UA82497C2 - thienopyridazinones and theair use - Google Patents

Abstract

The invention relates to thienopyridazinones compound of formula (I) wherein: R, Rand Q are as defined in the specification, and Ar and Arare selected from certain aromatic ring systems, which may be optionally substituted, as defined in the specification. Processes for the preparation of compounds of formula (I), pharmaceutical compositions containing them and their use in therapy is also described and claimed.

Description

Description of the invention

The invention relates to thienopyrimidinediones, processes for their preparation, pharmaceutical compositions containing 2 and their use in therapy. The invention also relates to their use in the modulation of autoimmune disease.

T cells play an important role in the immune response, but in autoimmune diseases, T cells are inappropriately activated against certain tissues and proliferate, causing, for example, the inflammation associated with rheumatoid arthritis. Inhibition of T-cell proliferation is beneficial in modulating autoimmune disease.

The invention relates to compounds useful in modulating autoimmune disease. 70 The invention relates to the compound of formula (1): t o On 15 ST

VU, Fr

And

Y A o M Z Ag-Ag and 1 s 25 Kk (o)

Where: r. 3o B" and B? each independently represent C1-alkyl, C3-valkenyl, C3-6cycloalkylC-4-alkyl or C3-6cycloalkyl, each of which can be, as an option, substituted by 1-3 halogen atoms;

O is SV", where K" is hydrogen, fluorine or C. alkyl, and KZ is hydrogen, fluorine or hydroxy; Cha

Ag is a 5-10-membered aromatic ring system in which up to 4 ring atoms can be He with heteroatoms independently selected from nitrogen, oxygen, and sulfur, and this ring system is optionally substituted with one or more substituents independently selected from S..lalkilu (as an option, replaced by 1, 2 or

with hydroxy groups), Sialkoxy, halogen, haloalkyl, dihaloalkyl or trihaloalkyl (where the alkyl groups respectively contain 1-4 carbon atoms), C.lalkoxyC. lalkyl, C-4alkylthio, C1-alkoxy-carbonyl,

Sodalkanoyl, oxo group, thioxo group, nitro group, cyano group, -M(VUV/ and -CHnorM(VUU, thydroxy, « 40 C. dalalkylsulfonyl, C. alkylsulfinyl, carbamoyl, C. alkyl-carbamoyl, / di-(C. lalkyl)carbamoyl , with c carboxy, XO; h Ag? is a 5- or b-membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, sulfur or oxygen, which may optionally be substituted by one or more groups , independently selected from

C.i.alkyl (as an option, substituted by 1, 2 or 3-ma hydroxy groups), C 44 alkoxy, halogen, haloalkyl, 45 dihaloalkyl or trihaloalkyl (where the alkyl groups, respectively, contain 1-4 carbon atoms), o Si lalkoxy-Si dalkylu, S..4alkylthio, Si. lalkoxycarbonyl, sodalkanoyl, oxo group, thioxo group, nitro group, t cyano group, -MSH(ВУ)" and -"СНо)рРМ(ВУ)ВУ, thydroxy, C. alkylsulfonyl, C. 4 alkylsulfinyl, carbamoyl,

C. dalkylcarbamoyl, di-(C. lalkyl)carbamoyl, carboxy, 5OoshchvZ in; p. is equal to from 1 to 4; se 20 25 of its KE" each independently represents a hydrogen atom, a Ci alkanoyl or a Ci 4 alkyl group, or together with the nitrogen atom to which they are attached, form a 5-7-membered saturated heterocyclic ring, which, as an option, additionally contains 0 , 5, MH or M-alkyl group; 28th KE each independently represents a hydrogen atom, C. 4-alkanoyl or C. dalalkyl group, or together with the nitrogen atom to which they are attached, form a 5-7-membered saturated heterocyclic ring, which optionally contains an additional 0, 5, MH or M-alkyl group;

HF) and its pharmaceutically acceptable salts and solvates, provided that the compound is not 5-(45)-4-hydroxyisoxazolidin-2-ylcarbonyl -phenyl-1H-pyrazol-4-ylmethylhyno|2,3-4|Ipyrimidine-2,4(1H,3H)-dione, 6-IZ,5-dimethyl-1-60 phenyl-1H-pyrazole-4 -ylmethyl|/|-5-((43)-4-hydroxyisoxazolidin-2-ylcarbonyl|-1-isobutyl-3-methylthieno|2,3-a4|-pyrimidine-2,4(1H,3H)-dione or 6-3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl/-5-((45)-4-hydroxyisoxazolidin-2-ylcarbonyl|-3-methyl-1-propylthieno|2,3 -4|Ipyrimidine-2,4(1H,ZH)-dione or their pharmaceutically acceptable salt or solvate.

B" is C-alkyl or C-cycloalkyl, in particular C-alkyl. It is preferable when K' is ethyl, propyl, butyl or 65 cyclopropyl. It is more preferable when KE! is ethyl, isobutyl, isopropyl or cyclopropyl. It is best when B is C. alkyl, for example, isobutyl or isopropyl.

Preferably, when B2 is C. alkyl, for example, ethyl or methyl, more preferably, methyl. a - SERE, where EK - hydrogen, S. valkyl, and KZ - hydrogen. Preferably, when C - SVE"B?, where B" and B? both are hydrogen.

Examples of 5- to 10-membered mono- or bicyclic aromatic ring systems for Ag are thienyl, furanyl, pyrrolyl, pyrrolopyridine, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl , tetrazolyl and quinolinyl.

Examples of 5-7-membered saturated heterocyclic rings formed by BO B and 8 and 29 include morpholine, piperidine, M-alkylpiperidine, piperazine, pyrrolidine, etc. Preferably, Ag is a 5- or b-membered aromatic ring system in which up to 2 ring atoms may be heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one or more substituents, independently chosen from S..lalkilu, Si. daloxy, halogen, halogensC..lalkyl, dihalogenS. 4 alkyls, trihalogens. dalkylai, oxogroup, thioxogroup, cyanogroup or C. dalkylsulfonyl.

More preferably, Ag is a 5-membered aromatic ring with two nitrogen atoms substituted as above.

A specific example of Ag is an optionally substituted pyrazole ring. Preferably, Ag is a substituted pyrazole ring.

It is best when Ag is a pyrazole ring disubstituted by C. alkyl, in particular, methyl.

For example, Ag is the corresponding group of the subformula (Her) to their sch

IS -

M o) and

AR m. () b "And where BK" and Kk" are independently selected from H, C. alkyl, halogenC. alkyl, dihalogenC. alkyl or C. trihalogenC. alkyl, and Ag is as defined above. co

BO" is selected from H or C alkyl, for example, methyl. In particular, both KO, EC" are C alkyl, for example, methyl.

Ag is a 5- or b-membered aromatic ring system in which up to C ring atoms can be heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring system is optionally substituted with one or more substituents independently selected from C-alkyl , C.-daloxy, halogen, - with dihaloalkyl, trihaloalkyl, oxo group, thioxo group, cyano group, C 1 -alkylsulfonyl. "» Preferably, when Ag? is not phenyl. In particular, Ag?" includes at least one heteroatom. " Examples of a haloalkyl group are haloalkyl groups, which include halomethyl groups, for example, fluorethyl groups. Examples of a dihaloalkyl group are dihaloalkyl groups, including difluoromethyl and dichloromethyl. Examples of a trihaloalkyl group are trihalogen. dalalkyl groups, for example, trifluoromethyl. In a preferred embodiment, Ag is a 5-membered aromatic ring containing nitrogen and sulfur atoms and is substituted as above. More preferably, Ag is a thiazole ring substituted with halogen, particularly fluorine. (Fe) 50 In another In an embodiment of the invention, Ag is pyridine or pyrimidine.The rings bear at least one substituent, but are preferably unsubstituted.

Preferably when Ah? is pyridinyl or pyrimidinyl.

Preferred compounds of formula (I) include: 6-(33,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl|methylyl-5-((45)-4-hydroxy-2-isoxazolidinyl)| carbonyl/|-3-methyl-1-(1-methylethyl)thieno(2,3-4|pyrimidine-2,А4(1Н,ЗН)-dione and

HF) 6-((3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl|methyl)-5-((45)-4-hydroxy-2-isoxazolidinyl)carbonyl|-3- m

F ethyl-1-(3-methylethyl)thieno|(2,3-4|Ipyrimidine-2,4(1H,ZB)-dione, and their pharmaceutically acceptable salts. Another preferred compound of formula (I) is (5) -2-I((6-(193,5-dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl|methyl/|-1,2,3,4-tetrahydro-3-methyl-1 -(1-methylethyl)-2,4-d ioxothieno|2,3-4|-pyrimidin-5-ylcarbonyl|)|-4-isoxazolidinol and its pharmaceutically acceptable salts.

Alkyl groups, alone or as part of another group, can be linear or branched. Unless otherwise specified, they may contain 1-6, preferably 1-4 carbon atoms. 65 It is clear that compounds of formula (I) or their salts can exhibit tautomerism; the drawings in this specification represent only one of the possible tautomeric forms. However, the invention includes any tautomeric form.

Some compounds of formula (1) can exist in stereoisomeric forms. The invention includes all geometric and optical isomers of compounds of formula (1) and their mixtures, including racemates. They also form an aspect of the invention.

Salts suitable for use in the pharmaceutical composition may be pharmaceutically acceptable salts, but other salts may also be useful in the preparation of compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula I sufficiently basic to form such salts. Such acid addition salts include, for example, salts with inorganic or organic acids that provide pharmaceutically acceptable anions, for example, with hydrohalic (in particular, hydrochloric or hydrobromic acid, preferably hydrochloric) or with 7/0 sulfate or phosphoric acids, or with trifluoroacetic, citric or maleic acids.

Suitable salts include hydrochlorides, hydrobromides, phosphates, sulfates, hydrosulfates, alkylsulfonates, arylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates. In addition, when the compounds of formula 1/ are sufficiently acidic, pharmaceutically acceptable salts may be formed with inorganic or organic bases that provide a pharmaceutically acceptable cation. Such salts with /5 inorganic or organic bases include, for example, alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts or, for example, Kk! methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Preferred salts include acid addition salts, for example hydrochloride, hydrobromide, phosphate, acetate, fumarate, homo maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or alkali metal salts, for example sodium or potassium.

According to a further aspect, the invention includes a method for the preparation of a compound of formula (I), which includes: (a) a reaction of a compound of formula (II): high school

Zo 5 U so o o - . and? in which BC! and K 2 are as defined in formula (I) or are protected derivatives thereof, and X and M are selected from C 1 -alkyl (optionally substituted with 1, 2 or 3 hydroxy groups), C 1 -alkyl, haloalkyl, dihaloalkyl , , y y (se) trihaloalkyl, Si dalkoxysS. dalalkyl, Si lalkoxy-carbonyl, "СНо)рМСХАУЗ У, "h with the compound of the formula (PP):

Ag2-051-02 (II) where is Ag? is as defined in formula (I) or is its protected derivative, and 21 is МН, 02 is МНо, ЗН or

OH, or (B) the reaction of the compound of the formula (IM): ko 60 b5 o

Co 5 E where in which B", B2, Ag and Ag? are those that were defined in formula (I) or are their protected derivatives, with the compound of formula (M) 0Оо-в сч

Ku o

НЙ, ) о и (2) "I c ( y ) (ge) in which P is a protecting group, or (c) for a compound of formula (I), where Ag has a MH group, the reaction of a compound of formula (MI): - "and; he with s g" M - and "in o so | M. v

FT"

And about "|and Ag (Se) -y I" . o (U) ki 5 ri;r2 : : : where Ki K- are as defined in formula (I), and Ag is as defined in formula (I) under the condition that Ag has MH group, or is its protected derivative, with a compound of the formula (MI):

Agg - And (MI) in which Ag? is the one defined in formula (I) or is its protected derivative, and | is a protected group, 65 and as an option, after performing operation (a), (5) or (c) in any order: - removal of protective groups

- formation of a pharmaceutically acceptable salt.

The reaction of compounds (II) and (I) is preferably carried out in an inert solvent, for example, ethanol, at a temperature from 09C to 1009C, preferably from 109C to 5092C, as an option, in the presence of a catalytic amount of acid, for example, trifluoroacetic acid.

The reaction of compounds (IM) and (M) is carried out by converting the carboxylic acid function into an activated form by reacting with a coupling agent, for example, EOSI and 1-hydroxybenzotriazole, in an inert solvent, for example, DCM, in the presence of a base, preferably triethylamine or ethyldiisopropylamine, at temperature from 02 to 1002C, preferably from 1092; to 502C, in the presence of compound (M).

The reaction of compounds (MI) and (MII) is carried out by heating in an inert solvent, for example, MMP in the presence of a base, for example, metal carbonate under microwave irradiation; or using a salt of Csh(i) with a diamine ligand under catalytic (or stoichiometric) Buchwald conditions, in a solvent, for example, dioxane, at a temperature of about 1002С. Group I. is any suitable leaving group, preferably when |. - halogen

Compounds of the formula (II) can be obtained by the reaction of the compound of the formula (MIP): x o o; re and i - si 25. M and their o "a shk: i. m 4 (2)

In which B, B, and P are as defined above, and I is a leaving group, with a nucleophilic fragment of the Ag group, for example, a zinc salt of beta-diketone. Preferably, when H! is a halogen, for example, bromine 2c Compounds of formula (III) can be obtained from compounds of formula (IX):

And" ' Oo-e che v. iv: what r - o ve and zm te; их 4 A; 5 o'clock ko 60 65 in which KO, BC? and Roe as defined above, for example, by bromination, using

M-bromosuccinamide in an inert solvent, for example, chloroform under light, at a temperature from 1590 to

802, preferably from 502C to 7090.

Compounds of formula (IX) can be obtained by protecting the corresponding alcohols of formula (X):

On ch ch

M.) "at 15. AH b t i y h B.

C) ch (8) in which KB", 2 and P are as defined above, for example, by reaction with a trialkylsilyl halide in an inert solvent, for example, DCM at a temperature from 09C to 602C, preferably from 109C to 309C, in the presence bases, for example, imidazole. Compounds of the formula (X) can be obtained from the acid of the formula (XII): (2)

Ж - с ом З " in so ko . » CO) (Ce) in which B", B2 and C are as defined above, by conversion to an acid chloride by treatment with a reagent, "and for example, oxalyl chloride, in an inert solvent, for example , DCM at a temperature from 09C to 602C, preferably from 109C to 309, with further treatment of the obtained anhydride chloride with hydroxyisoxazolidine in a solvent, for example, DCM at a temperature from 02C to 602C, preferably from 102 to 302C in the presence of a base, for example, triethylamine.

GF) Compounds of formula (XII) are obtained from the corresponding esters under standard conditions. t Compounds of formula (IM) can be obtained from compounds of formula (XII): 60 b5

: soda

And residential complex | eat

Kk g E yu (ХВ .

B. in which BO, KK? and Ag are as defined above, provided that Ag contains a MH group, and KO. is an ester-forming group, for example, reaction with a compound of formula (XII):

Ag?-halogen, (ХИИЙ) with de Ag? is as defined above, or by reaction with a compound Ag, where Ag is as defined above, provided that Ag has a nitrogen center.

The reaction of compounds (Xi) and (Xi) can be carried out in an inert solvent, for example, dioxane, at a temperature from 102C to 1202C in the presence of a copper (I) salt and alkylenediamine. Group 229 is an ester-forming group, for example, alkyl, in particular, methyl. -

The reaction of the compound (XII) and Ar" can be carried out in a solvent, for example, dimethylacetamide at a temperature from 1022 to 2002С in the presence of a base, for example, potassium carbonate, as an option, with microwave irradiation.

The compound of the formula (XII) can be obtained from the compound of the formula (ХМ): х с и со | ih sho s . » M. Z. and Fr

Her so Kk ko

FT"

F (XU)

Still you 1 2; ro : : in which KS, KK Her K- are as defined above, by reaction with a strong base, for example, lithium isopropylamide in a solvent, for example, THF, at a temperature of -782C to 09 followed by the addition of a compound of the formula (HMI):

Ag-SHO (HMI) (F. Compounds of the formula (IM) are obtained from compounds of the formula (HMI): ko 60 b5 a so,

Kk and; Huh. he "Zh A

OLTZHO7Z 0 Aevdr 7

AK in which B", 22 and 820. Ag and Ag? are as defined above, or by deoxygenation using a strong acid, e.g. TFC, in the presence of a hydride source, e.g. triethylsilane, alternatively, in a solvent, e.g. DCM, at a temperature from 109C to 4092C, or activation of the hydroxyl group by esterification with an inactivated carboxylic acid, for example, trifluoroacetic anhydride or methanesulfonyl chloride in an inert solvent, for example, ethyl acetate, followed by hydrolysis, for example, using palladium. /-: SEM on carbon at 1-5 bar and at 10-802C

Compounds of the formula (CHMI) are obtained from the compound of the formula (XU), defined above, by reaction with the compound (CHMI):

Ag2-Ag-CHO (HM) in which Ag and Ag? are as defined above under conditions similar to those used for the reaction of compounds (XM) and (XM). that

Compounds of the formula (MI) can be formed from compounds of the formula (Xi!) by hydrolysis of the ester function (from Ф) using alkali or alkaline-earth metal hydroxide in a water-containing solvent, for example, aqueous ethanol or methanol) at a temperature from 09C to 1009C, or by using aqueous inorganic - acid in an inert solvent at a temperature from 2097 to 1009, with subsequent coupling of the acidic Hezv residue with a compound of the formula (M) in the presence of a condensing agent, for example, RUVgOR in an inert co-solvent, for example, THF, in the presence of a base, for example, triethylamine, at a temperature from 09 to 3020.

The starting materials are as defined above. They are commercially available or can be obtained using conventional chemistry known to those skilled in the art.

The usefulness of the compounds of the invention lies in their pharmacological activity in humans and animals. they are prescribed as "pharmacological agents in the treatment (prophylaxis) of autoimmune, inflammatory, proliferative (KI z c hyperproliferative diseases and immunologically mediated diseases, including rejection of transplanted organs or tissues and AIDS. :z" Examples of such conditions are: (1) (respiratory tracts ) obstructive disease of the respiratory tract; asthma, in particular, bronchial, allergic,

Internal, external and dusty, chronic or persistent (for example, chronic asthma and hypersensitivity of the respiratory tract)); chronic obstructive pulmonary disease (COPD) (eg, irreversible COPD); bronchitis; acute, allergic, atrophic rhinitis or chronic rhinitis (for example, curdled rhinitis, hypertrophic rhinitis, purulent rhinitis, sicative rhinitis), medicinal rhinitis, membranous rhinitis (including croupous, fibrinous and their pseudomembranous rhinitis), seasonal rhinitis (including nervous rhinitis (hay fever) and vasomotor rhinitis); 5 o Varcoidosis; diseases related to farmer's lungs; fibroid lungs and related diseases and se) idiopathic intratissue pneumonia; "m (2) (bones and joints) rheumatoid arthritis, seronegative spondyloarthropathies (eg, ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Besse's disease, Sjorgen's syndrome, and systemic sclerosis; (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis, other eczematous dermatitis, bean seborrheic dermatitis, Gisnep riapis, pemphigus, pemphigus bullous, epidermolysis bullosa, urticaria, angioderma, vasculitis, erythema, skin eosinophils, chronic skin ulcers, uveitis, ulcerative areatacomne

GF) baldness and spring conjunctivitis;

F (4) (gastrointestinal tract) celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis; food allergies with an effect remote from the intestines (for example, migraine, rhinitis and eczema); (5) (other tissue and system diseases) multiple sclerosis, atherosclerosis, AIDS, lupus erythematosus; systemic lupus erythematosus; Hashimoto's thyroiditis, bulbospinal palsy, type I diabetes, nephrotic syndrome, Tazsiiv eosinophilia, hyper-(Z3E syndrome, lepromatous leprosy, Caesar's syndrome and idiopathic thrombocytopenia 65 (6) (allograft rejection) acute and chronic, after, for example, kidney, heart transplantation , liver, lung, bone marrow, skin, and cornea; and chronic graft rejection disease; and

(7) cancer.

Accordingly, the invention relates to a compound of formula (1) or a pharmaceutically acceptable salt thereof, defined above and intended for use in therapy

Another aspect of the invention is the use of the compound of formula (1) or its pharmaceutically acceptable salt, defined above, in the manufacture of a medicament for use in therapy.

Here, the term "therapy" also includes "prophylaxis" unless otherwise specified. The terms "therapeutic" and "therapeutically" should be understood accordingly.

Prophylaxis is especially appropriate in patients who already suffer from, or are considered more susceptible to, certain diseases or conditions. Individuals at risk for a given disease or condition generally include those with a family history of such diseases or those who have been shown by genetic testing or screening to be particularly susceptible to developing such diseases or conditions.

The invention also includes a method of providing immunosuppression (for example, in the treatment of allograft rejection), which includes administering to a patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, as defined above.

The invention further includes a method of treating or reducing the risk of respiratory tract diseases (eg, asthma or COPD) in patients suffering from these diseases or at increased risk of the disease, which comprises administering to said patient a therapeutically effective amount of a compound of formula (1) or its pharmaceutically acceptable salt, defined above.

In the above therapy, the dose of the compound administered depends on the type of compound, the route of administration, the type of therapy and the disorder for which the therapy is intended. However, in general, to create immunosuppression, the daily dose of the compound of formula (1) should be from 0.1mg/kg, preferably from 0.3mg/kg, more preferably from 0.5mg/kg, best from mg/kg to 30mg/kg patient's weight (inclusive). In the treatment of diseases of the respiratory tract, the daily dose of the compound of formula (1) should be from 0.001mg/kg to 30mg/kg of the patient's weight. with

Compounds of formula (1) and pharmaceutically acceptable salts thereof may be used as such, but most often they should be administered in the form of a pharmaceutical composition containing a compound of formula (1) or a salt/solvate thereof (8) (active ingredient) together with a pharmaceutically acceptable ad' excipient, diluent or carrier. Depending on the method of administration, the pharmaceutical composition preferably comprises from 0.05 to 9995 (by weight), preferably less than 0.10 to 7095 (by weight), preferably less than 5095 (by weight) of the active ingredient from the total weight of the composition.

Therefore, the invention also relates to a pharmaceutical composition containing a compound of formula (1) or b" a pharmaceutically acceptable salt, defined above, together with a pharmaceutically acceptable adjuvant, "U diluent or carrier.

The invention, in addition, relates to a method of preparing the pharmaceutical composition of the invention, which includes mixing the compound of formula (1) or its pharmaceutically acceptable salt, defined above, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention can be administered locally (for example, in the lungs and/or respiratory tract, on the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder compositions; or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules, or parenteral administration in the form of solutions or suspensions, or subcutaneously or rectally in the form of suppositories, with or transdermally.

The ability of compounds to inhibit PMA/Lonomycin-stimulated proliferation of peripheral blood mononuclear cells can be assessed, for example, using the procedure described below.

The invention is illustrated by the following Examples, in which, unless otherwise specified: () evaporation is carried out by rotary evaporation in a vacuum and processing procedures are carried out after the removal of solid residues by filtration, for example, drying agents; (i) operations are carried out at an external temperature, that is, at 18-25 9C and in an inert gas atmosphere, for example, argon or nitrogen; their output is for illustrative purposes only and is not always the maximum possible; (im) the structure of the final products of formula (I) is confirmed by nuclear (usually proton) magnetic resonance (NMR) and mass spectroscopy; the value of the proton magnetic resonance chemical shift is measured on the m delta scale, and the multiplicities of the peaks are marked: 5 - singlet; 4 - doublet; Hers is a triplet; t - multiplet; Bg - wide; 4 - quartet, acip - quintet; (m) intermediates do not receive full characterization at all, and purity is assessed by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), mass spectrometry (MS), infrared (IR), or NMR analysis; (F) Abbreviations t 2,3-dichloro-5,6-dicyano-1,4-benzoquinone - DDH

Dimethylformamide - DMF in Tetrahydrofuran - THF

Example 1 6-(33,5-dimethyl-1-(2-pyrimidinyl-1H-pyrazol-4-yl|methyl)-5-((45)-4-hydroxy-2-isoxazolidinyl)carbonyl/|-3-methyl -1-(1-methylethyl)thienoY2,3-4|Ipyrimidine-2,4H,ZH)-dione 2-methyl-5-(M,M-methylethylamino)-thiophene-3,4-dicarboxylate

Ethoxycarbonylmethylenetriphenylphosphorane (33.8g) in dry THF (200ml) is treated with isopropylisothiocyanate (10.1g) at 659 for 16 hours. under nitrogen. The mixture is cooled to -78 C and methyl is added

Z-bromo-2-oxobutanoate. The reaction is left to slowly warm to room temperature and after 24 h. at room temperature, methyl 3-bromo-2-oxobutanoate (2.8 g) is added and the mixture is heated at 609 for 16 hours. (5)

The cooled reaction is poured into water (1.5 l) and extracted into ether. Drying and evaporation give an oil which is chromatographed. (5105/10:1 isohexane-ethyl acetate and then 5:1 isohexane-ethyl acetate) to give the desired compound (23.5 g). 9 Carriers 31.23-1.35(9H, t), 2.26(ЗН 5), 3.46(1Н, t), 3.82(ЗН, 5), 4.2(2Н, а), 7.42(1H, Bg.5)/ -

B) Methyl 1,2,3,4-tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2.4-dioxothieno|(2.3-4|Ipyrimidine-5-carboxylate b

Silver cyanate (13.5g) suspended in anhydrous toluene (90ml) is treated dropwise with acetyl chloride (5.34ml) under nitrogen and vigorously stirred for 30 minutes. Add the product of operation a) (23 g), h dissolved in anhydrous toluene (1 bml), and the mixture is stirred for 72 h. Ether (ZbOml) is added, the insoluble material is filtered off and washed with a small amount of ether. The combined organic solutions are washed with saturated sodium bicarbonate solution, dried and evaporated. The residue is treated with sodium methoxide solution. 89 in methanol (2595 (by mass), b4iml) at room temperature for 72 hours. The reaction was cooled in ice, treated with trimethylsilyl chloride (50.8 mL) and stirred at room temperature overnight. All volatile components are removed in vacuo and the residue is partitioned between water and ethyl acetate. Drying and evaporation of the organic solution gives a residue, which is chromatographed (510 5/2:11 isohexane-ethyl acetate, then 3:22 isohexane-ethyl acetate) to isolate the main component (12.2 g), which is kept in dry DMF (15 Oml) with - with potassium carbonate (6.95 g) and methyl iodide (7.1 g) for 72 hours. at room temperature. The mixture is poured into "" water (2 L), acidified and extracted into ether. Washing with brine, drying and evaporation give a solid " substance, which is boiled in isohexane (200 ml) with ethyl acetate (3 ml). After cooling, the precipitated pale yellow solid was collected and dried to give the desired compound (10.5 g).

MS (ARSI) (MeNI" 297 so 9 Nesosiz 1.6 (6H, a), 2.44 (ZH, 5), 3.37 (ZH, 5), 3.95 (ZH, 5), 4.66 (1H, bg). ko s) 1,2,3,4-tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxothieno|2,3-4|Ipyrimidine-5-carbon acid

To a solution of the product of operation 5) (3.81g) in THF (50ml) in methanol (bml) add 1M Mahon (25.7ml) and the mixture is stirred under nitrogen for 18 hours, then acidified with 2.5M NOI and extracted with DCM , the organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the desired compound as a solid (3.40 g).

Also MS (E5I) 283 |IMANI" 9) 5-I(45)-4-hydroxy-2-isoxazolidinylcarbonyl|-3,6-dimethyl-1-(1-methylethyl)-thieno-(2,3-4| Ipyrimidine-2,4(1H,ZN)-dione 59 Oxalyl chloride (1.1bml) and DMF (1Oml) are added to a suspension of the product of part c) (3.40g) in DCM (5Oml) and

GF! the mixture is stirred under nitrogen for 2 hours. To a suspension of (5)-4-isoxazolidinol hydrochloride (1.53 g) and triethylamine (3.52 ml) in DCM (20 ml), a solution of hydrogen chloride is added at 02С under nitrogen and the mixture is stirred at room temperature for 3 hours, then washed with water, dried over anhydrous magnesium sulfate, filter and evaporate under reduced pressure. The residue is purified by column chromatography on silica with ethyl acetate as eluent to give the desired compound as a solid (2.52 g).

MS (E5I) 354 (MANI b Ndmso 1.50-1.52 (6BN, t), 2.30-2.34 (ZN, t), Z, 18-3.19 (ZN, t), 5, 42-4.08 (4H, t), 4.59-4.74 (2H, t), 5.49-5.50 (1H, t). b5 s) 5-I(45)-4-I (1,1-dimethylethyl)dimethylsilyl|oxy|-2-isoxazolidinylcarbonyl1|-3,6-dimethyl-1-(1-methylethyl)/thioene

2,3-4|Ipyrimidine-2,A(1H,ZN)-dione

Imidazole (0.53g) and tert-butyldimethylsilyl chloride (1.18g) were added to a solution of the product of part 4) (2.52) in DxHM (30ml) and the mixture was stirred under nitrogen for 24 hours, then acidified with 1M HCl and extracted with DHM. Organic extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica, with the eluent i-hexane/ethyl acetate (3:1), then i-hexane/ethyl acetate (1:1), obtaining the desired compound (2.42 g), 5 Ndmso 0.09 (6H , а), 0.86 (9Н, 8), 1.50 (6Н, а), 2.31-2.34 (ЗН, т), 3.18-3.19 (ЗН, т), 3, 44-4.15 (4H, t), 4.50-4.97 (2H, t). 70 I b-bromomethyl-5-I|(45)-4-I(1,1-dimethylethyl)dimethylsilyl|oxy|-2-isoxazolidinyl|-carbonyl|-3-methyl-1-(1-methylethyl)thieno (2,3-4|pyrimidine-2,A(1H,ZN)-dione

M-bromo-succinimide (1.01 g) is added to a solution of the product of part e) (2.42 g) in chloroform (100 ml) and the mixture is heated at boiling under a reflux condenser with a tungsten lamp (300 W) for 2 75 h, then cooled, washed with 1 M Mmaon solution, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure, obtaining the desired compound (2.83 g).

MS (EI) 546 and 548 MANI" 9) 6-(2-acetyl-3-oxobutyl)-5-((45)-4-K(1,1-dimethylethyl)dimethylsilyl|oxy|-2-isoxalidinylIcarbonyl|- 3-methyl-1-(1-methylethyl)thieno|2,3-4|pyrimidine-2,4(1H,ZH)-dione

A solution of the product (part of Her) (2.83g) and zinc hydrate acetylacetonate (1.47g) in chloroform (50ml) is heated at reflux for 1 hour, then cooled, washed with sodium bicarbonate solution, filtered through celite, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the desired compound (2.93 g). with

MS (E5I) 566 (MANI p) about 5-I(45)-4-((1,1-dimethylethyl)dimethylsilyl|oxy|-2-isoxazolidinyl|-carbonyl/|-6-((3,5-dimethyl -1-(2-pyrimidinyl)-1H-pyrazol-4-yl|methyl|-3-methyl-1-(1-methylsilyl)thieno|(2,3-4|Ipyrimidin-2,A(1H,ZH) - dion

Pyrimidin-2-ylhydrazine (0.27g) is added to a solution of the product of part 49) (0.73g) in chloroform (25ml) and the mixture is stirred for 48 hours, then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica, with Me-hexane/ethyl acetate (1:1) and then i-hexane/ethyl acetate (1:4) as eluent to give the desired compound (0.43 g). "Mr

MS (E5I) 640 MANI" i) c 8-III,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl)methyl|/-5-|(45)-4-hydroxy-2 -isoxazolidinyl|carbonyl|-3-methyl-1-(1-methylethyl)thieno|2,3-4|pyrimidine-2,4(1H,ZH)-dione

A solution of the product of part Pp) (0.43 g) and trifluoroacetic acid (0.5 ml) in DCM (1 ml) is stirred for 72 hours, then concentrated in vacuo, diluted with sodium bicarbonate solution and extracted with ethyl acetate, the organic extracts are washed with water, dried over anhydrous sulfate magnesium, filter and evaporate under reduced pressure. The residue is purified by column chromatography on silica with ethyl acetate as eluent, then with ethyl acetate/methanol (9:1), obtaining the desired compound (ZOmgHg). ts MS (ARSI) 526 MANI" "» 5 "Ndmso 1.44-1.46 (bH, t), 2.16-2.19 (ZN, t), 2.53-2.55 (ZN, t ), 3.17-3.19 (ZN, t), 3.48-4.14 (6Н, t), 4.38 (1Н, в, Bg), 4.60-4.80 (1Н, т ), 5.48-5.52 (1H, t), 7.46 (1H, ayu, 8.87 (2H,

Example 2 o 6-(3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl|methyl/-5-((45)-4-hydroxy-2-isoxazolidinylcarbonyl)|-3- m with ethyl-1-(1-methylethyl)thieno|2,3-4|Ipyrimidine-2,4(1H,ZH)-dione t «On

F 5 o g 4 M. o y:

AND

(F) at 6

OKO A

G and 60 n

F,

I b5 5 a) 5-I(45)-4-((1,1-dimethylethyl)dimethylsilyl|oxy|-2-isoxazolidinylcarbonyl)-6-((3,5-dimethyl-1-(2-pyridinyl)- 1

N-pyrazol-4-yl|methyl|-33-methyl-1-(1-methylethyl)thieno|(2,3-4|pyrimidin-2,4(1H,ZH)-dione

Pyridin-2-ylhydrazine (0.28g) is added to a solution of the product of example 1, part d) (0.73g) in chloroform (25ml) and the mixture is stirred for 48 hours, then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporate under reduced pressure. The residue is purified by column chromatography on silica with i-hexane as eluent, then i-hexane/ethyl acetate (1:11), obtaining the desired compound (0.28G).

MS (E5I) 639 (MANI 70 V) 6-((3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl|methyl)-5-((45)-4-hydroxy -2-isoxazolidinylcarbonyl|-3-methyl-1-(1-methylethyl)thieno|2,3-4|pyrimidine-2,4(1H,ZH)-dione

A solution of the product of part a) (0.28g) and trifluoroacetic acid (0.5ml) in DCM (10ml) was stirred for 72 hours, then concentrated in vacuo, diluted with sodium bicarbonate solution and extracted with ethyl acetate. The organic /5 extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with ethyl acetate, then ethyl acetate/methanol (49:1) to give the desired compound (88 mg).

MS (ARSI) 525 MANI" 5 "Ndmso 1.44-1.47 (bH, t), 2.17-2.19 (ZN, t), 2.56-2.58 (ZN, t), 3 ,47-4.14 (b6H, t), 4.38 (1H, 5, Bi), 4.60-4.80 (1H, t), 5.51-5.52 (1H, t), 7 ,30-7.34 (1H, t), 7.80 (1H, a), 7.95 (1H, ayu, 8.45-8.47 (1H, t).

Example C (5)-2-I(6-((3,5-dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl|methyl)-1,2,3,4-tetrahydro- 3-methyl-1-(1-methylethyl)-2-4-dioxothieno(2,3-4|pyrimidin-5-ylcarbonyl)|-4-isoxazolidinol

A (ee) o « - s Mixture h (5)-2-I(6-KZ,5-dimethyl-1H-pyrazol-4-yl)methyl/)-1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxothieno|2,3- -» Pyrimidin-5-yl|Icarbonyl|-4-isoxazolidinol (237 mg), 2-bromothiazole (237 mg), copper iodide (I) (2Omg), trans-cyclohexane-1,2-diamine (15mg) and potassium carbonate (145mg) are heated at 1002С in 1,4-dioxane (1Iml) for 24 hours. The reaction mixture is concentrated to dryness and purified by chromatography on 5000 (Violiade cartridge) with EtOAc as eluent to 595 Meon in EtOAc) and then by reverse phase chromatography, obtaining the desired compound as a white solid (11OmgHg).

MS (ARSI pit) MAN - 531.1- in 5 "Ndmso, 1209200 1.47 (6H, a), 2.17 (ZN, 5), 2.60 (ZN, 5), 3.20 (ZN, 5), 346 (IN, a), 3.75 (1H, a), "se 50 3.89-3.95 (2H, t), 3.89 (2H, c), 4.46 (1H, zer), 4.70 (1H, 5), 5.08 (1H, c), 7.38 (1H, a), 7.56 (1H a).

Pharmacological data "m Inhibition of RMALonomycin-stimulated proliferation of mononuclear cells in peripheral blood

This study was conducted in 96-cell flat-bottom microtiter plates. The compounds were obtained as 10 mm stock solutions in dimethyl sulfoxide, from which serial dilutions of this solution were obtained in a 50-fold dilution obtained in 99 ERMI. 100 ml of a 50-fold diluted mother solution,

He) or its dilutions were added to the cell, obtaining concentrations starting from 9.5 µM and below. 1x105 PBMC obtained from the peripheral blood of one human donor was added to each cell in ERMI1640 medium with the addition of 1095 human serum, 2 mM glutamine and penicillin/streptomycin. Acetate in phorbol myristrate (PMA) (final concentration 0.5 ng/ml) and ionomycin (final concentration 500 ng/ml) were added, and therefore the final volume of the assay was 0.2 ml. Cells were incubated at 372 in a humidified atmosphere of 595 carbon dioxide for 72 h. For final b h. ZN-thymidine (0.5 mCi) was added during incubation. The level of radioactivity incorporated by the cells is a measure of proliferation.

In this test, the compounds of the Examples showed an IA50 value of less than 1x109M. In particular, for Examples 1 65 |Avo was 8.3, and for Example C - 9.0

Claims (19)

The formula of the invention 1. The compound of formula (1): 2 o On o p "y v shi A, | 2 o AvATO v v v v v" i Kk? each independently represents C 1 alkyl, C 3 valkenyl, C 3 cycloalkylC alkyl or C 3 vcycloalkyl, each of which can be, as an option, substituted with 1-3 halogen atoms; O is SV"B?, where B" is hydrogen, fluorine or S. valkyl, and KE? - hydrogen, fluorine or hydroxy; Ag is a 5-10-membered aromatic ring system in which up to 4 ring atoms can be heteroatoms independently selected from nitrogen, oxygen, and sulfur, and this ring system is optionally substituted with one or more substituents independently selected from C. .4alkyl (as an option, substituted by 1, 2 or 3 hydroxy groups), C-.4alkyl, halogen, haloalkyl, dihaloalkyl or trihaloalkyl (where the alkyl groups, respectively, contain 1-4 carbon atoms), C 4.lalkoxySialkylu, C.. lalkylthio, S..Alkoxycarbonyl, Sodalkanoyl, oxogroup, thioxogroup, nitrogroup, cyanogroup, -M(VUV/ its -CH.-MZHEUV", thydroxy, C. dalkylsulfonyl, C. dalkylsulfinyl, carbamoyl, C. lalkylcarbamoyl, di-(C- dalkyl)carbamoyl, carboxy, and. 7 vom, c) Ag? is a 5- or 6-membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, sulfur or oxygen, which may optionally be substituted with one or more groups independently selected from C. alkyl (as an option, substituted by 1, 2 or C hydroxy groups), C 4 alkoxy, halogen, haloalkyl, M dihaloalkyl or trihaloalkyl (where the alkyl groups, respectively, contain 71 - 4 carbon atoms), C. lalkoxy-Si dalalkyl, C. lalkylthio, C-. allkoxycarbonyl, Sodlalkanoyl, oxo group, thioxo group, nitro group, FU) cyano group, -M(VUV" and -(CH)-MSH(VUV", hydroxy, C. alkylsulfonyl, S..alkylsulfinyl, carbamoyl, "ch C. dalkylcarbamoyl, di-(C. lalkyl)carbamoyl, carboxy, 5OoshchvZ in; p is from 1 to 4; ch 25 of its KE" each independently represents a hydrogen atom, a Ci alkanoyl or a Ci 4 alkyl group, or together with the (00) nitrogen atom to which they are attached, form a 5-7-membered saturated heterocyclic ring, which, as an option, additionally contains 0, 5, MH or M-alkyl group; BZ and EE each independently represent a hydrogen atom, a C. 4 alkanoyl or C. dalalkyl group, or together with the nitrogen atom to which they are attached, form a 5-7-membered saturated heterocyclic ring , which, as an option, additionally contains an O, 5, MH or M-alkyl group; - with its pharmaceutically acceptable salts and solvates, provided that the compound is not "» 5-(45)-4-hydroxyisoxazolidin-2-ylcarbonyl )-1-(isobutyl)-3-methyl-6-(5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl)no|2,3-4|Ipyrimidine-2,4(1H,ZH )-dione, 6-13,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl/-5-((45)-4-hydroxyoxazolidin-2-ylcarbonyl|-1-isobutyl-3-methylthieno| 2,3-a|-pyrimidine-2,4(1H,3H)-dione or (or) 6-3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl/-5-((45) -4-hydroxy isoxazolidin-2-ylcarbonyl|-3-methyl-1-propylthio with no|2,3-4|Ipyrimidine-2,4(1H,ZH)-dione or a pharmaceutically acceptable salt or solvate thereof. 2. The compound according to claim 1, which differs in that in it B is S. valkyl. t- 3. The compound according to claim 1 or claim 2, which differs in that it contains K2? is methyl. "at 50 4. The compound according to any of claims 1-3, which is distinguished by the fact that in it O is CH". 5. A compound according to any one of claims 1-4, which is characterized by the fact that Ag is a 5- or b--membered aromatic ring system in which up to 2 ring atoms can be heteroatoms independently selected from nitrogen, oxygen and sulfur, and this ring system is optionally substituted with one or more substituents independently selected from C-alkyl, C-alkyl, halogen, dihaloalkyl, trihaloalkyl, oxo, 59 thioxo, cyano, and C. alkylsulfonyl. HF) 6. The compound according to claim 5, which differs in that Ag is a group of the subformula (i) Eto t ikh bo" Y dig that de KO B" are independently selected from H, C, alkyl or halogens. valkyla, and Ag? is the one defined above. 6E 7. A compound according to any of the previous points, which differs in that it contains Ag? is not phenyl. 8. The compound according to claim 7, which differs in that it contains Ag? has at least one heteroatom. 9. A compound according to any of claims 1-6, which differs in that it contains Ag? is a 5- or b-membered aromatic ring system in which up to C ring atoms can be heteroatoms independently selected from nitrogen, sulfur, or oxygen, and this ring system is optionally substituted with one or more substituents independently selected from C .dalalkyl, Sialkoxy, halogen, dihaloalkyl, trihaloalkyl, oxo group, thioxo group, cyano group and Si. alkylsulfonyl. 10. The compound according to claim 9, which differs in that Ag" in it is pyridinyl or pyrimidinyl. 11. The compound according to claim 9, which differs in that it contains Ag? is a thiazolyl. 12. The compound of formula (I), which differs in that it is selected from the group consisting of: 6-(33,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl|methyl-1-5-( (45)-4-hydroxy-2-isoxazolidinyl|carbonyl/|-3-methyl-1-(1-methylethyl)thieno(|2,3-4|-pyrimidine-2,4-"1H,ZH)-dione and 6-(3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl|methyl/-5-((45)-4-hydroxy-2-isoxazolidinylcarbonyl)|-3-m ethyl -1-(1-methylethyl)thieno|2,3-4|-pyrimidine-2,4-(1H,ZH)-dione, (5)-2-I((6-(3,5-dimethyl-1 -(2-thiazolyl)-1H-pyrazol-4-yl|methyl/)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2, 4-dioxothieno|2,3 -4|-pyrimidin-5-ylcarbonyl)-4-isoxazolidinol and their pharmaceutically acceptable salts. 13. A compound according to any one of claims 1-12 for use in therapy. 14. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined in any one of claims 1-12, together with a pharmaceutical carrier. 15. A method of creating immunosuppression, which includes administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined in any of claims 1-12. 16. A method of treating or reducing the risk of respiratory tract diseases in patients suffering from these diseases or having an increased risk of developing these diseases, which includes administering to this patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, defined in any which of claims 1-12. with 17. The method of obtaining the compounds of the formula (I) according to claim 1, in which the compounds of the formula (I) interact: h (2) om h a "And EE! and MI) in which B and K2 are those defined in formula (I) or are their protected derivatives, and X and M are selected from C. dalalkyl (as an option, substituted by 1, 2 or 3 hydroxy groups), C/allkoxy, haloalkyl, dihaloalkyl, trihaloalkyl, C.4-alkyl alkyl, C.allkoxycarbonyl, "SNR, with the compound of formula (I): "Аг2-51-52 , (FDI) in which Ag? is defined in formula (I) or is its protected derivative, and 1 is МНиС2 is МНо, 5Н - с or ОН, "» and, as an option, after the interaction, in any order, carry out: " - removal of protective groups, - formation of a pharmaceutically acceptable salt. 18. The method of obtaining the compound of formula (I) according to claim 1, in which the interaction of the compound of formula (IM) is carried out: AtAB O.M) in! in which B", B2, Ag and Ag? are as defined in formula (I) or are their protected derivatives, with the compound of formula (M) He! o-P ko H Chy c) sho 60 in which P - protective group, and, as an option, after the interaction, in any order: - removal of protective groups, - formation of a pharmaceutically acceptable salt. 19. The method of obtaining the compound of the formula (I) according to claim 1, in which: for the compound of the formula (I), where Ag has a MH group, the reaction of the compound of the formula (MI) is carried out: he about those behind those Z a I A in M) in which B and B? are as defined in formula (I), and Ag is as defined in formula (I), provided that Ag contains a MH group, or is a protected derivative thereof, with a compound of formula (MI): Ag -1, (MI) in which Ag? is the one defined in formula (I) or is its protected derivative, and | is a leaving group, and, as an option, after interaction, in any order: - removal of protective groups, - formation of a pharmaceutically acceptable salt. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 8, 25.04.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o cha (2) "I s so - s ;" so ko FT" (This) that F) ko 60 b5