H), 2,86-2,82 (m, 2H), 2,69-to 2.65 (m, 10H), 1,11-of 1.09 (d, J=6.0 Hz, 6H); Mass spectrum (m/e): 443,5 (M+1).

Compound 113:

1H NMR (CD3OD, 400 MHz): δ 8,65 (s, 1H), charged 8.52 (s, 1H), 7.95 is-7,89 (m, 2H), 7,81-to 7.77 (m, 2H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,29-7,27 (d, J=8.0 Hz, 1H), 3,50 (s, 1H), 2,72 (m, 8H), 1,38-of 1.36 (d, J=6.8 Hz, 3H), 1,12-1,01 (d, J=6,4 Hz, 6H); Mass spectrum (m/e): 443,5 (M+1).

Compound 114:

1H NMR (DMSO-d6, 400 MHz): δ 10,27 (s, 1H), 10,04 (s, 1H), 9.28 are (s, 1H), 8,58 (s, 1H), 8,44(d, J=7.2 Hz, 1H), 8,29 (s, 1H), 8,16 (d, J=7,6 Hz, 1H), 7,78 (d, J=8,8 Hz, 1H), 7,39 (t, J=7,6 Hz, 1H), 7,21 (d, J=7.2 Hz, 1H), 4,22 (s, 1H), of 2.51 (s, 8H), 1.26 in (s, 6H), to 1.21 (s, 3H); Mass spectrum (m/e): 429 (M+1).

The 115 connection:

1H NMR (DMSO-d6, 400 MHz): δ becomes 9.97 (s, 1H), 9,84 (s, 1H), 8,78 (s, 1H), 8,56 (s, 1H), 8,16 (d, J=9,2 Hz, 1H), 8,07 (s, 1H), to 7.93 (d, J=8,4 Hz, 1H), 7,78 (d, J=9,2 Hz, 1H), 7,41 (t, J=8,4 Hz, 1H), 7,22 (d, J=8.0 Hz, 1H), to 4.23 (s, 1H), 2,61 (s, 8H), 1,24(s, 6H), 1,01 (d, J=10,8 Hz, 1H), 0,98-to 0.96 (m, 1H); Mass spectrum (m/e): 457 (M+1).

Compound 116:

1H NMR (DMSO-d6, 400 MHz): δ 9,99 (s, 1H), 9,87 (s, 1H), 8,73 (s, 1H), 8,56 (s, 1H), 8,15 (d, J=7,6 Hz, 1H), 8,08 (s, 1H), 8,7,95 (d, J=7.2 Hz, 1H), 7,78 (d, J=10,2 Hz, 1H), 7,41 (t, J=7,6 Hz, 1H), 7,22 (d, J=8.0 Hz, 1H), to 4.23 (s, 1H)and 3.15 (d, J=4,8 Hz, 1H) 2,55 (s, 8H), 1,25 (s, 6H), 1.0 to 0,971 (m, 3H); Mass spectrum (m/e): 443 (M+1).

Compound 117:

1H NMR (DMSO-d6, 400 MHz): δ 9,86 (s, 1H), 9,42 (s, 1H), 8,68 (s, 1H), to 8.57 (s, 1H), 8,18 (d, J=7.2 Hz, 1H), with 8.05 (s, 1H), 7,92 (d, J=7,6 Hz, 1H), 7,58 (d, J=7.2 Hz, 1H), 7,39 (t, J=6.0 Hz, 1H), 7,22 (d, J=7,6 Hz, 1H), 6,14 (s, 1H), 4,22 (s, 1H), 3,09-of 3.06 (m, 2H), 1,49 (s, 3H), 1,32 (s, 6H); Mass spectrum (m/e): 374 (M+1).

Compound 118:

1H NMR (DMSO-d6, 400 MHz): 10,00 (s, 1H), 9,82 (s, 1H), 9,04 (s, 1H), charged 8.52 (s, 1H), of 7.96 (s, 1H), 7,85-7,83 (d, J=7.2 Hz, 1H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,19 (s, 1H), 4,20 (s, 1H), 4,07 (s, 3H), 3,34 (s, 2H), 2,61-2,58 (m, 4H), 2,48-of 2.36 (m, 4H), 1,05-of 1.02 (t, J=9.6 Hz, 3H); Mass spectrum (m/e): 445,5 (M+1).

Compound 119:

1H NMR (DMSO-d6, 400 MHz): 10,04 (s, 1H), 9,82 (s, 1H), 9,04 (s, 1H), charged 8.52 (s, 1H), of 7.96 (s, 1H), 7,85-7,83 (d, J=7.2 Hz, 1H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), (s, 1H), 4,20 (s, 1H), 4,07 (s, 3H), 3,2 (s, 2H), 2,61-2,58 (m, 4H), 2,48-of 2.36 (m, 8H), 1,10 (Sirs, 6H); Mass spectrum (m/e): 459,5 (M+1).

Compound 120:

1H NMR (DMSO-d6, 400 MHz): 10,00 (s, 1H), 9,83 (s, 1H), 9,04 (s, 1H), 8,53 (s, 1H), of 7.96 (s, 1H), to 7.84 (d, J=7,6 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,32 (s, 1H), 7.20 (d, J=7,6 Hz, 1H), 4,21 (s, 1H), 4,08 (s, 3H), 3,22 (, 2H), 2,60 (m, 8H), of 2.23 (s, 3H); Mass spectrum (m/e): 431 (M+1).

Compound 121:

1H NMR (DMSO-d6, 400 MHz): δ 10,16 (s, 1H), 9,81 (s, 1H), remaining 9.08 (s, 1H), charged 8.52 (s, 1H), of 7.97 (s, 1H), to 7.84 (d, J=8,8 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,32 (s, 1H), 7,20 (d, J=8.0 Hz, 1H), 4,21 (s, 1H), 4,06 (s, 3H), 3.46 in (t, J=5,2 Hz, 1H), 3,26 (s, 3H), was 2.76 (t, J=5,2 Hz, 1H), 1,24 (s, 1H); Mass spectrum (m/e): 406 (M+1).

Compound 123:

1H NMR (CD3OD, 400 MHz): δ 8,93 (s, 1H), 8,48 (s, 1H), to 7.93 (s, 1H), to 7.77 (d, J=8.0 Hz, 1H), 7,38 (t, J=7,6 Hz, 1H), 7,27 (t, J=7.2 Hz, 2H), 4,14 (s, 3H), 3,37 (s, 1H), 3,25 (s, 2), 3,12-to 3.09 (m, 3H), 2,42-is 2.37 (m, 2H), 2,02 is 2.00 (m, 2H), 1,80-to 1.77 (m, 2H), 1,31-1,25 (m, 4H), of 1.20 (s, 6H); Mass spectrum (m/e): 487 (M+1).

Compound 124:

1H NMR (DMSO-d6, 400 MHz): δ 10,04 (s,1H), 9,81 (s, 1H), of 9.02 (s, 1H), 8,53 (s, 1H), of 7.97 (s, 1H), a 7.85 (d, J=8.0 Hz, 1H), 7,38 (t, J=8.0 Hz, 1H), 7,32 (s, 1H), 7,20 (d, J=7,6 Hz, 1H), 4,19 (s, 1H), 4,07 (s, 3H), 3,21 (s, 2H), 2,68-2,60 (m, 4H), 1,22 (s, 3H), 1,02 to 0.97(m, 6H); Mass spectrum (m/e): 445 (M+1).

Compound 125:

1H NMR (DMSO-d6, 400 MHz): δ 10,52 (s, 1H), 9,94 (s, 1H), of 8.95 (s, 1H), to 8.57 (s, 1H), to 7.99 (s, 1H), 7,86 (d, J=9,2 Hz, 1H), 7,39 (t, J=8,4 Hz, 1H), 7,33 (s, 1H), 6,76 (d, J=7,6 Hz, 1H), 4,23 (s, 1H), Android 4.04(s, 3H), 2,98 (s, 8H), 2,78 is 2.75 (m, 3H), 2,34-of 2.30 (m, 2H), of 1.37 (s, 6H); Mass spectrum (m/e): 473 (M+1).

Example 126: Synthesis of 1-(4-(3-ethynylphenyl)hinzelin-6-yl)-3-methyl-1H-imidazol-2(3H)-she (Compound 126)

To a solution of 5-nitroanthranilic (1,00 g, 6,13 mmol) in dioxane (25 ml) was added dimethylacetal of dimethylformamide (0.88 g, 7.36 mmol). The reaction mixture was stirred at 100°C for 2 hours and then cooled to room temperature and cooled in the refrigerator. The precipitate was filtered, washed several times with cold simple ether and then dried in vacuum, obtaining of 1.30 g (97%) of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in a solid yellow color.

A mixture of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1,00 g, 4,58 mmol) and 3-aminophenylacetylene (0.64 g, 5,49 mmol) in HOAc (15 ml) was stirred at 100°C for 3 hours and cooled to room the second temperature. The precipitate was filtered off, washed with simple ether and dried in vacuum, obtaining of 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine in the form of a solid yellow color.

N-(3-ethynylphenyl)-6-nitroquinazoline-4-amine (1,00 g of 3.45 mmol) and SnCl2·2H2O (3,10 g of 13.8 mmol) in ethyl acetate (35 ml) was heated at the boil under reflux for 2 hours. After cooling to room temperature, the mixture was treated with 5% aqueous solution of NaHCO3to bring its pH to 9-10, and then was extracted with EtOAc. The combined organic layers were washed with saturated salt solution and H2O, dried and concentrated under reduced pressure, getting 0,79 g (89%) of N4-(3-ethynylphenyl)hinzelin-4,6-diamine in the form of a solid yellow color.

To a solution of N4-(3-ethynylphenyl)hinzelin-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 ml)containing pyridine (37 μl, 0.46 mmol) was added dropwise at room temperature phenylcarbamate (49 μl, 0.38 mmol). After 10 minutes, was added dimethylacetal (methylamino)acetaldehyde (45,2 mg, 0.38 mmol) and the reaction mixture was heated at 100°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were concentrated and purified on a column of silica gel, receiving the connection 126 in the form of a solid yellow color with 83% yield.

1H NMR (CD3OD, 400 MHz): δ 8,84 (s, 1H), 8,83-8,82 (d, J=2.0 Hz, 1H), 8,60-to 8.57 (DD, J=2.0 Hz, 9.6 Hz, 1H), 7,98-of 7.96 (d, J=9,2 Hz, 1H), 7,95 (s, 1H), 7,81-7,79 (DD, J=1.6 Hz, 7.2 Hz, 1H), 7,52-7,49 (m, 2H), 7,17-7,16 (d, J=2,8 Hz, 1H), 6,82-for 6.81 (d,J=2,8 Hz, 1H), 3,64 (s, 1H), 3,38 (s, 3H); Mass spectrum (m/e): 342,3 (M+1).

Example 127: Synthesis of 1-(4-(3-ethynylphenyl)hinzelin-6-yl)-1H-imidazol-2(3H)-it

Compound 127 was obtained by a method similar to that described in example 126.

1H NMR (CD3OD, 400 MHz): δ 8,55 (s, 2H), 8,24 is 8.22 (DD, J=2,8 Hz and 9.2 Hz, 1H), of 7.97 (s, 1H), 7,88-7,86 (d, J=8,8 Hz, 1H), 7,82-7,81 (d, J=2.4 Hz, 1H), 7,40 and 7.36 (t, J=8.0 Hz, 1H), 7,28-7,26 (d, J=8,8 Hz, 1H), 7,09-was 7.08 (d, J=3.2 Hz, 1H), 6,79-of 6.78 (d, J=3.2 Hz, 1H), 3,52 (s, 1H); Mass spectrum (m/e): 327,9(M+1).

Example 128: Synthesis of 1-(4-(3-ethynylphenyl)hinzelin-6-yl)-3-(2-methoxy-ethyl)-1H-imidazol-2(3H)-she (Compound 128)

The way of synthesis of compound 128 is shown below:

To a solution of N4-(3-ethynylphenyl)hinzelin-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 ml)containing pyridine (37 μl, 0.46 mmol) was added dropwise at room temperature within 1 hour phenylcarbamate (49 μl, 0.38 mmol). The reaction mixture was diluted with ethyl acetate and washed with water and saturated salt solution. The combined organic layers were concentrated, receiving phenyl-4-(3-ethynylphenyl)hinzelin-6-ylcarbamate in a solid yellow color with a 95% yield and used in the next stage without purification.

To a solution of 2-methoxyethylamine (100 mg,of 1.33 mmol) in DMF (2 ml) was added K 2CO3(276 mg, 1,99 mmol) and 2-bromo-1,1-dimethoxyethane (236 mg, of 1.39 mmol). The mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated salt solution. The organic layer was concentrated, receiving 2,2-dimethoxy-N-(2-methoxyethyl)ethanamine in the form of a yellow oil with a 91% yield and used in the next stage without purification.

To a solution of phenyl 4-(3-ethynylphenyl)hinzelin-6-ylcarbamate (50 mg, 0.13 mmol) in DMF (2 ml) was added 2,2-dimethoxy-N-(2-methoxyethyl)ethanamine (22,0 mg, 0.13 mmol). The mixture was stirred at 80aboutC for 0.5 hour and then was added p-toluensulfonate acid (28.5 mg, 0.15 mmol). After stirring at 80°C. additionally for 1 hour, the mixture was cooled to room temperature and was diluted with ethyl acetate and washed with water and saturated salt solution. The organic layer was concentrated and was purified on a column of silica gel, receiving the connection 128 in the form of a solid yellow color with 82% yield.

1H NMR (CD3OD, 400 MHz): δ to 8.57 (s, 2H), 8,24 is 8.22 (DD, J=2,8 Hz and 9.2 Hz, 1H), 7,98 (s, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,82-7,81 (d, J=2.4 Hz, 1H), 7,40 and 7.36 (t,J =8.0 Hz, 1H), 7,29-7,27 (d, J=8,8 Hz, 1H), 7,09-was 7.08 (d, J=3.2 Hz, 1H), 6,79-of 6.78 (d, J=3.2 Hz, 1H), 3,92-3,90 (t,J =5,2 Hz, 2H), 3,68-3,66 (t,J =5,2 Hz, 2H), 3,52 (s, 1H), 3,40 (s, 3H); Mass spectrum (m/e): 386,4 (M+1).

Examples 129-156: Synthesis of compounds 129-156

Connected to the I 129-156 received by way similar to that described in example 128.

Compound 129:

1H NMR (DMSO-d6, 400 MHz): 10,06 (s, 1H), 8,71 (s, 1H), 8,7-0 (s, 1H), 8,51-8,48 (DD, J=1,6 Hz and 8.4 Hz, 1H), of 8.09 (s, 1H), 7,99-of 7.97 (d, J=8.0 Hz, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,45-7,41 (t, J=8.0 Hz, 1H), 7,34-7,33 (d, J=3.2 Hz, 1H), 7,26-7,24 (d,J=7.2 Hz, 1H), 6,93-6,92 (d, J=3.2 Hz, 1H), 4,23 (s, 1H), of 3.77-3,74 (t, J=6.4 Hz, 2H), 3,61-3,55 (m, 4H), 2,61-of 2.56 (t, J=6.4 Hz, 2H), 2,24 (m, 4H); Mass spectrum (m/e): 441,5 (M+1).

Compound 130:

1H NMR (DMSO-d6, 400 MHz): δ 10,04 (s, 1H), 8,69 (s, 1H), 8,63 (s, 1H), 8,49-8,46 (DD, J=1,6 Hz and 8.4 Hz, 1H), 8,08 (s, 1H), 7,99-of 7.97 (d, J=8.0 Hz, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,45-7,41 (t, J=8.0 Hz, 1H), 7,34-7,33 (d, J=3.2 Hz, 1H), 7,26-7,24 (d, J=7.2 Hz, 1H), of 6.96-to 6.95 (d, J=3.2 Hz, 1H), 4,23 (s, 1H), 3,86-a 3.83 (t, J=6,8 Hz, 2H), 2,84 is 2.80 (t, J=6,8 Hz, 2H), 2,12 (s, 3H); Mass spectrum (m/e): 402,5 (M+1).

Compound 131:

1H NMR (DMSO-d6, 400 MHz): δ 9,74 (s, 1H), 8,67 (s, 1H), 8,63 (s, 1H), 8,45-8,43 (DD, J=2,4 Hz and 8.8 Hz, 1H), 8,07 (s, 1H), 7,97-of 7.95 (d, J=8.0 Hz, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,45-7,41 (t, J=8.0 Hz, 1H), 7,31-7,30 (d, J=3.2 Hz, 1H), 7,26-7,24 (d, J=7.2 Hz, 1H), 7,08-7,07 (d, J=3.2 Hz, 1H), 4,23 (s, 1H), 4,14-4,10 (m, 1H), 3,99-of 3.96 (m, 2H), 3,50-of 3.45 (t, J=8,4 Hz, 2H), 1,91 is 1.86 (m, 2H), 1,79 is 1.75 (m, 2H); Mass spectrum (m/e): 412,4 (M+1).

Compound 132:

1H NMR (DMSO-d6, 400 MHz): δ 9,74 (s, 1H), 8,67 (s, 1H), 8,63 (s, 1H), 8,45-8,43 (DD, J=2,4 Hz and 8.8 Hz, 1H), 8,07 (s, 1H), 7,97-of 7.95 (d, J=8.0 Hz, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,45-7,41 (t, J=8.0 Hz, 1H), 7,31-7,30 (d, J=3.2 Hz, 1H), 7,26-7,24 (d, J=7.2 Hz, 1H), 7,08-7,07 (d, J=3.2 Hz, 1H), 4,23 (s, 1H), 3,98-of 3.97 (m, 1H), 3.25 to 3,24 (m, 2H), 3,03-to 2.99 (m, 2H), to 2.29 (s, 3H), 1,95-of 1.80 (m, 4H); Mass spectrum (m/e): 425,2 (M+1).

Compound 133:

1H NMR (DMSO-d6, 400 MHz): what to 9.93 (s, 1H), 8,63 (s, 2H), 8,46-8,43 (DD, J=2,8 Hz and 8.8 Hz, 1H), of 8.06 (s, 1H), of 7.96-7,94 (d, J=8,4 Hz, 2H), 7,45-7,41 (t, J=8.0 Hz, 1H), 7,26-7,24 (m, 2H), 6,93 (s, 1H), 4,24 (s, 1H), 3,65-3,62 (t,J=6,8 Hz, 2H), 1,67-of 1.64 (m, 2H), 1,35-1,24 (m, 2H), 0,95-of 0.91 (t, J=7.2 Hz, 3H); Mass spectrum (m/e): 384,4 (M+1).

Compound 134:

Mass spectrum (m/e): 466,5 (M+1).

Compound 135:

1H NMR (CD3OD, 400 MHz): δ 8,79 (s, 1H), to 8.62 (s, 1H), 8,55-of 8.33 (d, J=8,8 Hz, 1H), 8,13 (s, 1H), 8,04-8,02 (d, J=8.0 Hz, 1H), 7,88-a 7.85 (d, J=8.0 Hz, 1H), 7,46-7,40 (m, 2H), 6,91-of 6.90 (d, J=3.2 Hz, 1H), 4,23 (s, 1H), 3,74-3,71 (t, J=6.4 Hz, 2H), 2.57 m-of 2.54 (t, J=6.4 Hz, 2H), and 2.27 (s, 6H); Mass spectrum (m/e): RUB 399.4 (M+1).

Compound 136:

1H NMR (DMSO-d6, 400 MHz): δ 10,41 (s, 1H), 8,84 (s, 1H), to 8.62 (s, 1H), of 8.06 (s, 1H), 8,57-8,54 (DD, J=2,4 Hz and 8.8 Hz, 1H), 8,17 (s, 1H), 8.07-a with 8.05 (d, J=8,8 Hz, 1H), 7,87-a 7.85 (d, J=9,2 Hz, 1H), 7,58-EUR 7.57 (d, J=3.6 Hz, 1H), 7,42-7,39 (t, J=8.0 Hz, 1H), 7.24 to to 7.18 (m, 2H), 6.90 to (s, 1H), is 6.61 (d, J=3.2 Hz, 1H), 4,35-4,32 (t, J=6.0 Hz, 2H), 4,24 (s, 1H), was 4.02-to 3.99 (t, J=6.0 Hz, 2H); Mass spectrum (m/e): 422,5 (M+1).

Compound 137:

1H NMR (CD3OD, 400 MHz): δ 8,66 are 8.53 (m, 4H), 8,27-8,24 (DD, J=2.0 Hz, and 9.2 Hz, 1H), to $ 7.91-7,79 (m, 4H), to 7.50 (m, 1H), 7,43-7,39 (t, J=8.0 Hz, 1H), 7,31-7,29 (d, J=7,6 Hz, 1H), 7.18 in-7,17 (d, J=3.2 Hz, 1H), 6.90 to-6,89 (d, J=3,2 Hz, 1H), 5,02 (s, 2H), 3,38 (s, 1H); Mass spectrum (m/e): 419,5 (M+1).

Compound 138:

1H NMR (DMSO-d6, 400 MHz): δ 9,96 (s, 1H), 8,66 (s, 1H), 8,63 (s, 1H), 8,45-8,43 (d, J=8,4 Hz, 1H), with 8.05 (s, 1H), 7.95 is-7,87 (m, 2H), 7,45-6,99 (m, 8H), of 6.99 (s, 1H), is 6.61 (d, J=3.2 Hz, 1H), 4,88 (s, 2H), 4,24 (s, 1H); Mass spectrum (m/e): 436,5 (M+1).

Compound 139:

1H NMR (DMSO-d6, 400 MHz): δ 10,04 (s, 1H), 8,68 (s, 1H), to 8.62 (s, 1H), 8,46-8,44 (d, J=9,2 Hz, 1H), 8,07 (s, 1H), 7,97-of 7.95 (d, J=7,6 Hz, 1H), 7,88-7,86 (d, J=9,2 Hz, 1H), 7,44-7,40 (t, J=8.0 Hz, 1H), 7,28 (s, 1H), 7,25-of 7.23 (d, J=7.2 Hz, 1H), for 6.81 (s, 1H), 4,24 (s, 1H), of 3.07 (s, 1H), 0,90 (Sirs, 4H); Mass spectrum (m/e): 368,4 (M+1).

Compound 140:

1H NMR (CD3OD, 400 MHz): δ at 8.60 (s, 1H), 8,58-to 8.57 (d, J=2.4 Hz, 1H), 8,25 is 8.22 (DD, J=2.0 Hz, and 9.2 Hz, 1H), 8,01 (s, 1H), of 7.90-7,88 (d, J=9,2 Hz, 1H), 7,86-to 7.84 (d, J=8,4 Hz, 1H), 7,43-7,39 (t, J=8.0 Hz, 1H), 7,31-7,29 (d, J=7,6 Hz, 1H), 7,12 (s, 1H), 6,86 (s, 1H), 4,59-of 4.57 (m, 1H), 3,56 (s, 1H), 2,16-2,12 (m, 2H), 1,92 to 1.76 (m, 6H); Mass spectrum (m/e): 396,4 (M+1).

Compound 141:

1H NMR (DMSO-d6, 400 MHz): δ 9,92 (s, 1H), 8,63 (s, 2H), 8,42-8,39 (DD, J=2,4 Hz and 9.2 Hz, 1H), 8,01 (s, 1H), 7.95 is-to 7.93 (d, J=9,2 Hz, 1H), 7,88-7,86 (d, J=9,2 Hz, 1H), 7,44-7,40 (t, J=8.0 Hz, 1H), 7,25-of 7.23 (m, 2H), 7,03 (s, 1H), to 4.23 (s, 1H), 4,10 (Sirs, 1H), 3.04 from (s, 2H), 1,88 (Sirs, 8H), of 1.03 (Sirs, 3H); Mass spectrum (m/e): 439,4 (M+1).

Compound 142:

1H NMR (CD3OD, 400 MHz): δ 9,88 (s, 1H), 8,64 (s, 1H), 8,61 (s, 1H), 8,42-to 8.40 (d, J=8,8 Hz, 1H), 8,04 (s, 1H), 7,93-7,88 (m, 2H), 7,50-7,49 (d, J=4,8 Hz, 1H), 7,45-7,41 (t, J=7,6 Hz, 1H), 7,26-7,24 (d, J=7,6 Hz, 1H), of 7.23-7,22 (d, J=2,8 Hz, 1H), 7,15 (s, 1H),? 7.04 baby mortality-7,02 (t, J=4.0 Hz, 1H), 6,97-of 6.96 (d, J=2,8 Hz, 1H), 5,04 (s, 2H), 4,24 (s, 1H); Mass spectrum (m/e): 424,5 (M+1).

Compound 143:

1H NMR (DMSO-d6, 400 MHz): δ to 9.93 (s, 1H), 8,64 (s, 1H), 8,63 (s, 1H), 8,44-8,42 (DD, J=2.0 Hz, 8,8 Hz, 1H), with 8.05 (s, 1H), 7.95 is-to 7.93 (d, J=8,4 Hz, 1H), of 7.90-7,88 (d, J=8,8 Hz, 1H), 7,45-the 7.43 (t, J=8.0 Hz, 1H), 7,27-7,25 (m, 2H,), 6,86-6,85 (d, J=3.2 Hz, 1H), 6,00-to 5.93 (m, 1H), 5,24-5,16 (m, 2H), 4,29-4,27 (d, J=5,2 Hz, 2H), 4,24 (s, 1H); Mass spectrum (m/e): 368,4 (M+1).

Compound 144:

1H NMR (DMSO-d6, 400 MHz): δ of 9.89 (s, 1H), 8,62 (Sirs, 2H), 8,42 (Sirs, 1H), with 8.05 (s, 1H), to $ 7.91-7,80 (m, 2H), 7,44 (Sirs, 1H), 7,25-7,14 (m, 2H), 6,99 (s, 1H), 4,25 (s, 1H), 3,1 (Sirs, 2H), 3,26 (Sirs, 2H), 3.04 from-2,90 (m, 2H), 2,08 (Sirs, 2H), 1.93 and-a 1.88 (m, 4H); Mass spectrum (m/e): 453,5 (M+1).

Compound 145:

1H NMR (CD3OD, 400 MHz): δ to 9.91 (s, 1H), 8,64 (s, 1H), 8,63-to 8.62 (d, J=2.0 Hz, 1H), 8,39-at 8.36 (DD, J=1,6 Hz and 9.2 Hz, 1H), 8,04 (s, 1H), 7,93-7,89 (m, 2H), 7,46-7,42 (t, J=8.0 Hz, 1H), 7,27 (s, 1H), 7,25-7,24 (d, J=3.2 Hz, 1H), 6,97-of 6.96 (d, J=3.2 Hz, 1H), to 4.52-4,51 (d, J=2.0 Hz, 2H), 4,25 (s, 1H), 3,44 (s, 1H); Mass spectrum (m/e): 366,4 (M+1).

Compound 146:

1H NMR (CD3OD, 400 MHz): δ 9,88 (s, 1H), 8,63 (s, 1H), at 8.60 (s, 1H), 8,43-to 8.41 (d, J=8,8 Hz, 1H), 8,03 (s, 1H), 7,93-7,87 (m, 2H), 7,46-7,42 (t, J=7,6 Hz, 1H), 7,26-7,24 (d, J=8.0 Hz, 1H), 7,21-7,20 (d, J=3.2 Hz, 1H), 6,94-6,93 (d, J=2,8 Hz, 1H), 4,25 (s, 1H), 3,66-3,63 (t, J=6,8 Hz, 2H), 2,48-2,39 (m, 6H), 1,79 to 1.76 (m, 2H), 0,96 with 0.93 (t, J=7.2 Hz, 6 Hz); Mass spectrum (m/e): 441,5 (M+1).

Compound 147:

1H NMR (DMSO-d6, 400 MHz): δ 10,11 (s, 1H), 8,72 (d, J=2.0 Hz, 1H), 8,63 (s, 1H), 8,59 (DD, J=2.0 Hz, J=2.0 Hz, 1H), 8,10 (s, 1H), to 7.99 (d, J=8.0 Hz, 1H), 7,88 (d, J=9,2 Hz, 1H), 7,43 (t, J=8.0 Hz, 1H), 7,35 (d, J=2,8 Hz, 1H), 7,24 (d, J=7,6 Hz,1H), to 6.88 (d, J=2,8 Hz, 1H), 4,23 (s, 1H), 3,80-of 3.78 (m, 2H), 3,65-3,62 (m, 2H), 3,51-of 3.48 (m, 2H), 1,14-1,08 (m, 3H); Mass spectrum (m/e): 400 (M+1).

Compound 148:

1H NMR (CD3OD, 400 MHz): δ 9,88 (s, 1H), to 8.62 (s, 1H), at 8.60 (s, 1H), 8,03 (s, 1H), 7,93-to $ 7.91 (d, J=8.0 Hz, 1H), 7,89-7,87 (d, J=9,2 Hz, 1H), 7,45-the 7.43 (t, J=8.0 Hz, 1H), 7,26-7,24 (d, J=7.2 Hz, 1H), 7.18 in-7,17 (d, J=3,2 Hz, 1H), 6,91-of 6.90 (d, J=2,8 Hz, 1H), 4,23 (s, 1H), 3.75 to and 3.72 (t, J=6.4 Hz, 2H), 2,59-of 2.56 (t, J=6.4 Hz, 2H), of 2.51-2.40 a (m, 4H), 2,38 of-2.32 (m, 4H), and 2.14 (s, 3H); Mass spectrum (m/e): 454,5 (M+1).

Compound 149:

1H NMR (CD3OD, 400 MHz): δ 9,92 (s, 1H), 8,63 (s, 1H), at 8.60 (s, 1H), 8,44-8,42 (d, J=8,8 Hz, 1H), 8,04 (s, 1H), of 7.96-7,87 (m, 2H), 7,46-7,42 (t, J=7,6 Hz, 1H), 7,26-7,24 d, J=7,6 Hz, 1H), 7.18 in-7,17 (d, J=2,8 Hz, 1H), 6,91-of 6.90 (d, J=2.4 Hz, 1H), 4,25 (s, 1H), 3,37 at 3.69 (m, 1H), 3,52-3,47 (m, 1H), 2,30-of 2.26 (m, 2H), 2,19-to 2.06 (m, 2H), 1,78-1,71 (m, 2H), 1,65-to 1.59 (m, 2H), 1,42-1,45 (m, 1H), 1,07-1,10 (m, 3H); Mass spectrum (m/e): 439,5 (M+1).

Compound 150:

1H NMR (CD3OD, 400 MHz): δ to 8.57 (s, 1H), 8,53 (s, 1H), they were 8.22-to 8.20 (DD, J=1,6 Hz and 9.2 Hz, 1H), to 7.99 (s, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,39-7,37 (t, J=7,6 Hz, 1H), 7,29-7,27 (d, J=7.2 Hz, 1H), 7,03-7,02 (d, J=2,8 Hz, 1H), 6,82-for 6.81 (d, J=3.2 Hz, 1H), 4,16-4,12 (t, J=6,8 Hz, 2H), 3,56 (s, 1H), 2,59-of 2.56 (t, J=6.4 Hz, 2H); Mass spectrum (m/e): 400,4 (M+1).

Compound 151:

1H NMR (CD3OD, 400 MHz): δ 8,58-to 8.57 (m, 2H), 8,25 is 8.22 (DD, J=2.0 Hz, 8,8 Hz, 1H), 7,98 (s, 1H), 7,92-7,89 (d, J=8,8 Hz, 1H), 7,86-to 7.84 (d, J=8.0 Hz, 1H), 7,43-7,39 (t, J=7,6 Hz, 1H), 7,31-7,29 (d, J=7.2 Hz, 1H), 7,09-7,08 (d, J=2,8 Hz, 1H), 6,80-6,79 (d, J=3.2 Hz, 1H), 3,86-a 3.83 (t, J=6.4 Hz, 2H), 3,53 (s, 1H), 2.91 in-2,88 (t, J=6,8 Hz, 2H), 2.26 and-2,22 (m, 2H), 1.85 to of 1.66 (m, 5H); Mass spectrum (m/e): 425,1 (M+1).

Compound 152:

1H NMR (CD3OD, 400 MHz): δ 8,61 (s, 1H), 8,53 (s, 1H), they were 8.22-to 8.20 (DD, J=1,6 Hz and 9.2 Hz, 1H), to 7.99 (s, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,39-7,37 (t, J=7,6 Hz, 1H), 7,29-7,27 (d, J=7.2 Hz, 1H), 7,03-7,02 (d, J=2,8 Hz, 1H), 6,83-PC 6.82 (d, J=2,8 Hz, 1H), 4,08-of 4.05 (t, J=6,8 Hz, 2H), 3,55 (s, 1H), 3,52 is 3.40 (m, 4H), 2,85-2,82 (t, J=6,8 Hz, 2H), 2.00 in 1,89 (m, 4H); Mass spectrum (m/e): 453,4 (M+1).

Compound 153:

1H NMR (CD3OD, 400 MHz): δ 8,59 (s, 1H), 8,57-8,56 (d, J=2.0 Hz, 1H), 8,24-8,21 (DD, J=2,4 Hz and 8.8 Hz, 1H), to 7.99 (s, 1H), of 7.90-7,88 (d, J=8,8 Hz, 1H), 7,84-of 7.82 (d, J=7.2 Hz, 1H), 7,42-7,38 (t, J=8.0 Hz, 1H), 7,30-7,28 (d, J=7,6 Hz, 1H), 7,10-to 7.09 (d, J=3.2 Hz, 1H), for 6.81-to 6.80 (d, J=3.6 Hz, 1H), 3,90-a 3.87 (t, J=5.6 Hz, 2H), 3,54 (s, 1H), 3.45 points-of 3.42 (t, J=6.0 Hz, 2H), equal to 2.94 (s, 3H); Mass spectrum (m/e: 449,5 (M+1).

Compound 154:

1H NMR (CD3OD, 400 MHz): δ 8,58 (s, 1H), 8,56-8,55 (d, J=2.0 Hz, 1H), 8,23-to 8.20 (DD, J=2,4 Hz and 8.8 Hz, 1H), to 7.99 (s, 1H), 7,89-7,87 (d, J=8,8 Hz, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,41-7,37 (t, J=8.0 Hz, 1H), 7,29-7,27 (d, J=7,6 Hz, 1H), 7,08-7,07 (d, J=2,8 Hz, 1H), 6,80-6,79 (d, J=3.6 Hz, 1H), 3.96 points-3,93 (t, J=5.6 Hz, 2H), 3,53 (s, 1H), 3,52-of 3.48 (t, J=5.6 Hz, 2H), equal to 2.94 (s, 3H), 2,84 (s, 3H); Mass spectrum (m/e): 463,5 (M+1).

Compound 155:

1H NMR (CD3OD, 400 MHz): δ 8,58 (s, 1H), 8,56-8,55 (d, J=2.0 Hz, 1H), 8,23-to 8.20 (DD, J=2.0 Hz, 8,8 Hz, 1H), 7,98 (s, 1H), 7,89-7,87 (d, J=9,2 Hz, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,41-7,37 (t, J=7,6 Hz, 1H), 7,29-7,27 (d, J=8.0 Hz, 1H), 7,07-7,06 (d, J=2,8 Hz, 1H), 6.73 x-6,72 (d, J=2,8 Hz, 1H), 3,85-3,82 (t, J=5.6 Hz, 2H), 3,55-to 3.52 (t, J=6.0 Hz, 2H), 3,52 (s, 1H), 1.56 to of 1.52 (m, 1H), 0,83 is 0.81 (m, 2H), 074-0,71 (m, 2H); Mass spectrum (m/e): 439,5 (M+1).

Compound 156:

1H NMR (CD3OD, 400 MHz): δ 8,61 (d, J=2.0 Hz, 1H), 8,60-8,56 (DD, J=2.0 Hz, 1H), 8,24-8,21 (DD, J=2.0 Hz, and 9.2 Hz, 1H), 8,01-to 7.99 (DD, J=2.0 Hz, 4.4 Hz, 1H), 7,92-to $ 7.91 (DD, J=2,4 Hz and 9.2 Hz, 1H), 7,86-to 7.84 (d, J=8.0 Hz, 1H), 7,43-7,39 (t, J=8.0 Hz, 1H), 7,32-7,30 (d, J=8.0 Hz, 1H), 4,05-was 4.02 (t, J=5.6 Hz, 1H), 3,98-of 3.96 (t, J=5.6 Hz, 1H), 3,94-to 3.92 (t, J=5.6 Hz, 1H), 3,78 of 3.75 (t, J=5.6 Hz, 1H), 3,55 (s, 1H), 3.27 to (C, 1,5H), 3,05 (C, 1,5H), 1,92-of 1.85 (m, 1H), 0,82 of 0.77 (m, 3H), 0,69 is 0.65 (m, 1H); Mass spectrum (m/e): 453,5 (M+1).

Example 157: Synthesis of 3-(2-(dimethylamino)ethyl)-1-(4-(3-ethynylphenyl)hinzelin-7-yl)-1H-imidazol-2(3H)-she (Compound 157)

The way of synthesis of compound 157 shown below:

To a solution of 2-amino-4-nitrobenzoic acid (6,00 g, 32,94 mmol) in ethanol (40 ml) was added formamidine (6,80 g, 65,32 mmol). Reactionary see the camping was heated at the boil under reflux for 5 hours and cooled to room temperature and cooled in the refrigerator. The precipitate was filtered, washed with several portions of cold ethanol and then dried in vacuum, obtaining the ceiling of 5.60 g (89%) of 7-nitroquinazoline-4-ol in the form of a solid yellow color.

A mixture of 7-nitroquinazoline-4-ol (3.4 g, 17,79 mmol), chloride taanila (20 ml) and DMF (0.5 ml) was heated at the boil under reflux for 48 hours. After cooling the mixture to room temperature, excess chloride tiomila was removed by evaporation and the residue podlegali azeotropic otrance with toluene, getting 2,61 g (70%) of the product 4-chloro-7-nitroquinazoline in a solid yellow color.

A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9,54 mmol), isopropanol (30 ml) and 3-ethynylbenzene (1.2 g, 10,00 mmol) was heated at the boil under reflux for 5 hours. The resulting mixture was cooled to room temperature and cooled in the refrigerator. The precipitate was filtered, washed several times with cold isopropanol and dried in vacuum, obtaining 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazoline-4-amine in the form of a solid yellow color.

N-(3-ethynylphenyl)-7-nitroquinazoline-4-amine (2.0 g, 6,89 mmol), SnCl2(5.0 g, 26,37 mmol) and ethyl acetate (50 ml) was heated at the boil under reflux for 3 hours. The mixture was extracted with ethyl acetate (20 ml). The combined organic layers were washed with saturated salt solution (20 ml x2), sushi and above Na 2SO4and concentrated in vacuum, obtaining 1.6 g (86%) of N4-(3-ethynylphenyl)hinzelin-4,7-diamine in the form of a solid yellow color.

A mixture of N4-(3-ethynylphenyl)hinzelin-4,7-diamine (48 mg, 0.18 mmol), phenylcarbonylamino of 25.2 μl, 0.18 mmol), pyridine (32 μl) and DMF (2 ml) was stirred at room temperature for 1.5 hours. To the mixture was added N1-(2,2-dimethoxymethyl)-N2,N2-dimethylated-1,2-diamine (33,5 mg, 0,19 mmol). The mixture was stirred at 80aboutC for 1 hour and then was added p-toluensulfonate acid (35.6 mg, 0.20 mmol). The mixture was stirred at 80aboutC for another 1 hour. After cooling to room temperature, it was diluted with ethyl acetate and washed with water and saturated salt solution. The combined organic layers were concentrated and purified on a column of silica gel, receiving the Connection 157 in a solid yellow color with a 75% yield.

1H NMR (CD3OD, 400 MHz): δ to 8.57 (s, 1H), 8,48-of 8.47 (d, J=3.6 Hz, 1H), 8,46 (s, 1H), of 8.09 (s, 1H), 8,07 (s, 1H), 7,98 (s, 1H), 7,83-7,81 (d, J=8.0 Hz, 1H), 7,42-7,38 (t, J=8.0 Hz, 1H), 7,31-7,29 (d, J=7,6 Hz, 1H), 7,13-for 7.12 (d, J=2,8 Hz, 1H), 6,83-PC 6.82 (d, J=2,8 Hz, 1H), 3,89-of 3.85 (t, J=6,8 Hz, 2H), 3,56 (s, 1H), 2,72-2,69 (t, J=6.4 Hz, 2H), 2,35 (s, 6H); Mass spectrum (m/e): RUB 399.4 (M+1).

Examples 158-163: Synthesis of compounds 158-163

Connection 158-163 got a way similar to that described in example 157.

Compound 158:

1H NMR (CD3OD, 400 MHz): δ 8,59 (s, 1H), charged 8.52-8,49 (d, J=8,8 Hz, 1H), 8,11-8,08 (d, J=24 Hz, 1H), 8,09-8,08 (d, J=2.4 Hz, 1H), 7,98 (s, 1H), 7,83-7,81 (d, J=8.0 Hz, 1H), 7,43-7,39 (t, J=7,6 Hz, 1H), 7,32-7,30 (d, J=7,6 Hz, 1H), 7.18 in-7,17 (d, J=2,8 Hz, 1H), 6,85-6,84 (d, J=3.2 Hz, 1H), 3,81-of 3.77 (t, J=6,8 Hz, 2H), 3,56 (s, 1H), 2,74-to 2.67 (m, 6H), 2,02-of 1.95 (m, 2H), 1,14-1,10 (t, J=7.2 Hz, 6H); Mass spectrum (m/e): 441,5 (M+1).

Compound 159:

1H NMR (MeOD, 400 MHz): δ 8,58 (s, 1H), 8,48-to 8.45 (DD, J=1.6 Hz, 8.0 Hz, 1H), 8,09-8,08 (d, J=2.4 Hz, 1H), 8,07 (s, 1H), 7,98 (s, 1H), 7,83-7,81 (d, J=8.0 Hz, 1H), 7,42-7,38 (t, J=8.0 Hz, 1H), 7,31-7,29 (d, J=7,2 Hz, 1H), 7,12-7,11 (d, J=2,8 Hz, 1H), 6,84-6,83 (d, J=3.2 Hz, 1H), 3,90-of 3.85 (m, 1H), 3,67-to 3.64 (m, 1H), 3,55 (s, 1H), 3,23-3,18 (m, 1H), 3,01-to 2.94 (m, 1H), 2,86-2,82 (m, 1H), 2,44-of 2.38 (m, 1H), 2,32-of 2.26 (m, 1H), 1,98 is 1.91 (m, 1H), 1,75 was 1.69 (m, 1H), 1,18 (s, 3H); Mass spectrum (m/e): 439,5 (M+1).

Compound 160:

1H NMR (CD3OD, 400 MHz): δ 8,59 (s, 1H), 8,51-8,49 (DD, J=2.0 Hz and 7.6 Hz, 1H), 8,13-to 8.12 (d, J=2.0 Hz, 1H), 8,11-8,10 (d, J=2.0 Hz, 1H), 7,98 (s, 1H), 7,83-7,81 (d, J=8.0 Hz, 1H), 7,43-7,39 (t, J=8,4 Hz, 1H), 7,32-7,30 (d, J=8.0 Hz, 1H), 7,16-to 7.15 (d, J=3.6 Hz, 1H), 6,82-for 6.81 (d, J=3.2 Hz, 1H), 3,82-of 3.78 (t, J=7.2 Hz, 2H), 3,61 (s, 1H), 2,73 is 2.33 (m, 10H), of 2.28 (s, 3H), 2.00 in of 1.93 (m, 2H); Mass spectrum (m/e): resulting in 468.5 (M+1).

Compound 161:

1H NMR (CD3OD, 400 MHz): δ 8,59 (s, 1H), 8,51-8,49 (d, J=9.6 Hz, 1H), 8,11-8,08 (m, 2H), 7,98 (s, 1H), 7,83-7,81 (d, J=8.0 Hz, 1H), 7,43-7,39 (t, J=7,6 Hz, 1H), 7,32-7,30 (DD, J=1.6 Hz, 6.8 Hz, 1H), 7,17-7,16 (d, J=3.2 Hz, 1H), 6,86-6,85 (d, J=2,8 Hz, 1H), 3,85-of 3.78 (t, J=6,8 Hz, 2H), 3,55 (s, 1H), 3,12-of 3.07 (m, 1H), of 2.38 (s, 3H), 2,30-2,12 (m, 4H), 1.85 to of 1.78 (m, 2H), 1,69-of 1.55 (m, 2H); Mass spectrum (m/e): 439,5 (M+1).

Compound 162:

1H NMR (CD3OD, 400 MHz): δ 8,59 (s, 1H), 8,51-8,48 (d, J=10.0 Hz, 1H), 8,11-of 8.09 (m, 2H), 7,98 (s, 1H), 7,84-7,81 (d, J=8,8 Hz, 1H), 7,43-7,39 (t, J=8.0 Hz, 1H), 7,32-7,30 (d,J=7,6 Hz, 1H), 7,15-7,14 (d, J=3.2 Hz, 1H), 6,88-6,87(d, J=2,8 Hz, 1H), of 3.77-to 3.73 (t, J=7.2 Hz, 2H), 3,54 (s, 1H), 3,54-3,50 (t, J=7.2 Hz, 2H), 3,42-3,39 (t, J=7.2 Hz, 1H), 2,44-to 2.40 (t, J=7,6 Hz, 2H), 2,12-2,07 (m, 2H), 2,04 of 1.99 (m, 2H); Mass spectrum (m/e): 453,5 (M+1).

Compound 163:

1H NMR (CD3OD, 400 MHz): δ at 8.60 (s, 1H), 8,53-of 8.50 (d, J=10.0 Hz, 1H), 8,12-8,10 (m, 2H), to 7.99 (s, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,84-of 7.82 (d, J=8.0 Hz, 1H), 7,44-7,41 (t, J=7,6 Hz, 1H), 7,33-7,31 (d, J=7.2 Hz, 1H), 7,19-to 7.18 (d, J=2,8 Hz, 1H), 6,86-6,85 (d, J=3.6 Hz, 1H), 3,94-3,91 (t, J=6,8 Hz, 2H), 3,56 (s, 1H), 3,26 is 3.23 (m, 2H), 3,03 (s, 3H), 2,30-of 2.26 (m, 2H); Mass spectrum (m/e): 448,4 (M+1).

Example 164: Synthesis of 3-(2-(diethylamino)ethyl)-1-(4-(3-ethynylphenyl)-7-florinopolis-6-yl)-1H-imidazol-2(3H)-he (Compound 164)

The way of synthesis of compound 164 shown below:

2-Amino-4-fermenting acid (1.55 g, 10 mmol) was dissolved in formamide (5 ml) and stirred at 150aboutC for 6 hours. The mixture was cooled to room temperature under stirring. The precipitate was filtered and washed with diethyl ether, obtaining 1.3 g of 7-florinopolis-4-ol (78%).

7-Florinopolis-4-ol (1 g, 6.0 mmol) was dissolved in concentrated H2SO4(3 ml) at 0°C. for 15 minutes was added dropwise with stirring a concentrated HNO3(3 ml). The mixture was stirred at 100aboutC for 3 hours and cooled to room temperature. The mixture was poured into a mixture of ice-water with stirring. The precipitate was filtered and recrystallized from HOAc, receiving of 0.60 g of 7-fluoro-6-nitroquinazoline-4-ol 38%).

7-Fluoro-6-nitroquinazoline-4-ol (518 mg, 2 mmol) was dissolved in chloride tionale (3 ml)containing 2 drops of DMF. The solution was heated at the boil under reflux for 3 hours. The solvent was removed under reduced pressure, obtaining 4-chloro-7-fluoro-6-nitroquinazoline, which was used directly in the next stage without purification.

4-Chloro-7-fluoro-6-nitroquinazoline and 3-ethynylbenzoate (234 mg, 2 mmol) was dissolved in isopropanol (5 ml). The mixture was heated at the boil under reflux for 3 hours and cooled to room temperature. The precipitate was filtered and washed with water, getting a 0.59 g of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazoline-4-amine (95%).

A mixture of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazoline-4-amine (310 mg, 1 mmol) and SnCl2·2H2O (171 mg, 4.5 mmol) in ethyl acetate (35 ml) was heated at the boil under reflux for 2 hours. After cooling to room temperature, the mixture was treated with 5%aqueous solution of NaHCO3to bring its pH to 9-10, and then was extracted with EtOAc. The organic layers were washed with saturated salt solution and H2O and dried. The solvent was removed under reduced pressure, receiving 225 mg (81%) of N4-(3-ethynylphenyl)-7-florinopolis-4,6-diamine in the form of a solid yellow color.

N4-(3-ethynylphenyl)-7-florinopolis-4,6-diamine (50 mg, 0.18 mmol) was dissolved in DMF (2 ml)containing Piri is in (of 17.5 μl, 0.21 mmol). To the mixture was added phenylcarbamate (23 μl, 0.18 mmol) at room temperature and was stirred at 70°C for 1 hour, receiving phenyl 4-(3-ethynylphenyl)-7-florinopolis-6-ylcarbamate. Added Nl-(2,2-diatexite)-N2,N2-diethylether-1,2-diamine (42 mg, 0.18 mmol) and stirred at 70°C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated and was purified on a column of silica gel, receiving 45 mg (70%) of 1-(2,2-diatexite)-1-(2-(diethylamino)ethyl)-3-(4-(3-ethynylphenyl)-7-florinopolis-6-yl)urea.

To a solution of 1-(2,2-diatexite)-1-(2-(diethylamino)ethyl)-3-(4-(3-ethynylphenyl)-7-florinopolis-6-yl)urea (45 mg, 0.08 mmol) in DMF (2 ml) was added p-toluensulfonate acid (28.5 mg, 0.15 mmol). The mixture was stirred at 80°C for 1 hour and then cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and saturated salt solution. The organic layer was concentrated and was purified on a column of silica gel, receiving the connection 164 in the form of a solid yellow color with 90% yield.

1H NMR (DMSO-d6, 400 MHz): δ 10,18 (s, 1H), 8,89 (d, J=8.0 Hz, 1H), 8,67 (s, 1H), of 8.06 (s, 1H), to 7.93 (d, J=7,6 Hz, 1H), 7,65 (d, J=11.2 Hz, 1H), 7,42 (t, J=8.0 Hz, 1H), 7,25 (d, J=7.2 Hz, 1H), to 6.88 (s, 1H) 6.87 in (d, J=2,8 Hz, 1H), 4,24 (s, 1H), 3,66 (t, J=2,8 Hz, 2H), 2,66 (t, J=6.4 Hz, 2H), 2.49 USD of $ 2.53 (m, 4H), 0,98 with 0.93 (m,6H); Mass when ECTR (m/e): 445 (M+1).

Example 165: Synthesis of 3-(2-(diethylamino)ethyl)-1-(4-(3-ethynylphenyl)-7-methoxyquinazoline-6-yl)-1H-imidazol-2(3H)-he (Compound 165)

The way of synthesis of compound 165 shown below:

Sodium (92 mg, 4 mmol) was dissolved in methanol (4 ml) under nitrogen atmosphere at 0°C. was Added 7-fluoro-6-nitroquinazoline-4-ol (418 mg, 2 mmol). The mixture was heated at the boil under reflux for 3 hours, cooled to room temperature and was treated with 2N HCl to bring its pH to 3-4. After concentrating the mixture, the residue was diluted with ethyl acetate and washed twice with water. The organic layer was concentrated, getting 405 mg (92%) of 7-methoxy-6-nitroquinazoline-4-ol.

7-Methoxy-6-nitroquinazoline-4-ol was converted in connection with 165 in a manner similar to that described in example 160.

1H NMR (DMSO-d6, 400 MHz): δ 9,98 (s, 1H), 8,69 (s, 1H), 8,63 (s, 1H), with 8.05 (s, 1H), 7,92 (d, J=7.2 Hz, 1H), 7,35-7,29 (m, 2H), 7,21 (d, J=7,6 Hz, 1H), 6.75 in (d, J=2.0 Hz, 1H), return of 6.58 (d, J=2,8 Hz, 1H), 4,15 (s, 1H), 3,91 (s, 3H), of 3.64 (t, J=7,6 Hz, 2H), 2,65 (t, J=7.2 Hz, 2H), 2,58 (m, 4H), of 0.97 (m,6H); Mass spectrum (m/e): 457 (M+1).

Examples 166-170: Synthesis of compounds 166-170

Connection 166-170 by using a method similar to that described in example 165.

Compound 166:

1H NMR (DMSO-d6, 400 MHz): δ 9,90 (s,1H), 8,67 (s, 1H), to 8.62 (s, 1H), 8,08 (s, 1H), 7,92 (d, J=8,4 Hz,1H), 7,42-7,37 (m, 2H), 7,21 (d, J=7,6 Hz, 1H), 6,72 (s, 2H), 4,22 (s, 1H), 3,95 (s, 3H), of 3.77 (t, J=2,8 Hz, 2H), 3,59 (t, J=4,8 Hz, 2H), and 3.31 (s, 3H); the ACC-spectrum (m/e): 416 (M+1).

Compound 167:

1H NMR (DMSO-d6, 400 MHz): δ 9,94 (s, 1H), 8,69 (s, 1H), to 8.62 (s, 1H), of 8.09 (s, 1H), to 7.93 (d, J=7,6 Hz, 1H), 7,42-7,37 (m, 2H), 7,21 (d, J=7,6 Hz, 1H), 6,79 (d, J=2.4 Hz, 1H), 6.73 x (d, J=2.4 Hz, 1H), 4,22 (s, 1H), 3,94 (s, 3H), of 3.75 (t, J=2,8 Hz, 2H), 3,68 is 3.57(m,4H)and 3.59 (t, J=4,8 Hz, 2H), of 2.51-2,48 (m, 4H); Mass spectrum (m/e): 471(M+1).

Compound 168:

1H NMR (DMSO-d6, 400 MHz): δ 9,90 (s, 1H), 8,66 (s, 1H), to 8.62 (s, 1H), 8,08 (s, 1H), 7,92 (d, J=8.0 Hz, 1H), 7,42-7,37 (m, 2H), 7,21 (d, J=7.2 Hz, 1H), 6,76 (d, J=2,8 Hz, 1H), 6,70 (d, J=2,8 Hz, 1H), 4,24 (s, 1H), 3,94 (s, 3H), 3,71 (t, J=6.0 Hz, 2H), has 2.56 (t, J=8,4 Hz, 2H), 2,42 (s, 8H), was 2.34 (s, 3H); Mass spectrum (m/e): 484 (M+1).

Compound 169:

1H NMR (DMSO-d6, 400 MHz): δ 9,94 (s, 1H), 8,69 (s, 1H), to 8.62 (s, 1H), 8,08 (s, 1H), 7,92 (d, J=8.0 Hz, 1H), 7,41-7,35 (m, 2H), 7,21 (d, J=7,6 Hz, 1H), 6,76 (d, J=2.4 Hz, 1H), 6,72 (d, J=2.4 Hz, 1H), 4,24 (s, 1H), 3,93 (s, 3H), and 3.72 (t, J=6,8 Hz, 2H), 2,46-of 2.50 (m, 6H), of 1.80 (t, J=7.2 Hz, 2H), 1,00-to 0.96 (m, 6H); Mass spectrum (m/e): 471 (M+1).

Compound 170:

1H NMR (DMSO-d6, 400 MHz): δ 9,92 (s,1H), 8,67 (s, 1H), 8,65 (s, 1H), 8,07 (s, 1H), to $ 7.91 (d, J=8,8 Hz, 1H), 7,43-7,39 (m, 2H), 7,22 (d, J=7.2 Hz, 1H), 6,78 (s, 2H), 4,49 (d, J=2.0 Hz, 2H), 4,23 (s, 1H), 3,95(s,3H); Mass spectrum (m/e): 396 (M+1).

Example 171: Inhibition of EGFR activity

Cells A431 (squamous cell carcinoma) was sown in DMEM (modified by way of Dulbecco Wednesday Needle) 2,5x104cells/well in 96-well plates and incubated over night. The DMEM was removed, and the tablets were washed in 200 μl containing no serum medium DMEM. After the medium was removed, each well add ulali 90 µl containing no serum medium DMEM. Tablets are again incubated overnight.

Each test compound was dissolved in DMSO containing (5%) medium DMEM without fetal calf serum (FBS) to obtain series solutions in concentrations 10, 3,3, 1,1, 0,37, 0,12, 0,04, 0,013 and of 0.004 μm. Solutions of the compounds in various concentrations was added to the wells (10 μl/well) except the control wells. The plates were incubated in an atmosphere of 5% CO2at 37°C for 60 minutes. In each of the holes processed by the connection, and in some of the control wells were added 10 μl of a solution of 200 ng/ml EGF (Biosource, PHG0064) followed by incubation in an atmosphere of 5% CO2at 37°C again for 45 minutes.

After removal of the medium in each well was added 100 μl of cell lisanova buffer containing 50 mm Tris-Cl (pH 8.0), 0.5 M NaCl and 0.2 mm EDTA, 0,1% Triton X-100 and protease inhibitors (1 μg/ml Aprotinin, 0,75 μg/ml leupeptin, 1 μg/ml of pepstatin, 1mm DTT, 500 μm sodium Vanadate, and 1 mm PMSF). Note that the protease inhibitors were added immediately before use. The cell lysate was kept at -80°C during the night.

100 μl of 0.5 μg/ml antibodies against EGFR (Perkin Elmer, AF231) in PBS was added to the 96-hole yellow tablet kits are used (Perkin Elmer, AAAND-0001), and incubated at 25°C overnight with gentle shaking. The medium was removed, and the plate was washed 3 times using 200 μl of wash buffer kits are used. To initiate the process is URS block was added 200 μl of blocking buffer (PBS buffer, containing 0,137 M NaCl, 0,0027 M KCl, 0.01 M Na2PO4-12H2O 0,0015 M KH2PO4, pH=7.4 and 1% BSA). Tablet incubated at 25°C for 1 hour with gentle shaking.

Blocking buffer was removed and the plate washed 3 times using 200 μl of wash buffer kits are used (PBS buffer containing 0.05% Tween-20). Then to each well was added 80 μl of diluent (20 mm Tris-Cl/pH7,3, 150 mm NaCl, 0.1% BSA and 0.05% Tween-20) and 20 μl of the above cell lysate. Incubation was continued at 25°C for 1 hour with gentle shaking.

The tablet again washed 3 times using 200 μl of wash buffer kits are used. Added 100 μl of 0.5 μg/ml antibodies Eu-PT66 (Perkin Elmer, AD0040) in the buffer for analysis kits are used (Perkin Elmer, 1244-106) was added and incubated at 25°C for 1 hour with gentle shaking. After 3 times washing using 200 ál wash buffer kits are used) was added 100 μl of amplifier kits are used (Perkin Elmer, 4001-0010). Incubation was continued at 25°C for 30 minutes with gentle shaking.

Fluorescence was measured at 620 nm using a Victor3(excitation at 340 nm and emission at 620 nm). The degree of inhibition was calculated as follows:

where signal-hole connection" represents the fluorescence measured for the wells that contained cells, test Obedinenie and EGF; "signal the wells with cells" represents the fluorescence measured for the wells that contained cells, but did not contain the test compound and EGF; and signal holes with EGF represents the fluorescence measured for the wells that contained cells and EGF, but did not contain the test compound.

The values of the IC50(the concentration required for inhibition of EGFR activity by 50%) was subsequently calculated using the software XL-Fit 2.0.

The results show that all connections 1-170 inhibited the activity of EGFR. The values of the IC50ranged from 0.001 μm to 10 μm.

Other embodiments of the

All features of the invention disclosed in this specification may be combined in any combination. Each hallmark, disclosed herein, can be replaced by an alternative hallmark, which is in the same, equivalent or similar purpose. Thus, if it is not clear from the other, each distinctive feature is opened only as an example of a generic series of equivalent or similar distinctive signs.

From the above description, the person skilled in the art can easily find out the essential characteristics of this invention and, without departing from its spirit and essence, can make various changes what is possible and modifications of the invention, in order to adapt it to various uses and conditions. For example, can be obtained and used for the practical implementation of the present invention, compounds structurally similar to the compounds according to this invention. Thus, other embodiments of the present invention is also included in the scope of the claims.

1. The compound of the following formula:

where each of R1, R2and R5independently, represents H;
one of R3and R4represents a

where n represents 1 or 2;
each Raindependently, represents H, C1-10alkyl, optionally substituted Deputy selected from the group comprising C1-10alkoxy, C1-10alkanesulfonyl, carboxypropyl, 5-6-membered monocyclic heteroseksualci having one or more heteroatoms selected from O and N, where the N atom may be substituted C1-10the alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl having one or more heteroatoms selected from N and S, 7-membered bicyclic heteroseksualci with 2 N atom; C2-10alkenyl; C2-10quinil; cycloalkyl, represent a saturated cyclic group containing 3-6 carbon atoms;
each and the R band Rcindependently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rband Rctogether with the nitrogen atom to which they are attached, form a bicyclic ring of the following formula:

where each of m1, m2, m3and m4independently, represents 0, 1 or 2;
And represents CH; a represents a NR, where R represents H or C1-10alkyl; and each of Ri, Rii, Riii, Riv, Rv, Rvi, Rviiand Rviiirepresents H;
or 6-7-membered monocyclic heteroseksualci containing 1-2 N atom, optionally substituted Deputy selected from the group comprising hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted C3-6cycloalkyl; and each of Rdand Reindependently, represents H, C2-10alkenyl; C2-10quinil; or (C1-10alkyl, optionally substituted Deputy selected from the group comprising From1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heteroseksualci having 1 or 2 N atom, optionally substituted C1-10by alkyl, halogen or 5-6-membered heterocyclization with 1 N atom, phenyl, optionally substituted with halogen, cyclol the sludge, represent a saturated cyclic group containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl containing one or 2 N atom; or Rdand Retogether with the nitrogen to which they are attached, form a 5-6-membered saturated heteroseksualci having 1-2 heteroatom selected from N and O, optionally substituted Deputy selected from the group comprising From1-10alkyl (which is optionally substituted C3-6cycloalkyl,1-10alkoxy, halogen), 5-membered heteroseksualci having one N atom, halogen, C1-10alkanesulfonyl,1-10alkylsulphonyl, optionally substituted with halogen; or Rdand Retogether with the nitrogen to which they are bound, form a 7-10-membered, saturated, bicyclic heteroseksualci containing 1-2 heteroatoms selected from N and O, optionally substituted C1-10by alkyl;
and the other of R3and R4represents H, halogen or1-10alkoxy;
X represents NRfwhere Rfrepresents H;
Y represents phenyl, substituted C2-4the quinil; and
Z represents N.

2. The compound according to claim 1, where one of R3and R4represents a

where n is 1, Rarepresents N, and each of Rband Rcindependently, represents H or C1-10/sub> alkyl, optionally substituted C1-10alkoxy.

3. The compound according to claim 1, where one of R3and R4represents a

where n represents 1 or 2; Rarepresents H; and Rband Rctogether with the nitrogen atom to which they are bound, form a 6-7 membered monocyclic heteroseksualci containing 1-2 N atom, optionally substituted Deputy selected from the group comprising hydroxyl,1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted C3-6cycloalkyl.

4. The compound according to claim 1, where Rband Rctogether with the nitrogen atom to which they are attached, form a bicyclic ring of the following formula:

where each of m1, m2, m3and m4independently, represents 0, 1 or 2;
And represents CH; a represents a NR, where R represents H or C1-10alkyl; and each of Ri, Rii, Riii, Riv, Rv, RviRviiand Rviiirepresents N.

5. The compound according to claim 1, where one of R3and R4represents a

in which Rarepresents H, C1-10alkyl, optionally substituted Deputy selected from the group comprising C1-10alkoxy, C 1-10alkanesulfonyl, carboxypropyl, 5-6-membered monocyclic heteroseksualci having one or more heteroatoms selected from O and N, where the N atom may be substituted C1-10the alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl having one or more heteroatoms selected from N and S, 7-membered bicyclic heteroseksualci with 2 N atom; C2-10alkenyl; C2-10quinil; cycloalkyl, represent a saturated cyclic group containing 3-6 carbon atoms.

6. The compound according to claim 1, where one of R3and R4represents a

in which Rarepresents N, and each of Rdand Reindependently represents a C2-10alkenyl; C2-10quinil; or (C1-10alkyl, optionally substituted Deputy selected from the group comprising From1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heteroseksualci having 1 or 2 N atom, optionally substituted C1-10by alkyl, halogen or 5-6-membered heterocyclization with 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, represent a saturated cyclic group containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl having one or 2 atoms n

7. The compound according to claim 1, where the Institute of R 3and R4represents a

in which Rarepresents H; and Rdand Retogether with the nitrogen to which they are attached, form a 5-6-membered saturated heteroseksualci having 1-2 heteroatom selected from N and O, optionally substituted Deputy selected from the group comprising C1-10alkyl (which is optionally substituted C3-6cycloalkyl,1-10alkoxy, halogen), 5-membered heteroseksualci having one N atom, halogen, C1-10alkanesulfonyl,1-10alkylsulphonyl, optionally substituted with halogen; or Rdand Retogether with the nitrogen to which they are bound, form a 7-10-membered, saturated, bicyclic heteroseksualci containing 1-2 heteroatoms selected from N and O, optionally substituted C1-10the alkyl.

8. Connection, representing a compound selected from the following:

9. The pharmaceutical composition inhibiting EGFR activity, containing an effective amount of a compound according to claims 1 to 8 and a pharmaceutically acceptable carrier.

10. A method of treating cancer, comprising introduction the needy in this subject an effective amount of a compound according to claims 1-8.

11. The method according to claim 10, where the cancer is a lung cancer, head and neck cancer, colorectal cancer or pancreatic cancer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-[5-(3-dimethylamino-acryloyl)-2-fluorophenyl]-N-methylacetamide of formula (I). The method is realised by reacting N-(5-acetyl-2-fluorophenyl)-N-methylacetamide of formula (VI) with excess N,N-dimethylformamide dimethylacetal (NNDMF-DMA) in the presence of a nonpolar solvent at temperature of 70-90°C. The invention discloses a method of producing a N-{2-fluoro-5-[3-(thiophene)-2-carbonyl-pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methylacetamide compound of formula (II), which involves methylation of N-(5-acetyl-2-fluorophenyl)-acetamide at temperature of 15-50°C, reacting the obtained compound of formula (VI) with NNDMF-DMA, and reacting the obtained compound of formula (I) with (5-amino-1H-pyrazol-4-yl)thiophen-2-yl-methanone in glacial acetic acid at temperature of 60-90°C in the presence of an aliphatic alcohol. The invention also relates to an intermediate compound of formula (VI).

EFFECT: improved method of producing a compound which is an intermediate compound in synthesis of compounds with affinity for the GABAA receptor.

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel imidazopyridine or imidazopyrimidine derivatives of formula (I) and to pharmaceutically acceptable salts and esters thereof, where A is N or C(R6); R1 is hydrogen, lower alkyl; R2 is halogen, C(O)NR7R8 or C(O)OR9; R3 is hydrogen, NR10R11; R4 is hydrogen, lower alkyl; R5 is phenyl or thiazolyl or pyridine, which can be substituted with one substitute independently selected from a group consisting of halogen; R6 is hydrogen, halogen, CN, C3-C6cycloalkyl; R7 and R8 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, fluoro-lower alkyl, C3-C6cycloalkyl, N(H,lower alkyl)-lower alkyl, hydroxy- lower alkyl, hydroxy-lower alkoxy- lower alkyl, N(lower alkyl2)C(O)- lower alkyl, lower alkoxy, hydroxy-lower alkyl-oxetanyl- lower alkyl, oxo-tetrahydrofuranyl, tetrahydrofuranyl-lower alkyl, hydroxy-fluoro-lower alkyl, tetrahydrofuranyl, phenyl and thiazolyl or pyridine, or R7 and R8 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of pyrrolidinyl, azetidinyl, morpholinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, 3,4-dihydro- 1H-pyrrolo[1,2-a]pyrazinyl, 2-oxa-6-aza-spiro[3.3]heptyl, 5,6-dihydro- 8H-imidazo[1,2-a]pyrazinyl, [1,4]oxazepanyl, piperazinyl, thiomorpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl, where the heterocyclyl is optionally substituted with 1 or 2 substitutes independently selected from a group consisting of halogen, lower alkyl, lower alkyl-C(O), lower alkoxy-lower alkyl, oxo, hydroxy, hydroxy-lower alkyl, N(lower alkyl2); R9 is lower alkyl; R10 and R11 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of piperidinyl, morpholinyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel imidazopyridine or imidazopyrimidine derivatives which are PDE10A inhibitors.

24 cl, 94 ex

FIELD: chemistry.

SUBSTANCE: described are novel triazolopyridazines of general formula , stereoisomeric or tautomeric forms thereof and physiologically acceptable salts thereof, where Q1 denotes H, -C1-6alkyl, optionally substituted with fluorine, or -C3-6cycloalkyl; Q2 and Q3 independently denote H, -C1-6alkyl; R1-R3 independently denote H, -C1-6 alkyl, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -O-C1-8alkyl, a heterocyclic residue etc; R4-R8 independently denote H, -C1-6 alkyl, -OH, -O-C1-8 alkyl, halogen, SF5 etc, a method for production thereof and use as medicinal agents.

EFFECT: compounds have antithrombotic activity and particularly inhibit the protease-activated receptor.

6 cl, 2 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formulas

and or pharmaceutically acceptable salts thereof, wherein the values R1-R13, Ra, Rb, Rc, Rd, Rf, Rq, n are presented in the patent claim possessing the properties of protein p53 activator.

EFFECT: compounds may be used in treating cancer and diseases caused by a fungal, bacterial or parasitic infection, eg malaria.

16 cl, 38 dwg, 12 tbl, 16 ex

Solid forms // 2496780

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to crystalline forms of 4-[9-(tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino]cyclohexan-1-ol of formula , which have kinase inhibiting properties and can be used to treat or prevent: (a) cancer; (b) an inflammatory condition or (c) an immunologic condition. The invention particularly relates to a crystalline form A, having an X-ray powder diffraction pattern with peaks at about 12.4, 16.0 and 18.5°2θ and further has peaks at about 17.7, 23.2 and 24.1°2θ; a hydrate crystalline form A, having an X-ray powder diffraction pattern with peaks at about 6.5, 13.0 and 23.0°2θ and further has peaks at about 13.4, 20.1 and 23.8°2θ; a crystalline form of a hydrochloride salt A, having an X-ray powder diffraction pattern with peaks at about 17.3, 18.7 and 22.4°2θ, and contains about two mole equivalents of chloride ions.

EFFECT: invention relates to methods of producing a crystalline form A, a pharmaceutical composition containing said crystalline forms and a treatment method.

15 cl, 16 dwg, 9 ex

FIELD: medicine.

SUBSTANCE: present invention describes compounds of formula I: wherein: X1 and X2 independently represent CH or N; R1 represents fluorine or hydrogen; R2 represents hydrogen, halogen; Ar represents phenyl substituted by 1-3 groups optionally substituted in each specific case in a group consisting of hydrogen, halogen, cyano group; R3 is independently specified in each specific case in a group consisting of: (i) CH2OH; (ii) CH2O-C(=O)(CH2)nCO2R4, wherein n has a value of 2 to 5; (iii) CH2O-C(=O)CH2OCH2CO2R4; (iv) CH2OCOR5; (v) CH2OC(=O)CHR6NH2; (vi) C(=O)R5, and (vii) CH2OP(=O)(OH)2; R4 represents hydrogen or C1-10 alkyl; R5 represents hydrogen or C1-10 alkyl, C1-3 dialkylamino-C1-10 alkyl, C1-6 alkoxy or pyridinyl, R6 represents C1-6 alkyl or a side chain of a natural amino acid; or a pharmaceutically acceptable salt thereof. Besides, the invention describes a pharmaceutical composition having HTVRT inhibitory activity and containing a compound according to cl.1.

EFFECT: there are prepared and described new compounds inhibiting HIV-1 reverse transcriptase and effective for preventing and treating HIV-1 infections and treating AIDS or ARC.

13 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new triazolium salts of general formula (I) stereo- and tautomer forms and physiologically acceptable salts thereof, wherein X- C-R1 or N, R1-hydrogen, C1-6alkyl or halogen; A- is an anion of a pharmacologically acceptable organic or inorganic acid; Q1 is hydrogn, -C1-6alkyl optionally substituted, -C3-6cycloalkyl, -C(O)-O-R11 or - C(O)-R11; R11 -C1-6alkyl; Q2 and Q3 are hydrogen; R2- R9 independently mean hydrogen, -C1-6alkyl optionally substituted, -O-(C1-8)alkyl optionally substituted, etc., and using the above compounds as a drug preparation.

EFFECT: compounds possess antithrombotic activity, particularly, they inhibit the protease-activated receptor 1 (PAR1), and may be used in treating the diseases such as myocardial infarction, angina, stroke, and others.

4 cl, 2 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: described is a sodium salt of 2-methyl-6-fluoro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7(4H)-one , having antiviral activity with respect to influenza virus A(H1N1).

EFFECT: improved properties of the compound.

1 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes pyrrolo[2,3-d]pyrimidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof, where R1 is C1-4 alkyl, optionally substituted with a hydroxy group, as well as a crystalline form A of a salt of N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl} methane sulphonamide with maleic acid. Disclosed also is a method of producing a salt of N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl} methane sulphonamide with maleic acid.

EFFECT: improved properties of the composition, having inhibiting activity on Janus kinase and a method of treating allergic reactions, allergic dermatitis, atopic dermatitis, eczema or itching in mammals.

17 cl, 7 ex, 4 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and/or stereoisomeric forms thereof and/or mixtures of said forms in any ratio and/or a physiologically tolerant salt of the compound of formula , where: X denotes -C(O)- or -SO2-, U denotes an oxygen atom or -(C0-C4)alkylene, A denotes an oxygen atom, -C(O)-NH-, -NH-C(O)- or -(C0-C4)alkylene, V denotes: 1) -(C2-C9)alkylene, where alkylene is unsubstituted or mono-, di- or tri-substituted, independently of each other, by an -OH group, 2) -(C3-C9)alkenylene, D denotes -(C1-C2)alkylene, Y denotes: 1) a covalent bond, 2) -(C6-C14)arylene-, or 3) Het, where Het denotes pyridyl or imidazolyl, R1 denotes: 1) a hydrogen atom, 2) -(C1-C6)alkyl, R3 denotes: 1) -(C2-C6)alkylene-NH2, 2) -(C1-C4)alkylene-SO2-(C1-C4) alkylene-NH2 or 3) -(C0-C4) alkylene-Het, where Het denotes pyridyl or piperidyl, where Het is unsubstituted or substituted with -NH2, R6 denotes: 1) a hydrogen atom, 2) -(C1-C6) alkyl, where the alkyl is unsubstituted or substituted, independently of each other, by a R16 group, 3) -(C0-C4) alkylene-Het, where Het denotes pyridyl, where -(C0-C4) alkylene and Het are unsubstituted or substituted, independently of each other, by a R16 group, 4) -(C0-C4) alkylene-phenyl, where -(C0-C4) alkylene and phenyl are unsubstituted or substituted, independently of each other, by a R16 group, or 5) -(C0-C4) alkylene-(C3-C8)cycloalkyl, R7 denotes a hydrogen atom, halogen or -(C1-C6)alkyl, R8 denotes a hydrogen atom or -(C1-C6)alkyl, R9 denotes a hydrogen atom, and R16 denotes -NH2, which are inhibitors of the active thrombin-activated fibrinolysis inhibitor, as well as a method for production thereof, a medicinal agent based thereon and use for prevention, secondary prevention and treatment of one or more disorders associated with thrombosis, embolism, hypercoagulation or fibrosis changes.

EFFECT: improved properties of compounds.

7 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: starting substances used are thiosemicarbazide, acetic anhydride, sodium hydroxide, monochloroacetic acid; the liquid medium used is 95% ethanol and purified water, wherein the thiosemicarbazide is dissolved in the purified water, the reaction mass is cooled to 0°C±0.5°C and while mixing, acetic anhydride is added at such a rate that temperature of the reaction mass does not rise above 4°C; after adding all the acetic anhydride, the mass is mixed for another 20-30 minutes at temperature not higher than 1°C±1°C; the precipitate is filtered, washed with cooled water (2-4°C), pressed and the purified water and the obtained moist precipitate are then placed in a round-bottom flask with a mixer; while stirring for 0.5-1 hours, sodium hydroxide solution is added to the reaction mass and then boiled for 1 hour; the monochloroacetic acid is then added to water, stirred for 30 minutes and boiled for 1 hour, cooled to 2-4°C; the precipitate is filtered, washed with cold water thrice and twice with cold 95% ethanol; the obtained moist precipitate is transferred into the round-bottom flask with a mixer; 95% ethanol is added, stirred and while stirring, morpholine solution is added to 95% ethanol, boiled while stirring for 30 minutes and then cooled to 85-90°; activated carbon is added, boiled for 10-20 minutes; the carbon is filtered, the filtrate is cooled to 4-5°C, the precipitate of the end product is filtered, washed with 95% ethanol and dried at 50-70°C.

EFFECT: high output of the end product, high quality of said product, cheap production and faster process.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I , in which X1, X2, X3, X4 and X5 independently denote -CH- or N; or X3, X4 and X5 independently denote -CH- or N, and X1 and X2 independently denote C and are part of an additional 6-member aromatic ring; in which R1 denotes methyl or ethyl, or R1 denotes hydrogen; R2 denotes methyl, ethyl, propyl, tert-butoxy carbonylmethyl, allyl, difluoromethyl, ethylbenzene, methylbenzene, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butynyl, propynyl, methylcarbonyloxy, cyclopentyl, each of which can be substituted with one or more identical or different substitutes selected from R5; or R2 denotes hydrogen; R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, halogenalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, each of which can be substituted with one or more identical or different substitutes selected from R6; or R3 denotes hydrogen, -CH2-C(O)-heterocycloalkyl or -CH2-C(O)NR9-R12; R11 denotes one or more identical or different substitutes selected from hydrogen, halogen, cyano, amino, alkyl, methylthionyl, methylsulphonyl, amino, cyano or alkoxy; where R5, R6, R9, R12 are as indicated in claim 1, under the condition that R1, R2 and R3 cannot be methyl at the same time; under the condition that when R2 and R3 both denote hydrogen, R1 cannot be methyl or hydrogen; under the condition that when R1 denotes methyl or hydrogen, R2 denotes methyl and R3 denotes hydrogen when ring B cannot be phenyl; and pharmaceutically acceptable salts and N oxides thereof. The invention also describes a pharmaceutical composition for use in case of skin diseases, said composition containing a compound of formula I, and use of said compound in preparing a medicinal agent for preventing conditions associated with skin wounds.

EFFECT: novel compounds which can be useful in treating skin diseases are obtained and described.

19 cl, 304 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

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