RU2601410C1 - {3-[(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)AZOLYL]AZETIDIN-3-YL} ACETONITRILES AS JANUS KINASE INHIBITORS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel {3-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-azolyl]azetidin-3-yl}-acetonitriles of general formula 1 or pharmaceutically acceptable salts thereof. Compounds are JAK inhibitors and can be used for treating autoimmune disease, which is multiple sclerosis, rheumatoid arthritis, psoriatic arthritis or juvenile arthritis. In compounds of general formula 1

R¹ is SO₂(CH₂)_nCH₂OH, SO₂(CH₂)_nCH₂F, SO₂(CH₂)_nCHF₂, SO₂(CH₂)_nCF₃, SO₂(CH₂)_nCO₂R^1a, SO₂(CH₂)_nCO₂H, CH₂CH₂SO₂CH₃, CH₂CH₂SO₃H, CH₂CH₂CH₂OH, CH₂CH₂SO₂NH₂; n = 1 or 2. R^1a is an alkyl or cycloalkyl, preferably C₁-C₃alkyl; X and Y are a nitrogen atom; or X is a nitrogen atom, Y is an methine; or X is a methine, and Y is a nitrogen atom; or R¹ is SO₂CH₂CH₃; X and Y are a nitrogen atom or X is methine, Y is a nitrogen atom. Invention also relates to a method of producing compounds of formula 1, involving removal of protective group R² from compound of formula 1a, where R¹ has said values, R² denotes 2-(trimethylsilyl)ethoxymethyl, hydroxymethyl.

EFFECT: removal of protective group R² is performed by lithium tetrafluoroborate or boron trifluoride diethyl etherate for bonding with subsequent treatment with ammonium hydroxide.

17 cl, 2 tbl, 18 ex

Description

The present invention relates to {3 - [(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -azolyl] azetidin-3-yl} -acetonitriles, as well as their compositions, methods of use and preparation. These compounds and their compositions are inhibitors of Janus kinases (JAK) and can be used in the treatment of JAK associated diseases, including, for example, inflammatory and autoimmune disorders, as well as cancer.

Oncogenic protein kinases are one of the largest and most attractive groups of protein targets for drug development. JAKs play an important role in the cytokine-dependent regulation of proliferation and function of cells involved in the immune response. Four JAKs are currently known: JAK1, JAK2, JAK3 (also known as white blood cell Janus kinase; JAKL; L-JAK) and TYK2 (also known as tyrosine kinase T).

Blocking signal transmission at the JAK level is promising for the development of methods for treating inflammatory diseases, autoimmune diseases, myeloproliferative and human cancers. JAK inhibition is believed to have a therapeutic effect in patients suffering from immune disorders of the skin, such as psoriasis and skin sensitization. Effective JAK inhibitors are of undoubted interest in the development of new drugs. Some JAK inhibitors, including pyrrolopyrimidines, are presented in WO 2009/114512. In this series of compounds, Baricitinib is the most advanced drug candidate. Baricitinib showed fast (after 6 months of treatment) and sustained effectiveness in the treatment of rheumatoid arthritis in three phase III studies [NCT02340104, NCT02263911, NCT01710358. http://www.medpagetoday.com/MeetingCoverage/EULAR/52084. http://www.fiercepharma.com/press-releases/lilly-and-incyte-announce-positive-top-line-results-phase-3-trial-baricitin].

Thus, the search for new improved JAK inhibitors is one of the main directions for the development of new, more effective drugs for the treatment of rheumatoid arthritis, cancer and other diseases. The compounds and methods described herein are intended to meet these needs.

The following are definitions of terms that are used in the description of this invention.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more “lower alkyl” (C ₁ -C ₆ ) alkyl substituents. Preferred alkyl groups are (C ₁ -C ₆ ) alkyl, even more preferred (C ₁ -C ₃ ) alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl , cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl. Alkyl may have substituents.

“Substituted alkyl” - substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy or R _k ^a R _{k + 1} ^a N-, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meanings of which are defined in this section for example, a hydrogen atom a, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a, together with the N atom to which they are bonded, form ^a 4-7-membered via R _k ^a and R _{k + 1} ^a heterocyclyl or heterocyclenyl. The preferred "alkyl substituents" are aryl, heteroaryl, heterocyclyl, hydroxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or R _k geteroaralkiloksikarbonil ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.

“Amino group” means an R ₁ R ₂ N group optionally substituted or unsubstituted with the same substituents R ₁ and R ₂ . An amino group may have substituents.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

"Metin" is a group of one carbon atom and one hydrogen atom CH.

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Pharmaceutical composition" means a composition comprising an active component and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceptive means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial Gent, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal such as ointments and creams, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002.]. Соли заявленных кислот также могут быть специально получены реакцией очищенной кислоты с подходящим основанием, при этом могут быть синтезированы соли металлов и аминов. К металлическим относятся соли натрия, калия, кальция, бария, цинка, магния, лития и алюминия, наиболее желательными из которых являются соли натрия и калия. Подходящими неорганическими основаниями, из которых могут быть получены соли металлов, являются гидроксид, карбонат, бикарбонат и гидрид натрия, гидроксид и бикарбонат калия, поташ, гидроксид лития, гидроксид кальция, гидроксид магния, гидроксид цинка. В качестве органических оснований, из которых могут быть получены соли заявленных кислот, выбраны амины и аминокислоты, обладающие достаточной основностью, чтобы образовать устойчивую соль, и пригодные для использования в медицинских целях (в частности, они должны обладать низкой токсичностью). К таким аминам относятся аммиак, метиламин, диметиламин, триметиламин, этиламин, диэтиламин, триэтиламин, бензиламин, дибензиламин, дициклогексиламин, пиперазин, этилпиперидин, трис(гидроксиметил)аминометан и подобные им. Кроме того, для солеобразования могут быть использованы гидроокиси тетраалкиламмония, например, такие как холин, тетраметиламмоний, тетраэтиламмоний и им подобные. В качестве аминокислот могут быть использованы основные аминокислоты - лизин, орнитин и аргинин.“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, dichloroacetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, c tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like and Use. VHCA, Verlag Helvetica C himica Acta,

, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002.]. Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

An object of the present invention is to provide novel JAK inhibitors for the treatment of rheumatoid arthritis, cancer and other diseases.

The goal is achieved by {3 - [(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -azolyl] azetidin-3-yl} -acetonitriles of the general formula 1:

or their pharmaceutically acceptable salts, where:

R ¹ represents SO ₂ (CH ₂ ) _n CH ₂ OH, SO ₂ (CH ₂ ) _n CH ₂ F, SO ₂ (CH ₂ ) _n CHF ₂ , SO ₂ (CH ₂ ) _n CF ₃ , SO ₂ (CH ₂ ) _n CO ₂ R ^1a , SO ₂ (CH ₂ ) _n CO ₂ H, CH ₂ CH ₂ SO ₂ CH ₃ , CH ₂ CH ₂ SO ₃ H, CH ₂ CH ₂ SO ₂ NH ₂ ; n = 1 or 2.

R ^1a represents alkyl or cycloalkyl, preferably C ₁ -C ₃ alkyl;

X and Y represent a nitrogen atom; or X represents a nitrogen atom, and Y represents methine; or X represents methine, and Y represents a nitrogen atom;

or R ¹ represents SO ₂ CH ₂ CH ₃ ; X and Y represent a nitrogen atom, or X represents a methine, and Y represents a nitrogen atom.

The subject of the present invention is a new JAK inhibitor of general formula 1.

The present invention relates in particular to a JAK inhibitor selected from: {1- (2-hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1 -yl] -azetidin-3-yl} -acetonitrile (1.1);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2-fluoro-ethanesulfonyl) -azetidin-3-yl} -acetonitrile ( 1.2);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2,2-difluoro-ethanesulfonyl) -azetidin-3-yl} - acetonitrile (1.3);

[3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2,2,2-trifluoro-ethanesulfonyl) -azetidin-3-yl ] -difluoroethanesulfonyl (1.4);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} acetic acid methyl ester (1.5);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} acetic acid (1.6);

2- {3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-yl} ethanesulfonic acid (1.7);

amide of 2- {3 [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-yl} ethanesulfonic acid (1.8);

{1- (2-methanesulfonyl-ethyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -azetidin-3-yl} -acetonitrile (1.9 );

{3- [3- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -1-ethanesulfonyl-azetidin-3-yl} -acetonitrile (1.10);

{1- (2-hydroxy-ethanesulfonyl) -3- [3- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -azetidin-3-yl} -acetonitrile (1.11 );

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - [1,2,3] triazol-2-yl] -1-ethanesulfonyl-azetidin-3-yl} -acetonitrile (1.12);

{1- (2-hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl) - [1,2,3] triazol-2 -yl] -azetidin-3-yl} -acetonitrile (1.13);

{1- (3-hydroxy-propan-1-sulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl)] azetidin-3-yl } -acetonitrile (1.14);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} propionic acid methyl ester (1.15);

{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (3-fluoropropanesulfonyl) -azetidin-3-yl} -acetonitrile (1.16)

{1- (3-Hydroxypropyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile trifluoroacetate ( 1.17)

or their pharmaceutically acceptable salts.

The subject of the present invention are also hydrates and solvates of the compounds of general formula 1 of the present invention, as well as anhydrous and unsolvated forms.

The term “compound” as used herein means all stereoisomers, geometric isomers, tautomers and isotopes of compounds of general formula 1. All compounds and pharmaceutically acceptable salts can be isolated together with other substances, such as water and solvents (eg hydrates and solvates) .

The compounds of the present invention may also include all isotopes of atoms present in the intermediate or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium.

The phrase “pharmaceutically acceptable” is used herein to mean compounds, materials, compositions and / or dosage forms that, within the limits of the medical evaluation error, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problem or complication, proportionate to a reasonable benefit / risk ratio.

, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002.].The present invention also includes pharmaceutically acceptable salts of the compounds described herein. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids; alkaline or organic salts of acidic residues of compounds of formula 1, such as carboxylic or sulfonic acids. Pharmaceutically acceptable salts of the present invention include the usual non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic group by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the corresponding base or acid in water or in an organic solvent, or in a mixture of the two. Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, acetone or acetonitrile (ACN). Lists of suitable salts can be found in the Pharmaceutical Salts Handbook [PH Stahl, CG Wermuth (Eds.). Handbook of Pharmaceutical Salts, Properties, Selection, and Use. VHCA, Verlag Helvetica Chimica Acta,

, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002.].

The compounds of the present invention, including their salts, can be prepared using known methods of organic synthesis and can be synthesized in accordance with any of the many possible synthetic routes. The reaction for the preparation of the compounds of the invention can be carried out in suitable solvents, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents can essentially react with starting materials (reagents), intermediates at reaction temperatures, for example, the temperature of which can vary from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in one solvent or in a mixture of solvents. Depending on the particular reaction step, suitable solvents for the particular reaction step may be selected by one skilled in the art.

The inhibitory activity and selectivity of the compounds of general formula 1 with respect to JAK are generally comparable to the activity and selectivity of Baricitinib, which is currently undergoing phase III clinical trials [NCT02340104; NCT02263911; NCT01710358; JD Clark, ME Flanagan, J.-B. Telliez. Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases. J. Med. Chem. 2014, 57, 5023-5038]. However, some inhibitors have a higher selectivity for interaction with JAK. For example, the 1.16 inhibitor is less active with respect to JAK3 (IC ₅₀ = 117 nM) than Baricitinib (IC ₅₀ = 92 nM). As a result, the selectivity of JAK3 / JAK1 = 261 and the selectivity of JAK3 / JAK2 = 113 of the 1.16 inhibitor is two times higher than the selectivity of Baricitinib (Table 1).

An advantage of the new compounds of general formula 1 is their significantly higher solubility in aqueous solutions than in Baricitinib (Table 2). For example, the solubility of the 1.8 · CHCl ₂ CO ₂ H inhibitor in water at pH7 (> 33.17 mg / ml) is more than 829 times, and at pH2 (> 17.84 mg / ml) more than 17 times higher than the solubility of Baricitinib.

A process for preparing the compounds of the invention may include a protecting group and its removal. The need for a protective group and its removal, and the selection of appropriate protective groups, can be easily determined by a person skilled in the art. Chemistry of protective groups can be found, for example, in T.W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^{rd Ed., Wiley & Sons,} Inc., New York ( 1999), which is incorporated herein by reference in its entirety.

The present invention relates to a method for producing a compound of general formula 1, which comprises treating a compound of formula 1a, which removes the protective group R ² (Scheme 1).

Where:

R ¹ represents SO ₂ (CH ₂ ) _n CH ₂ OH, SO ₂ (CH ₂ ) _n CH ₂ F, SO ₂ (CH ₂ ) _n CHF ₂ , SO ₂ (CH ₂ ) _n CF ₃ , SO ₂ (CH ₂ ) _n CO ₂ R ^la , SO ₂ (CH ₂ ) _n CO ₂ H, CH ₂ CH ₂ SO ₂ CH ₃ , CH ₂ CH ₂ SO ₃ H, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH ₂ SO ₂ NH ₂ ; n is 1 or 2;

R ^la represents alkyl or cycloalkyl, preferably C ₁ -C ₃ alkyl;

X and Y represent a nitrogen atom; or X represents a nitrogen atom, and Y represents methine; or X represents methine, and Y represents a nitrogen atom;

or R ¹ represents SO ₂ CH ₂ CH ₃ ; X and Y represent a nitrogen atom, or X represents methine, and Y represents a nitrogen atom;

R ² denotes protecting groups that include, but are not limited to, protecting groups for amines presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007 ], which is incorporated into this description by reference in its entirety.

In some embodiments of the invention, the protective group R ² is stable under the conditions of removal of the protective groups R ³ and R ⁴ (scheme 1 and scheme 2). In some embodiments, the R ² protecting group is a group that is not removed from 1N to 5N hydrochloric acid at room temperature, at a temperature of from about 10 ° C to 40 ° C, at a temperature of from about 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C. In some embodiments, R ² is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2- (trimethylsilyl) ethoxycarbonyl (Teoc), 2- (4-trifluoromethylphenylsulfonyl) ethoxycarbonyl (TSC), tert-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Special), L, L-dimethyl-2,2,2- trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-diphenyl-pyridylmethyl, N ′, N′-dimethylhydrazinyl, me hydroxymethyl, tert-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP). hydroxymethyl (HM). In some embodiments, R ² is 2- (trimethylsilyl) ethoxymethyl (SEM). In some embodiments, R ² is N-pivaloyloxymethyl (polyoxymethylene) or hydroxymethyl (HM).

Methods known in the art for removing specific amine protecting groups [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696- can be used to remove the R ² protecting group from the compound of formula 1a. 887, 2007]. For example, in some embodiments, the protecting group R ² can be removed by treatment with a fluoride ion (e.g., treatment with tetrabutylammonium fluoride), hydrochloric acid or Lewis acid (e.g., lithium tetrafluoroborate). In some embodiments, the treatment includes treatment with lithium tetrafluoroborate followed by treatment with ammonium hydroxide (for example, when R ² is 2- (trimethylsilyl) ethoxymethyl)). The resulting corresponding hydroxymethyl intermediate is then treated with an aqueous solution of ammonium hydroxide at room temperature to give a compound of general formula 1.

Scheme 1

Scheme 2

A compound of formula 1a can be prepared by reacting compound 1b and a compound of formula R ¹ -Z (Scheme 1). Z in the compound R ¹ -Z represents a leaving group. In some embodiments of the invention, the leaving group Z is a group well known in the art, for example, halogen. A more preferred leaving group Z is chloro or fluoro.

The compound of formula 1b can be obtained by removing the protective group R ³ of compound 1c (Scheme 1).

R ³ protecting groups include, but are not limited to, amine protecting groups presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007], which is included in the present description by reference in its entirety. R ³ represents a protective group that can be selectively removed under conditions that do not displace the protective group R ² . In some embodiments of the invention, R ³ is a protecting group that can be removed in acidic environments at room temperature, at a temperature of 15 ° C to 40 ° C, or at a temperature of 15 ° C to about 30 ° C. In some embodiments, R ³ is alkoxycarbonyl, for example tert-butoxycarbonyl. To remove the R ³ group by treating the compound of formula 1c, well-known methods are used, for example, those presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007], which is included in the present description by reference in its entirety. Suitable processing conditions do not displace the protecting group R ² . In some embodiments, the treatment of the compound of formula 1c is carried out in acidic media at room temperature, at a temperature of from 15 ° C to 40 ° C, or at a temperature of from 15 ° C to about 30 ° C. In some embodiments, treating a compound of Formula 1c involves treating with hydrochloric acid in 1,4-dioxane.

In Scheme 1, a compound of formula 1a is prepared by a process comprising reacting a compound of formula 1d and a compound of formula 1e.

Michael addition reactions between the compound of formula 1d and the compound of formula 1e (Scheme 1) can be carried out in the presence of a base (Michael catalyst). In some embodiments, tetraalkylammonium halides, tetraalkylammonium hydroxides, guanidine, amidine, alkali metal hydroxide, alkali metal phosphate, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine or alkali metal salt are used as Michael catalyst carboxylic acid, etc. In some embodiments, tetramethylguanidine, 1,8-diazabicyclo (5.4.0) undec -7-ene, 1,5-diazabicyclo (4.3.0) non-5-ene, 1,4-diazabicyclo- (2.2.2) octane, tert-butyl ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, ethoxide sodium, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenylphosphine, triethylphosphine, potassium acetate, or potassium acrylate. In some embodiments, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) is used as a Michael catalyst. In some embodiments, a stoichiometric or catalytic amount of base is used to facilitate the Michael addition reaction. In some embodiments, the reaction is carried out in an organic solvent, such as acetonitrile or dimethylacetamide, at room temperature for two to six hours.

A compound of formula 1f is prepared by a process comprising treating a compound of formula 1d (Scheme 2).

If R ^{1 is} removed from compound 1f, a compound of formula 1d is formed. R ⁴ represents a protective group. The corresponding R ⁴ groups include, but are not limited to, amine protecting groups presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007], which is included in the present description by reference in its entirety. R ⁴ represents a protective group that can be selectively removed under conditions that do not displace the protective group R ² . In some embodiments, R ⁴ is a protecting group that can be removed with acid at room temperature, at a temperature of 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C. In some embodiments, R ⁴ is 1- (ethoxy) ethyl, tri (C ₁ -C ₆ alkyl) silyl (e.g. tert-butyldimethylsilyl or triisopropylsilyl), p-methoxybenzyl (PMB), triphenylmethyl (Tr), diphenylmethyl, hydroxymethyl, methoxymethyl (MOM), diethoxymethyl, or tert-butyldimethylsilyl. In some embodiments, R ⁴ is L- (ethoxy) ethyl.

The removal of the protective group R ⁴ from the compound of formula 1f can be achieved by methods known in the art for the removal of specific amine protecting groups presented in [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey , 696-887, 2007], which is incorporated herein by reference in its entirety. In some embodiments, the compound of Formula 1f is treated with an acid (e.g., hydrochloric acid or trifluoroacetic acid) at room temperature, at a temperature of 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C. A compound of formula 1f is prepared using a process comprising reacting a compound of formula 1g with a compound of formula 1h (Scheme 2).

Compounds of formula 1f are prepared by the Suzuki reaction from compounds of formulas 1g and 1h in the presence of a palladium catalyst and a base (Scheme 2), where Z represents a tosylate group, triflate group, iodine, chlorine, bromine, and R ^a and R ^b in compound 1h independently others are hydrogen or alkyl; or R ^a and R ^b together with the oxygen atoms to which they are attached and the boron atom form a 5- or 6-membered heterocyclic ring, which is optionally substituted with one, two, three or four C ₁ -C ₄ alkyl groups.

The Suzuki reaction can be carried out using a number of Pd (0) and Pd (II) catalysts under conditions known in the art (see, for example, a review by Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, which is included in the description in its entirety). In some embodiments, Pd (DPPF) 2Cl ₂ or tetrakis (triphenylphosphine) palladium (0) or tetrakis (tri (o-tolyl) phosphine) palladium (0), or tetrakis (triphenylphosphine) palladium (0) is used as a palladium catalyst.

In some embodiments, from about 0.0010 to about 0.0015 equivalents of a palladium catalyst are used. In some embodiments, an approximately stoichiometric ratio of compounds of formula 1g and 1h is used, for example from about 1 to about 1.05, or from about 1 to about 1.35. In some embodiments, an organic solvent containing water is used for this synthesis step. The organic solvent used is 1,4-dioxane, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene or ethanol, or combinations thereof. In some embodiments, the organic solvent comprises a combination of 1-butanol and dimethyl ether.

In some embodiments, the base is an inorganic base, and in some an organic base. In some embodiments, the base is an alkali metal carbonate or an alkali metal hydrogen carbonate. In some embodiments, the base is potassium carbonate (K ₂ CO ₃ ). In some embodiments, two to five equivalents of a base (eg, K ₂ CO ₃ ) or two to five equivalents of a base (eg, NaHCO ₃ ) are used.

In some embodiments, the Suzuki reaction is carried out at a temperature of from about 80 ° C to 100 ° C. In some embodiments, the reaction is carried out for two to twelve hours.

In some embodiments, Z in a compound of formula 1g is chloro, bromo or iodo.

A compound of formula 1g (Scheme 2) is prepared from a compound of formula 1i by the introduction of a protecting group R ² as described above, preferably (trimethylsilyl) ethoxymethyl or N-pivaloyloxymethyl.

The introduction of the protective group R ^{2 is} carried out using known in the field of chemistry protective groups for amines [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007]. For example, indole nitrogen is deprotonated with a base (e.g. sodium hydride) in an organic solvent (e.g. THF, 1,4-dioxane, 1,2-dimethoxyethane (DME), or N, N-dimethylacetamide (DMAC)) at low temperature (e.g. , from 0 ° C to 5 ° C), and then treated with trimethylsilylethoxymethyl chloride (SEM-Cl) or pivaloyloxymethyl chloride (POM-Cl). SEM or POM protected 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (1i: Z = Cl) is then isolated and used in the subsequent Suzuki 1i reaction with or without further purification.

A method of obtaining a compound of formula 1 includes the step of reacting a compound of formula 1j with a compound of formula R ¹ -Z; where Z represents a leaving group. In some embodiments of the invention, Z is halogen, including chlorine or fluorine.

The reaction of a compound of formula 1j with a compound of formula R ¹ -Z is carried out in the presence of a base, for example, a tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

The compound of formula 1j is obtained by removing the protective group R ^{2 of} the compound of formula 1b (Scheme 1).

The above synthetic methods can be used to obtain any of the compounds described here or their combinations or any of the compounds described in the examples. The present invention relates to any combination of separate methods for preparing a compound of general formula 1, a compound of formula 1a, etc.

The present invention further relates to any of the intermediates described above, or salts thereof.

A method for preparing salts of compounds of general formula 1 involves reacting a compound of formula 1a with hydrochloric acid, dichloroacetic acid, methanesulfonic acid, phosphoric acid, benzenesulfonic acid (PhSO ₃ H), para-toluenesulfonic acid (n-CH ₃ PhSO ₃ H) or with 1, 5-naphthalene disulfonic acid (1,5-NDSA) to form the corresponding salt. Salts of the compounds of general formula 1 can be prepared by treating a solution of the corresponding free base of formula 1a in an organic solvent such as ethanol (EtOH), an acid solution in an organic solvent such as ethanol at room temperature or at elevated temperature (for example, from 60 ° C to 70 ° C). The salt obtained, if necessary, can be further purified by recrystallization or other well-known methods, for example reprecipitation or washing.

Compounds of general formula 1 and their salts can be prepared according to the synthetic protocols described in the examples section below.

The compounds of the present invention can modulate the activity of one or more JAKs. The term “modulate” means the ability to increase or decrease the activity of one or more members of the JAK family. Accordingly, the compounds of the invention can be used in methods for modulating JAK activity by any one or more of the compounds of general formula 1 or compositions thereof.

In accordance with the present invention, compounds of general formula 1 may act as inhibitors of one or more JAKs.

In accordance with the present invention, compounds of general formula 1 can be used to modulate JAK activity in a patient who needs such modulation of the receptor by introducing a modulating amount of a compound of general formula 1.

An object of the present invention is a method of treating diseases or disorders in patients associated with JAK by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

A JAK-related disease can include any disease, disorder or condition directly or indirectly associated with expression or activity in a JAK, including overexpression and / or an abnormal level of activity. A JAK concomitant disease may also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulating JAK activity.

The subject of the present invention is a method for treating JAK-associated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathy, and immunoglobulins, thyroid disease and the like.

In accordance with the present invention, the compounds of general formula 1 can be administered to a patient in the form of pharmaceutical compositions. These compositions can be obtained by a method well known in the pharmaceutical field, and can be administered in various ways depending on whether local or systemic treatment is required and on the area to be treated. The compositions may be in the form of tablets, pills, powders, lozenges, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. The compositions may be formulated in unit dosage form, each dose containing from about 5 mg to about 1000 mg, usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dose" refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

The active compound can be effective over a wide range of doses and is usually administered in a pharmaceutically effective amount. It should be understood, however, that the amount of actually taken compound will usually be determined by the attending physician in accordance with the condition of the patient to be treated.

Below the invention will be described in more detail using specific examples, which are presented for purposes of illustration and are not intended to limit the invention in any way. Specialists in the art will easily understand the difference in non-critical parameters that can be changed or modified to obtain the same results.

Example 1. {1- (2-Hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3-yl} -acetonitrile (1.1) was obtained in accordance with scheme 3.

Scheme 3

Stage (a). 3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin- tert-butyl ester 1-carboxylic acid (1.1 (3)). 4- (1H-pyrazol-3-yl) -7 - {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidine (1.1 (1): 300 mg, was placed in a round bottom flask 0.951 mmol, 1 equiv) and 3- (cyanomethylene) azetidine-1-carboxylic acid tert-butyl ester (1.1 (2): 208 mg, 1.071 mmol, 1.126 equiv) in acetonitrile (V = 18 ml). To the resulting suspension, 1.8-diazabicyclo [5.4.0] undec-7-ene (DBU, 15 mg, 0.095 mmol, 0.10 eq) was added at room temperature. The resulting solution was stirred at room temperature overnight. After completion of the reaction (control using TLC-eluent CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1), the reaction mixture was evaporated to dryness on a rotary evaporator, water (V = 50 ml) was added to the residue, and EtOAc was extracted (three times 50 ml), the combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 4: 1-3: 1-2: 1-1: 1). 3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidine tert-butyl ester was obtained -1-carboxylic acid (1.1 (3)) as a yellow foam (350 mg, 72%). ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.84 (t, J = 8 Hz, 2H), 1.42 (s, 9H), 3.53 (t, J = 8 Hz, 2H ), 3.7 (s, 2H), 4.27 (d, J = 9.2 Hz, 2H), 4.48 (d, J = 9.2 Hz, 2H), 5.66 (s, 2H), 7.17 (d, J = 2.4 Hz, 1H ), 7.23 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H).

Stage (b). (3- {4- [7- (2-Trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-3-yl ) -acetonitrile dihydrochloride (1.1 (4) · HCl). To a solution of 3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl- tert-butyl ester azetidine-1-carboxylic acid (1.1 (3): 350 mg, 0.687 mmol) in 10 ml of THF was added 10 ml of 3N HCl in dioxane. The solution was stirred at room temperature overnight and concentrated in vacuo (control using TLC-hexane: EtOAc = 1: 1). Product 1.1 (4) was used in the next reaction without purification. Yield 300 mg, 91% as a yellow powder. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.85 (t, J = 8 Hz, 2H), 3.55 (t, J = 8 Hz, 2H), 3.99 (s, 2H ), 4.33-4.44 (m, 2H), 4.64-4.78 (m, 2H), 5.69 (s, 2H), 7.39-7.48 (m, 2H), 7.95 (d, J = 3.6 Hz, 1H), 8.47 ( d, J = 2.4 Hz, 1H), 8.97 (s, 1H), 9.89 (br.s, 1H), 10.14 (br.s, 1H).

Stage (c). (3-Cyanomethyl-3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl methyl ether -azetidine-1-sulfonyl) -acetic acid (1.1 (5)). To a solution of (3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-3 -yl) -acetonitrile dihydrochloride (1.1 (4) · HCl (1.1 (4) · HCl: (300 mg, 0.622 mmol, 1 equiv) in dichloromethane (V = 20 ml) containing Et ₃ N (220 mg, 2.18 mmol, 3.5 equiv) methyl (chlorosulfonyl) acetate (161 mg, 0.933 mmol, 1.5 equiv) was added, the mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 1: 2). The appropriate fractions were combined and concentrated in vacuo to give Connections 1.1 (5) (200 mg, 59%) ¹ H-NMR (DMSO-d _6, 400 MHz):. -0.05 (s, 9H), 0.92 (t, J = 8.3 Hz, 2H), 3.43 (s , 2H), 3.56 (t, J = 8.3 Hz, 2H), 3.83 (s, 3H), 4.16 (s, 2H), 4.40 (d, J = 9.3 Hz, 2H), 4.74 (d, J = 9.3 Hz , 2H), 5.68 (s, 2H), 6.81 (d, J = 3.7 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H), 8.36 (s, 1H), 8.53 (s, 1H), 8.85 (s, 1H).

Stage (d). (1- (2-Hydroxy-ethanesulfonyl) -3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-3-yl) -acetonitrile (1.1 (6)). To a solution of methyl ester (3-cyanomethyl-3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3 -cyanomethyl-azetidine-1-sulfonyl) -acetic acid (1.1 (5): 300 mg, 0.55 mmol, 1 eq.) in THF (V = 20 ml) LiBH ₄ (36 mg, 1.65 mmol, 3) was added eq). The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by column chromatography (silica gel, methanol: ethyl acetate = 1:20). The appropriate fractions were combined and concentrated in vacuo to give 1.1 (6) compounds (160 mg, 56%). ¹ H-NMR (DMSO-d ₆ , 400 MHz): -0.07 (s, 9H), 0.91 (t, J = 8.3 Hz, 2H), 3.36 (t, J = 5.7 Hz, 2H), 3.43 (s, 2H), 3.54 (t, J = 8.3 Hz, 2H), 4.06 (t, J = 5.7 Hz, 2H), 4.31 (d, J = 9.3 Hz, 2H), 4.67 (d, J = 9.3 Hz, 2H) , 5.64 (s, 2H), 6.77 (d, J = 3.7 Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 8.30 (s, 1H), 8.49 (s, 1H), 8.78 (s, 1H).

Stage (e). {1- (2-Hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3-yl} -acetonitrile ( 1.1). Solution of (1- (2-hydroxy-ethanesulfonyl) -3- {4- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl ] -3-cyanomethyl-azetidin-3-yl) -acetonitrile (1.1 (6): 160 mg, 0.309 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) was stirred for 2 hours. Solvents were removed in vacuo. The residue is {1- (2-hydroxy-ethanesulfonyl) -3- [4- (7-hydroxymethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3- il} -acetonitrile (1.1 (7)) was dissolved in methanol (V = 30 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the resulting solution. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, methanol: ethyl acetate = 1:20). The appropriate fractions were combined and concentrated in vacuo to give the desired product 1.1 (72 mg 1.1, 60%) as a white powder. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 3.41 (t, J = 6.1 Hz, 2H), 3.67 (s, 2H), 3.78 (qw, J = 6.1 Hz, 2H), 4.28 (d, J = 9.3 Hz, 2H), 4.62 (d, J = 9.3 Hz, 2H), 5.15 (t, J = 6.1 Hz, 2H), 7.08 (d, J = 3.7 Hz, 1H), 7.62 (d, J = 3.7 Hz, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H), 12.1 (s, 1H).

Example 2. {1- (2,2-Difluoroethane-sulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3- silt} -acetonitrile (1.3) was obtained in accordance with scheme 4.

Scheme 4

Stage (a, b). {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile (1.3 (2)). Solution of 4- (1H-pyrazol-4-yl) -7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.1 (1): 400 mg, 0.977 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) were stirred for 2 hours. Solvents were removed in vacuo. The residue (a mixture of 1.3 (1) and 1.3 (2)) was dissolved in methanol (V = 30 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the resulting solution. The mixture was stirred at room temperature overnight and then evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography (silica gel, CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1-150: 10: 1). Product 1.3 (2) was obtained as a white foam (200 mg, 73%). ¹ H-NMR (DMSO-d _6, 400 MHz): 3.59 (s, 2H ), 3.66 (d, J = 9.6 Hz, 2H), 4.1 (d, J = 9.6 Hz, 2H), 7.06 (d, J = 3.6 Hz, 1H), 7.6 (d, J = 3.6 Hz, 1H), 8.41 (s, 1H), 8.69 (s, 1H), 8.8 (s, 1H), 12.11 (br.s, 1H).

Stage (c). {1- (2,2-Difluoroethane-sulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3-yl} - acetonitrile (1.3). To a solution of {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile (1.3 (2): 260 mg, 0.931 mmol, 1 equiv) in DCM (V = 30 ml) containing Et ₃ N (94 mg, 0.931 mmol, 1 equiv) was added 2,2-difluoroethanesulfonyl chloride (153 mg, 1 equiv 0.931 mmol) at -10 ° C. The mixture was stirred at room temperature for 12-15 hours. The precipitate was filtered off and purified by column chromatography (silica gel-CHCl ₃ : MeOH = 19: 1-9: 1). Product 1.3 was obtained as a white crystalline solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 3.71 (s, 2H), 4.14-4.27 (m, 2H), 4.35 (d, J = 9.2 Hz, 2H), 4.70 (d, J = 9.2 Hz , 2H), 6.26-6.61 (m, 1H), 7.08 (s, 1H), 7.62 (s, 1H), 8.48 (s, 1H), 8.71 (s, 1H), 8.93 (s, 1H), 12.14 ( br.s, 1H).

Example 3. {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1 - [(2,2,2-trifluoroethane-sulfonyl] -azetidine -3-yl} acetonitrile (1.4) was obtained in accordance with scheme 5.

Scheme 5

3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -1 - [(2,2,2-trifluoroethyl) sulfonyl] -azetidin-3 -yl} acetonitrile (1.4). To a solution of {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile (1.3 (2): 100 mg, 0.358 mmol, 1 equiv) in DCM (V = 4 ml) containing Et ₃ N (40 mg, 0.4 mmol, 1.1 equiv), 2.2,2-trifluoroethanesulfonyl chloride (65.4 mg, 0.358 mmol, 1 equiv) was added ) The resulting mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with DCM (V = 2 ml). Product 1.4 was purified by column chromatography (silica gel CHCl ₃ : MeOH = 19: 1-9: 1). Product 1.4 was obtained as a white crystalline solid (48 mg, 31%). ¹ H-NMR (DMSO-d ₆ , 400 MHz): 3.7 (s, 2H), 4.41 (d, J = 9.2 Hz, 2H), 4.71-4.88 (m, 4H), 7.05-7.1 (m, 1H) 7.6-7.65 (m, 1H), 8.49 (s, 1H), 8.71 (s, 1H), 8.94 (s, 1H), 12.14 (br.s, 1H).

Example 4. Methyl ester of {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} -acetic acid ( 1.5) received in accordance with scheme 6.

Scheme 6.

{3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} -acetic acid methyl ester (1.5) was obtained by the interaction of {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl} acetonitrile (1.4 (2)) with methyl (chlorosulfonyl) - acetate under the synthesis conditions of {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -1 - [(2,2,2-trifluoroethyl) sulfonyl ] -azetidin-3-yl} acetonitrile (1.4) (Example 3). ¹ H-NMR (DMSO-d ₆ , 400 MHz) inhibitor 1.5: 3.69 (s, 2H), 3.70 (s, 3H), 4.38 (d, J = 9.3 Hz, 2H), 4.64 (s, 2H), 4.72 (d, J = 9.3 Hz, 2H), 7.07-7.10 (m, 1H), 7.61-7.64 (m, 1H), 8.48 (s, 1H), 8.71 (s, 1H), 8.94 (s, 1H), 12.14 (s, 1H)

Example 5. {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} -acetic acid (1.6) received in accordance with scheme 7.

Scheme 7.

To a suspension of 110 mg (0.26 mmol) of compound 1.5 in 5 ml of MeOH was added a solution of 16 mg (0.39 mmol) of NaOH in 5 ml of water. The mixture was stirred at room temperature overnight and then MeOH was removed in vacuo. The aqueous residue was acidified with 2 TH hydrochloric acid to pH5 under ice-cooling. The precipitate was filtered off and dried in air. Received 92 mg (90%) of compound 1.6 in the form of a white powder. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 3.68 (s, 2H), 4.37 (d, J = 9.3 Hz, 2H), 4.47 (s, 2H), 4.72 (d, J = 9.3 Hz, 2H ), 7.07-7.10 (m, 1H), 7.61-7.64 (m, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.94 (s, 1H), 13.46 (br.s, 1H).

Example 6. 2- {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-1-nl} ethanesulfonic acid ( 1.7) received in accordance with scheme 8.

Scheme 8.

Stage (a). 4- (1H-Pyrazol-4-yl) -7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.7 (2)). To a solution of 4-chloro-7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.7 (1): 1.0 g, 3.5 mmol, 1 equiv) in dioxane (V = 10 ml) 1H-pyrazol-5-ylboric acid (0.51 g, 4.6 mmol, 1.30 eq) and Na ₂ CO ₃ (1.11 g, 10.5 mmol, 3.0 eq) were added and water (V = 5 ml). The solution was degassed by passing through a solution of an argon stream for 3 minutes, after which tetrakis (triphenylphosphine) palladium (0) (0.23 g, 1.4 mmol, 0.05 eq) was added and the resulting reaction mixture was heated in a microwave system (120 ° C, 2 h). When, according to TLC (hexane: ethyl acetate = 1: 1), the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (V = 30 ml) and water (V = 40 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (twice 30 ml). The organic layers were combined, washed with saturated NaHCO ₃ solution (V = 20 ml), brine (V = 20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (MTBE, V = 40 ml), the solid was collected by filtration and washed with MTBE (twice 20 ml). The product 1.7 (2) (133 mg) was obtained as a white crystalline solid. ¹ H-NMR (CDCl _3, 400 MHz): 0.0 (s, 9H ), 0.94 (t, J = 8 Hz, 2H), 3.58 (t , J = 8 Hz, 2H), 5.71 (s , 2H), 7.08 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.47 (d, 3.6 Hz, 1H), 7.78 (d, 1.6 Hz, 1H), 8.95 ( s, 1H).

Stage (b). 3- {4- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -3-cyanomethyl-azetidin-1- tert-butyl ester carboxylic acid (1.7 (3)). At room temperature, 4- (1H-pyrazol-4-yl) -7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.7 (2): 300 mg, 0.951 mmol, was placed in a round bottom flask. 1 equiv) and tert-butyl-3- (cyanomethylene) azetidine-1-carboxylate (1.1 (2): 208 mg, 1.071 mmol, 1.126 equiv) in acetonitrile (V = 18 ml). To the resulting pink suspension was added 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU: 15 mg, 0.095 mmol, 0.10 eq). The resulting brown solution was stirred at room temperature for 12-15 hours. After TLC (CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1), the reaction was complete, the reaction mixture was evaporated to dryness on a rotary evaporator, to water (V = 50 ml) was added to the residue and extracted with EtOAc (three times 50 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 4: 1-3: 1-2: 1-1: 1). The product 1.7 (3) was obtained as a yellow foam (350 mg, 72%). ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.84 (t, J = 8 Hz, 2H), 1.42 (s, 9H), 3.53 (t, J = 8 Hz, 2H ), 3.7 (s, 2H), 4.27 (d, J = 9.2 Hz, 2H), 4.48 (d, J = 9.2 Hz, 2H), 5.66 (s, 2H), 7.17 (d, J = 2.4 Hz, 1H ), 7.23 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H).

Stage (c). (3- {4- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -azetidine-acetonitrile (1.7 (4)). K a solution of 3- {4- [7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -3-cyanomethyl-azetidin-1 tert-butyl ester -carboxylic acid (1.7 (3): 350 mg, 0.687 mmol) in 10 ml of THF was added 10 ml of 3N HCl in dioxane.The solution was stirred at room temperature overnight and concentrated in vacuo to give 1.7 (4) (300 mg, 91%) as a yellow powder, which was used in the next step without purification: ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.85 (t, J = 8 Hz, 2H), 3.55 (t, J = 8 Hz, 2H), 3.99 (s, 2H), 4.33-4.44 (m, 2H), 4.64-4.78 (m, 2H), 5.69 (s, 2H ), 7.39-7.48 (m, 2H), 7.95 (d, J = 3.6 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.97 (s, 1H), 9.89 (br.s, 1H) 10.14 (br.s, 1H).

Stage (d). 2- (3- {4- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -3-cyanomethyl-azetidin-1-yl ) -ethanesulfofluoride (1.7 (5)). To a solution of (3- {4- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -azetidine-acetonitrile (1.7 (4): 300 mg, 0.622 mmol, 1 equiv) in DCM (V = 20 ml) containing Et ₃ N (251 mg, 2.49 mmol, 4 equiv) was added 2-fluoroethanesulfonyl fluoride fluoride (82 mg, 0.622 mmol, 1 equiv). stirred at room temperature for 12-15 hours. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 1: 2). The appropriate fractions were combined and concentrated in vacuo. The product 1.7 (5) (150 mg, 46%) was obtained. ¹ H-NMR (CDCl ₃ , 400 MHz): -0.07 (s, 9H), 0.91 (t, J = 8 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H), 3.39 (s, 2H), 3.49 (t, J = 6.6 Hz, 2H) , 3.54 (t, J = 8 Hz, 2H), 3.74 (d, J = 8.3 Hz, 2H), 3.83 (d, J = 8.3 Hz, 2H), 5.66 (s, 2H), 6.80 (d, J = 3.7 Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 8.31 (s, 1H), 8.45 (s, 1H), 8.84 (s, 1H).

Stage (e, f). 2- {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-yl} ethanesulfonic acid (1-7). Solution 2- (3- {4- [7- (2-trimethylsilanyl-ethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -3-cyanomethyl-azetidin- 1-yl) ethanesulfofluoride (1.7 (5): 150 mg, 0.289 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) was stirred for 2 hours. The solvents were removed in vacuo. The residue 1.7 (6) was dissolved in MeOH (V = 30 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the solution. The mixture was stirred at room temperature for 12-15 hours and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, methanol: ethyl acetate = 1: 2). The appropriate fractions were combined, concentrated in vacuo to give the desired product 1.7 (55 mg, 49%) as a gray powder. ¹ H-NMR (CH ₃ OD, 400 MHz): 2.91-2.98 (m, 2H), 3.02-3.09 (m, 2H), 3.51 (s, 2H), 3.80 (d, J = 8.9 Hz, 2H), 3.87 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 3.7 Hz, 1H), 7.51 (d, J = 3.7 Hz, 1H), 8.40 (s, 1H), 8.68 (s, 1H), 8.71 (s, 1H).

Example 7. Amide 2- {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-1-nl} ethanesulfonic acid (1.8) and its dichloroacetate 1.8 · CHCl ₂ CO ₂ H were obtained in accordance with scheme 9.

Scheme 9.

Stage (a). Amide 2- {3- [4- (7 - {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] - 3- (cyanomethyl) azetidin-1-yl} ethanesulfonic acid (1.8 (1)). To the suspension of {3- [4- (7 - {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3 - (cyanomethyl) -azetidin-1-yl} acetonitrile dihydrochloride 1.7 (4) · 2HCl: 508 mg, 1.05 mmol, 1 equiv) in acetonitrile (15 ml = V) containing triethylamine (213 mg, 2.11 mmol, 2 equiv) ethylene sulfamide (140 mg, 1.16 mmol, 1.1 equiv) was added. The mixture was stirred and refluxed for 12-15 hours. The end of the reaction was monitored by TLC (CHCl ₃ : MeOH: 25% NH ₄ OH = 100: 10: 1). the reaction mixture was evaporated to dryness on a rotary evaporator, water (V = 50 ml) was added to the residue, and EtOAc was extracted (3 times with 20 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness on a rotary evaporator. The product was purified by column chromatography (silica gel, CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1). Product 1.8 (1) was obtained as a yellow oil (300 mg, 55%). ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.93 (t, J = 8 Hz, 2H), 3.13-3.32 (m, 4H), 3.37 (s, 2H), 3.5 (s , 2H), 3.56 (t, J = 8 Hz, 2H), 3.8-3.99 (m, 4H), 5.68 (s, 2H), 6.82 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 8.31 (s, 1H), 8.53 (s, 1H), 8.84 (s, 1H).

Stage (b, c). Amide 2- {3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -3-cyanomethyl-azetidin-1-nl} ethanesulfonic acid (1.8) . The amide 2- {3- [4- (7 - {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1- was stirred for 2 hours yl] -3- (cyanomethyl) azetidin-1-yl} ethanesulfonic acid (1.8 (1): 300 mg, 0.581 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml). Solvents were removed in vacuo. The residue was dissolved in methanol (V = 15 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the resulting solution. The mixture was stirred for 12-15 hours. The precipitate was filtered off and dried in air. 70 mg of compound 1.8 was obtained. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 2.88-2.97 (m, 2H), 3.03-3.12 (m, 2H), 3.54-3.67 (m, 4H), 3.73-3.82 (m, 2H), 6.78 (s, 2H), 7.03-7.08 (m, 1H), 7.57-7.62 (m, 1H), 8.42 (s, 1H), 8.7 (s, 1H), 8.81 (s, 1H), 12.12 (br. s, 1H). To a solution of 50 mg (0.129 mmol). In 10 ml of tetrahydrofuran, 16.7 mg (0.129 mmol) of dichloroacetic acid are added. The mixture was evaporated to dryness on a rotary evaporator. Dichloroacetate 1.8. CHCl ₂ CO ₂ H was obtained as a white solid.

Example 8. {1- (2-Metasulfonyl-ethyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3-yl} acetonitrile (1.9) was obtained in accordance with scheme 10.

Pattern 10

Stage (a). To a suspension of 588 mg (1.22 mmol) of compound 1.7 (4) · 2HCl in 15 ml of acetonitrile was added 247 mg (2.44 mmol) of triethylamine and 194 mg (1.83 mmol) of methyl vinyl sulfone. The mixture was refluxed overnight with stirring. The reaction mixture was evaporated to dryness in vacuo, 50 ml of water was added to the residue, and extracted with ethyl acetate (three times with 20 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The resulting product was purified by column chromatography (silica gel, CHCl ₃ : MeOH: 25% aqueous NH ₄ OH = 800: 10: 1-500: 10: 1-300: 10: 1). 400 mg (63%) of product 1.9 (1) were obtained as a yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 8 Hz, 2H), 3.04 (s, 3H), 3.07-3.18 (m, 4H), 3.37 (s , 2H), 3.57 (t, J = 8 Hz, 2H), 3.77 (d, J = 8.4 Hz, 2H), 3.86 (d, J = 8.4 Hz, 2H), 5.7 (s, 2H), 6.85 (d , J = 4 Hz, 1H), 7.45 (d, J = 4 Hz, 1H), 8.33 (s, 1H), 8.59 (br.s, 1H), 8.87 (s, 1H).

Stage (b, c). 400 mg (0.78 mmol) of product 1.9 (1) were stirred for 2 hours in a mixture of 20 ml of methylene chloride and 10 ml of trifluoroacetic acid. Solvents were removed in vacuo. The residue 1.9 (2) was dissolved in 20 ml of methanol, a solution of 1 ml of 25% NH ₄ OH in 2 ml of water was added. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness in vacuo, 70 ml of water was added to the residue and extracted with ethyl acetate (30 ml each three times). The combined organic extract was washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. Received 184 mg (61%) of inhibitor 1.9 as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 2.94 (t, J = 6.8 Hz, 2H), 3.04 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 3.55 (s, 2H ), 3.64 (d, J = 8.4 Hz, 2H), 3.79 (d, J = 8.4 Hz, 2H), 7.03-7.08 (m, 1H), 7.58-7.62 (m, 1H), 8.42 (s, 1H) 8.69 (s, 1H); 8.81 (s, 1H); 12.11 (br.s, 1H).

Example 9. {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1-ethanesulfonyl-azetidin-3-yl} acetonitrile (1.10) was obtained in according to scheme 11.

Scheme 11.

Stage (a). 4- (1H-Pyrazol-3-yl) -7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.10 (1)). To a solution of 4-chloro-7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.7 (1): 1.0 g, 3.5 mmol, 1 equiv) in dioxane (V = 10 ml) was added 1H-pyrazol-5-ylboric acid (0.51 g, 4.6 mmol, 1.30 eq), Na ₂ CO ₃ (1.11 g, 10.5 mmol, 3.0 eq) and water (V = 5 ml). The solution was degassed by passing a stream of argon through the solution for 3 minutes, after which it was treated with tetrakis (triphenylphosphine) palladium (0) (0.23 g, 1.4 mmol, 0.05 equiv). The resulting reaction mixture was heated in a microwave system (MW 120 ° C, 2 h). After completion of the reaction (controlled by TLC-hexane: ethyl acetate = 1: 1), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (V = 30 ml) and water (V = 40 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (twice 30 ml). The combined organic layers were washed with saturated NaHCO ₃ solution (V = 20 ml), brine (V = 20 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (MTBE, V = 40 ml), the solid was collected by filtration and washed with MTBE (twice 20 ml). Product 1.10 (1) (133 mg, 13% yield) was obtained as a white crystalline solid. ¹ H-NMR (CDCl _3, 400 MHz): 0.0 (s, 9H ), 0.94 (t, J = 8 Hz, 2H), 3.58 (t , J = 8 Hz, 2H), 5.71 (s , 2H), 7.08 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.47 (d, 3.6 Hz, 1H), 7.78 (d, 1.6 Hz, 1H), 8.95 ( s, 1H).

Stage (b). 3- {3- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -3-cyanomethyl-azetidin-1- tert-butyl ester carboxylic acid (1.10 (2)).

4- (1H-pyrazol-3-yl) -7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidine (1.10 (1): 300 mg, 0.951 mmol, 1 was placed in a round bottom flask eq) and tert-butyl 3- (cyanomethylene) -azetidine-1-carboxylate (208 mg, 1.071 mmol, 1.126 eq) in acetonitrile (V = 18 ml) at room temperature. To the resulting pink suspension was added 1,8-diazabicyclo [5.4.0] undec-7-ene (15 mg, 0.095 mmol, 0.10 eq). The resulting brown solution was stirred at room temperature for 12-15 hours. After the completion of the reaction (control using TLC-CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1), the reaction mixture was evaporated to dryness on a rotary evaporator, water was added to the residue (V = 50 ml) and was extracted with EtOAc (three times 50 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 4: 1-3: 1-2: 1-1: 1). The product 1.10 (2) was obtained as a yellow foam (350 mg, 72%). ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.84 (t, J = 8 Hz, 2H), 1.42 (s, 9H), 3.53 (t, J = 8 Hz, 2H ), 3.7 (s, 2H), 4.27 (d, J = 9.2 Hz, 2H), 4.48 (d, J = 9.2 Hz, 2H), 5.66 (s, 2H), 7.17 (d, J = 2.4 Hz, 1H ), 7.23 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H).

Stage (c). (3- {3- [7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -azetidin-3-yl) -acetonitrile (1.10 ( 3) 2HCl). To a solution of 3- {3- [7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -3-cyanomethyl-azetidin- tert-butyl ester 1-carboxylic acid (1.10 (2): 350 mg, 0.687 mmol) in 10 ml of THF was added 10 ml of 3N HCl in dioxane. The solution was stirred at room temperature for 12-15 hours and concentrated in vacuo. The end of the reaction was monitored by TLC-hexane: EtOAc = 1: 1. The resulting product 1.10 (3) · 2HCl (300 mg, 91%) as a yellow powder, which was used in the next step without purification. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.85 (t, J = 8 Hz, 2H), 3.55 (t, J = 8 Hz, 2H), 3.99 (s, 2H ), 4.33-4.44 (m, 2H), 4.64-4.78 (m, 2H), 5.69 (s, 2H), 7.39-7.48 (m, 2H), 7.95 (d, J = 3.6 Hz, 1H), 8.47 ( d, J = 2.4 Hz, 1H), 8.97 (s, 1H), 9.89 (br.s, 1H), 10.14 (br.s, 1H).

Stage (d). (3- {3- [7- (2-Trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -1-ethanesulfonyl-azetidin-3-yl) - acetonitrile (1.10 (4)). To a solution of (3- {3- [7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrazol-1-yl} -azetidin-3-yl) -acetonitrile ( 1.10 (3) · 2HCl: 300 mg, 0.622 mmol, 1 equiv) in DCM (V = 30 ml) containing Et ₃ N (251 mg, 2.49 mmol, 4 equiv) ethanesulfonyl chloride (80 mg, 0.622 mmol, 1 eq). The mixture was stirred at room temperature for 12-15 hours. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 3: 1-2: 1-1: 1-1: 2). Product 1.10 (4) (200 mg, 64%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.84 (t, J = 8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 3.25 (q, J = 7.2 Hz, 2H), 3.53 (t, J = 8 Hz, 2H), 3.74 (s, 2H), 4.28 (d, J = 9.6 Hz, 2H), 4.59 (d, J = 9.6 Hz, 2H), 5.66 ( s, 2H), 7.2 (d, 2.4 Hz, 2H), 7.27 (d, 3.6 Hz, 2H), 7.78 (d, 3.6 Hz, 2H), 8.31 (d, 2.4 Hz, 2H), 8.86 (s, 1H )

Stage (e, f). (3- {3- [7H-Pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -1-ethanesulfonyl-azetidin-3-yl) -acetonitrile (1.10). Solution (3- {3- [7- (2-trimethylsilanylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] pyrazol-1-yl} -1-ethanesulfonyl-azetidin-3-yl) -acetonitrile (1.10 (4): 150 mg, 0.298 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) was stirred for 2 hours. The solvents were removed in vacuo. The residue 1.10 (5) was dissolved in methanol (V = 30 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added and stirred at room temperature for 12-15 hours. The precipitate was filtered off, washed water (V = 5 ml) and dried in air. Product 1.10 (61 mg, 41%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 1.25 (t, J = 7.2 Hz, 3H), 3.25 (q, J = 7.2 Hz, 2H), 3.73 (s, 2H), 4.27 (d, J = 9.6 Hz, 2H), 4.58 (d, J = 9.6 Hz, 2H), 7.18 (s, 1H), 7.6 (s, 1H), 8.28 (s, 1H), 8.78 (s, 1H), 12.11 (br .s, 1H).

Example 10. {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -triazol-2-yl] -1-ethanesulfonyl-azetidin-3-yl} acetonitrile (1.12) was obtained in according to scheme 12.

Pattern 12

Stage (a). 7- (2-Trimethylsilanylethoxymethyl) -4-trimethylsilanylethynyl-7H-pyrrolo [2,3-d] pyrimidine (1.12 (1)). To a mixture of 7 - {[2-trimethylsilyl-ethoxy] methyl} -4-chloro-7H-pyrrolo [2,3-d] pyrimidine (1.7 (1): 5.3 g, 18.7 mmol, 1 equiv), ethynyltrimethylsilane (3.67 g, 37.4 mmol, 2 eq), PdCl ₂ (PPh ₃ ) ₂ (1.33 g, 1.9 mmol, 0.1 eq), CuI (0.36 g, 1.9 mmol, 0.1 eq) in TEA (V = 95 ml) was added anhydrous DMF (V = 19 ml) and heated under reflux for 3 hours. The reaction mixture was filtered while hot and concentrated in vacuo. The resulting residue was dissolved in EtOAc (V = 100 ml) and filtered through celite. The ethyl acetate layer was washed with water and brine. The organic phase is evaporated to dryness on a rotary evaporator. The product was purified by column chromatography (silica gel, hexane: EtOAc = 30: 1-20: 1). Product 1.12 (1) was obtained as a brown oil (1.6 g, 25%). ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.34 (s, 9H), 0.91 (t, J = 8 Hz, 2H), 3.52 (t, J = 8 Hz, 2H), 5.66 (s, 2H), 6.71 (d, J = 3.6 Hz, 1H), 7.4 (d, J = 3.6 Hz, 1H), 8.86 (s, 1H).

Stage (b). 7 - {[2-trimethylsilylethoxy] methyl} -4-ethynyl-7H-pyrrolo [2,3-d] pyrimidine (1.12 (2)). 7- (2-Trimethylsilanylethoxymethyl) -4-trimethylsilanylethynyl-7H-pyrrolo [2,3-d] pyrimidine (1.12 (1): 1.6 g, 4.6 mmol, 1 equiv) was dissolved in THF (V = 50 ml ), the resulting solution was cooled to 0 ° C and water (V = 3.4 ml) was added, and then 75% TBAF in water (1.88 g, 1.41 g, 5.4 mmol, 1.17) was added dropwise. equiv). The reaction mixture was allowed to warm from 0 ° C to 15 ° C for 1 h. The end of the reaction was monitored by TLC (hexane: EtOAc = 4: 1). Water (V = 150 ml) and EtOAc (V = 50 ml) were added to the reaction mixture with stirring, the aqueous phase was separated, washed with additional ethyl acetate (twice with 50 ml). The combined organic phases were washed with water (three times 50 ml), then with brine, then dried over Na ₂ SO ₄ and evaporated to dryness on a rotary evaporator. Product 1.12 (2) was obtained as a brown oil (1.26 g, 99%).

Stage (c). 4- (1H-1,2,3-Triazol-4-yl) -7 - {[2-trimethylsilylethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidine (1.12 (3)). To a stirred solution of 7 - {[2-trimethylsilylethoxy] methyl} -4-ethynyl-7H-pyrrolo [2,3-d] pyrimidine (1.12 (2): 1.26 g, 4.6 mmol, 1 equiv) and CuI (40 mg, 0.2 mmol, 0.05 eq) in a DMF / MeOH solution (V = 30 ml, 9: 1), trimethylsilyl azide (0.79 g, 6.9 mmol, 1.5 eq) was added under argon atmosphere . The resulting solution was stirred at 100 ° C for 24 hours. After the disappearance of compound 1.12 (2) in the reaction mixture (TLC control - hexane: EtOAc = 1: 1), the mixture was cooled to room temperature and evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 2: 1-1: 1). Product 1.12 (3) was obtained as a brown oil (300 mg, 20%).

¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.0 (s, 9H), 0.84 (t, J = 8 Hz, 2H), 3.54 (t, J = 8 Hz, 2H), 5.67 (s, 2H ), 7.21 (br.s, 1H), 7.81 (s, 1H), 8.87 (s, 1H), 15.52 (br.s, 1H).

Stage (d). 3- {4- [7- (2-Trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] - [1,2,3] triazol-2-yl} -3 tert-butyl ester -cyanomethyl-azetidine-1-carboxylic acid (1.12 (4)). 4- (1H-1,2,3-triazol-4-yl) -7 - {[2-trimethylsilylethoxy] methyl} -7H-pyrrolo [2,3-d] pyrimidine was placed in a round bottom flask at 20 ± 5 ° C (1.12 (3): 300 mg, 0.948 mmol, 1 equiv) and tert-butyl-3- (cyanomthylene) azetidine-1-carboxylate (207 mg, 1.07 mmol, 1.126 equiv) in acetonitrile (V = 6 ml) . To the resulting solution was added 1,8-diazabicyclo [5.4.0] undec-7-ene (15 mg, 0.095 mmol, 0.10 eq). The brown solution was stirred at 20 ° C for 12-15 hours. The end of the reaction was monitored by TLC (CHCl ₃ : MeOH: 25% NH ₄ OH = 200: 10: 1) After the completion of the reaction, water (V = 35 ml) was added with stirring for 80 minutes at 20 ° C. The mixture was stirred at room temperature for 12 hours. If no precipitate formed, water (V = 50 ml) was added to the mixture and EtOAc was extracted (three times with 20 ml). The combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 4: 1-3: 1-2: 1). Product 1.12 (4) (200 mg, 41%) was obtained as a dark yellow crystalline solid. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 8 Hz, 2H), 1.51 (s, 9H), 3.51 (s, 2H), 3.57 (t, J = 8 Hz, 2H), 4.35 (d, J = 9.6 Hz, 2H), 4.79 (d, J = 9.6, 2H), 5.72 (s, 2H), 7.23 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 8.57 (s, 1H), 8.97 (s, 1H).

Stage (e). (3- {4- [7- (2-Trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] - [1,2,3] triazol-2-yl} -azetidin-3- sludge-acetonitrile dihydrochloride (1.12 (5) · 2HCl). To a solution of 3- {4- [7- (2-trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] - [1,2,3] triazol-2-yl} tert-butyl ester} -3-cyanomethyl-azetidine-1-carboxylic acid (1.12 (4): 200 mg, 0.39 mmol) in 15 ml of THF was added 15 ml of 3N HCl in dioxane. The solution was stirred for 12-15 hours at room temperature and concentrated in vacuo. The end of the reaction was monitored by TLC (hexane: EtOAc = 1: 1). The resulting product 1.12 (5) · 2HCl (189 mg, 99%) as a yellow powder was used in the next step without purification.

Stage (f). {1- (Ethylsulfonyl) -3- [4- (7 - {[2-trimethylsilylethoxymethyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -2H-1,2,3-triazol-2 -yl] azetidin-3-yl) -acetonitrile (1.12 (6)). To a solution of (3- {4- [7- (2-trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] - [1,2,3] triazol-2-yl} -azetidine- 3-yl) -acetonitrile dihydrochloride (1.12 (5) · 2HCl): 189 mg, 0.391 mmol, 1 equiv) in DCM (V = 30 ml) containing Et ₃ N (0.22 ml, 159 mg, 1.56 mmol, 4 eq) ethanesulfonyl chloride (50.3 mg, 0.391 mmol, 1 eq) was added at -10 ° C. The mixture was stirred at room temperature for 12-15 hours. The reaction mixture was evaporated to dryness on a rotary evaporator, saturated NaHCO ₃ solution (V = 30 ml) was added to the residue, and extracted with ethyl acetate (three times with 20 ml). The combined extract was washed with brine and evaporated to dryness on a rotary evaporator. The residue was washed with hexane, filtered, dried in air and purified by column chromatography (silica gel, hexane: EtOAc = 3: 1-2: 1-1: 1). Product 1.12 (6) (150 mg, 76%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 11.2 Hz, 2H), 1.46 (t, J = 9.6 Hz, 3H), 3.07-3.2 (m, 2H ), 3.51-3.53 (m, 4H), 4.31 (d, J = 12.4 Hz, 2H), 4.93 (d, J = 12.4 Hz, 2H), 5.73 (s, 2H), 5.51 (d, J = 4 Hz , 1H), 8.66 (br.s, 1H), 8.99 (s, 1H).

Stage (g, h). {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -triazol-2-yl] -1-ethanesulfonyl-azetidin-3-yl} acetonitrile (1.12). {1- (ethylsulfonyl) -3- [4- (7 - {[2-trimethylsilylethoxymethyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -2H-1,2,3-triazol-2 -yl] azetidin-3-yl) -acetonitrile (1.12 (6): 150 mg, 0.298 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) was stirred for 2 hours. The solvents were removed in vacuo. . The residue 1.12 (7) was dissolved in methanol (V = 30 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the solution. The mixture was stirred at room temperature for 12-15 hours, the precipitate was filtered off, washed with water (V = 5 ml) and dried in air. Product 1.12 (55 mg, 47%) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 1.28 (t, J = 7.2 Hz, 3H), 3.22-3.33 (m, 2H), 3.89 (s, 2H), 4.31 (d, J = 9.2 Hz , 2H), 4.69 (d, J = 9.2 Hz, 2H), 7.17 (s, 1H), 7.71 (s, 1H), 8.7 (s, 1H), 8.85 (s, 1H), 12.3 (br, s. 1H).

Example 11. {1- (3-Hydroxypropyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -azetidin-3-yl} acetonitrile trifluoroacetate (1.17 · CF ₃ CO ₂ H) was obtained in accordance with scheme 13.

Stage (a). {1- (3-Hydroxypropyl) -3- [4- (7- [2-trimethylsilylethoxymethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin- 3-yl} acetonitrile (1.17 (1)). To a solution of {3- [4- (7 - {[2-trimethylsilylethoxymethyl} -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile dihydrochloride (1.7 (4) · 2HCl: 500 mg, 1.036 mmol, 1 eq) in DMF (15 ml V =) containing K ₂ CO ₃ (430 mg, 3.11 mmol, 3 eq), 3-bromopropane was added 1-ol (173 mg, 1.24 mmol, 1.2 equiv). The mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and extracted with EtOAc (three times with 20 ml). The combined extract was washed with saturated brine, dried over Na2SO ₄ and evaporated to dryness on a rotary evaporator. Product 1.17 (1) was used in the next step without further purification.

Stage (b, c). {1- (3-Hydroxypropyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile trifluoroacetate ( 1.17 CF ₃ CO ₂ H).

{1- (3-Hydroxypropyl) -3- [4- (7- [2-trimethylsilylethoxymethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin- 3-yl} acetonitrile (1.17 (1): 410 mg, 0.876 mmol) in methylene chloride (V = 10 ml) and trifluoroacetic acid (V = 5 ml) was stirred for 2 hours. The solvents were removed in vacuo. The residue (a mixture of 1.17 (1) and 1.17 (2)) was dissolved in methanol (V = 15 ml), a solution of 25% NH ₄ OH (V = 1 ml) in water (V = 2 ml) was added to the solution. The mixture was stirred at room temperature for 12-15 hours. The reaction mixture was evaporated to dryness on a rotary evaporator, a 5% aqueous solution of K ₂ CO ₃ (V = 40 ml) was added to the residue, EtOAc was extracted (three times with 20 ml) and the combined extract was evaporated on a rotary evaporator to dryness. The residue was purified using preparative HPLC. Product 1.17 · CF ₃ CO ₂ H was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 0.33-0.44 (m, 2H), 2.07 (t, J = 7.2Hz, 2H), 2.18-2.30 (m, 4H), 3.22-3.38 (m, 4H), 3.54 (d, J = 12Hz, 2H), 5.71 (d, J = 3.6Hz, 1H), 6.27 (d, J = 3.6Hz, 1H), 7.09 (s, 1H), 7.37 (s, 1H ), 7.52 (s, 1H).

The compound {1- (3-hydroxy-propan-1-sulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl)] - azetidine was obtained -3-yl} -acetonitrile (1.14).

Example 12. {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} propionic acid methyl ester (1.15 ) were obtained in accordance with scheme 14.

Scheme 14

To a solution of 2.6 g (5.4 mmol) of compound 1.7 (4) · 2HCl in 100 ml of dichloromethane was added 2.2 g (21.6 mmol) of triethylamine, cooled to -20 ° C and 1.6 g (8.1 mmol) was added dropwise. ethyl 3- (chlorosulfonyl) propanoate. The resulting mixture was stirred at room temperature overnight, evaporated to dryness in vacuo, 70 ml of water was added to the residue, extracted with ethyl acetate (three times with 30 ml). The combined organic extract was washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 2: 1-1: 1-1: 20: 1). Obtain 2.3 g (74%) of compound 1.15 (1) as a colorless oil. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 8.4 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 2.84 (t, J = 7.2 Hz, 2H), 3.36-3.46 (m, 4H), 3.57 (t, J = 8.4 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 4.28 (d, J = 9.2 Hz, 2H), 4.63 (d, J = 9.2 Hz, 2H), 5.7 (s, 2H), 6.85 (d, J = 4 Hz, 1H), 7.47 (d, J = 4 Hz, 1H), 8.37 (s, 1H), 8.66 (br.s, 1H); 8.88 (s, 1H). A solution of 445 mg (0.776 mmol) of compound 1.15 (1) in 20 ml of methylene chloride and 10 ml of trifluoroacetic acid was stirred for 3 hours. The solvents were removed in vacuo. The residue 1.15 (2) is dissolved in 15 ml of ethanol, a solution of 1 ml of 25% NH ₄ OH in 2 ml of water is added to the resulting solution. The resulting mixture was stirred at room temperature overnight. The precipitate was filtered off and purified by column chromatography (silica gel, CHCl ₃ : MeOH = 19: 1-10: 1). 150 mg of compound 1.15 are obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 1.16 (t, J = 7.2 Hz, 3H), 2.75 (t, J = 7.2 Hz, 2H), 3.5 (t, J = 7.2 Hz, 2H), 3.69 (s, 2H), 4.05 (q, J = 7.2 Hz, 2H), 4.26 (d, J = 9.2 Hz, 2H), 4.6 (d, J = 9.2 Hz, 2H), 7.06-7.10 (m, 1H ), 7.60-7.64 (m, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.93 (s, 1H), 12.14 (br.s, 1H).

Example 13. {3- [4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (3-fluoropropanesulfonyl) -azetidin-3-yl} -acetonitrile (1.16) and its dichloroacetate 1.16 · CHCl ₂ CO ₂ H were obtained in accordance with scheme 15.

Scheme 15

To a solution of 1.7 g (3 mmol) of compound 1.15 (1) in 50 ml of tetrahydrofuran was added 0.2 g (9.0 mmol) of LiBH ₄ . The mixture was stirred at room temperature overnight, then 10 ml of methanol and 250 ml of water were added. The resulting mixture was extracted with ethyl acetate (30 ml each time), the combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , evaporated to dryness in vacuo, the residue was purified by column chromatography (silica gel, hexane: EtOAc = 1: 1-0: 1, then ethyl acetate: methanol = 9: 1). Compound 1.16 (1) was obtained. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 8.4 Hz, 2H), 2.06-2.16 (m, 2H), 2.71-2.80 (m, 1H), 3.28 (t, J = 7.6 Hz, 2H), 3.45 (s, 2H), 3.57 (t, J = 8 Hz, 2H), 3.79 (t, J = 6 Hz, 2H), 4.32 (d, J = 9.6 Hz , 2H), 4.6 (d, J = 9.6 Hz, 2H), 5.71 (s, 2H), 6.88 (d, J = 3.6 Hz, 1H), 7.5 (d, J = 3.6 Hz, 1H), 8.36 (s , 1H), 8.81 (br.s, 1H), 8.87 (s, 1H). To a solution of 800 mg (1.505 mmol) of compound 1.16 (1) in 20 ml of dichloromethane, 0.5 ml (606 mg, 3.76 mmol) of DAST is added at −20 ° C. The mixture was stirred at room temperature overnight, 100 ml of a saturated aqueous NaHCO ₃ solution was added at 0 ° C, and stirred for 20 minutes. The resulting reaction mass was extracted with ethyl acetate (three times in 30 ml), the combined extract was washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, hexane: EtOAc = 1: 1-1: 2). Compound 1.16 (2) was obtained. ¹ H-NMR (CDCl ₃ , 400 MHz): 0.0 (s, 9H), 0.94 (t, J = 8 Hz, 2H), 2.17-2.34 (m, 2H), 3.18-3.26 (m, 2H), 3.42 (s, 2H), 3.57 (t, J = 8 Hz, 2H), 4.28 (d, J = 9.6 Hz, 2H), 4.54 (t, J = 5.6 Hz, 1H), 4.62-4.7 (m, 3H) , 5.7 (s, 2H), 6.82 (d, J = 3.6 Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H), 8.37 (s, 1H), 8.51 (s, 1H), 8.87 (s, 1H).

A solution of 300 mg (0.562 mmol) of compound 1.16 (2) in 20 ml of methylene chloride and 10 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. The solvents were removed in vacuo, 30 ml of methanol and 3 ml of solution were added to residue 1.16 (3), obtained from 1 ml of 25% NH ₄ OH and 2 ml of water. The mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, CHCl ₃ : MeOH = 19: 1-15: 1). 60 mg of compound 1.16 are obtained as a white solid. ¹ H-NMR (DMSO-d ₆ , 400 MHz): 2.01-2.18 (m, 2H), 3.30-3.39 (m, 2H), 2.7 (s, 2H), 4.27 (d, J = 9.2 Hz, 2H) , 4.49 (t, J = 6 Hz, 1H), 4.57-4.66 (m, 3H), 7.06-7.1 (m, 1H), 7.59-7.64 (m, 1H), 8.48 (s, 1H), 8.71 (s , 1H), 8.93 (s, 1H), 12.13 (br.s, 1H). To a solution of 80.7 mg (0.2 mmol) of compound 1.16 in 10 ml of tetrahydrofuran was added 25.8 mg (0.2 mmol) of dichloroacetic acid. The mixture was evaporated to dryness on a rotary evaporator. Dichloroacetate 1.16 · CHCl ₂ CO ₂ H was obtained as a white solid.

Example 14. Determination of the inhibitory activity of compounds against JAK. Compounds were tested according to Life Technologi's standard Z`-Lyte screening protocol. Test compounds are tested in 1% DMSO (final) in the well. 100 nl 100x test compounds in 100% DMSO add 2.4 μl kinase buffer (50 mM HEPES, pH6.5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA, 0.02% NaN ₃ ) in low volume NBS, black 384-well plate (Corning Cat. # 4514). After this, 5 μl of the 2X peptide / kinase mixture (Tyr06 / JAK1, final concentrations of 21.2-91.5 ng JAK1 and 2 μm Tyr 06) and 2.5 μl of 4xATP (final concentration of 75 μM) are added to the kinase buffer. After 30 seconds on a shaker, the kinase reaction was incubated for 60 min at room temperature. After this, 5 μl of a 1: 128 dilution of reagent A development and incubated for another 60 min at room temperature. Fluorescence was measured upon excitation at 400 nm and emission at 445 nm and 520. The degree of phosphorylation of the FRET peptide can be calculated from the emission ratio. The emission factor will remain low if the Lada peptide is not phosphorylated (i.e., not kinase inhibition) and will be high if the Lada peptide is non-phosphorylated (i.e., kinase inhibition). % phosphorylation is calculated according to the formula indicated on page 6 in the standard Z′-LYTE screening protocol (Life Technologies).

The concentration curve of the kinase activity versus the concentration of the tested substances was constructed using the sigmoid model.

The activity data of the compounds of general formula 1 in relation to JAK1 are presented in table 1.

Example 15. Determination of thermodynamic solubility of the compounds of formula (1) and the prototype Baricitinib. 5 mg of the test compound was mixed with 1 ml of universal buffer (pION) with a pH of 2.0, 4.0 or 7.0 for 15 min at 25 ° C. Additional amounts of substances were added until the solution became cloudy. Vials with solution were incubated with stirring for 24 hours at 25 ° C to achieve equilibrium between solution and precipitate at saturation. After equilibration, 200 μl of the solution (in 2 repetitions) was filtered through a 96-well filter plate (Millipore) to separate the precipitate. The concentration of compounds in the filtrate was determined spectrophotometrically using a standard calibration curve. The optical absorption spectrum of the substance was measured and a calibration curve was constructed at the selected wavelength (usually corresponding to the maximum absorption of the substance λmax). The concentration of the substance in the filtrate (i.e. solubility) was calculated by the formula below:

Solubility = (OD _λmax filtrate - OD _λmax blank) / Slope × 1.67 × Filtrate dilution,

where: OD _λmax filtrate is the optical density of the filtrate,

OD _λmax blank - optical density of a blank solution without a substance,

Slope - slope of the calibration curve,

1.67 - dilution factor of the filtrate with acetonitrile,

Filtrate dilution - factor dilution of the filtrate with a buffer.

The results are presented in table 2.

Example 16. Obtaining a drug in the form of tablets. A mixture of 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of the inhibitor 1.16 · CHCl ₂ CO ₂ H was pressed. The obtained bar was crushed into granules and sieved through a sieve, collecting granules of 14-16 mesh in size. The granules obtained were tabletted into tablets of suitable forms weighing 500 mg each.

Example 17. Obtaining a drug in the form of capsules. Inhibitor 1.16 · CHCl ₂ CO ₂ H was thoroughly mixed with lactose in a ratio of 2: 1. The resulting powder mixture was packaged in 600 mg in gelatin capsules of the appropriate size.

Example 18. Obtaining a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of the inhibitor 1.16 · CHCl ₂ CO ₂ H, 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of water for injection were mixed. The solution was filtered and placed in 1 ml ampoules, which were sealed.

From the above description, various modifications of the invention are apparent to those skilled in the art in addition to those described herein.

Claims (17)

1. The compound of General formula 1:

or its pharmaceutically acceptable salt, where:
R ¹ represents SO ₂ (CH ₂ ) _n CH ₂ OH, SO ₂ (CH ₂ ) _n CH ₂ F, SO ₂ (CH ₂ ) _n CHF ₂ , SO ₂ (CH ₂ ) _n CF ₃ , SO ₂ (CH ₂ ) _n CO ₂ R ^1a , SO ₂ (CH ₂ ) _n CO ₂ H, CH ₂ CH ₂ SO ₂ CH ₃ , CH ₂ CH ₂ SO ₃ H, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH ₂ SO ₂ NH ₂ ; n is 1 or 2;
R ^la represents C ₁ -C ₃ alkyl;
X and Y represent a nitrogen atom; or X represents a nitrogen atom, and Y represents methine; or X represents methine, and Y represents a nitrogen atom;
or R ¹ represents SO ₂ CH ₂ CH ₃ ; X and Y represent a nitrogen atom, or X represents a methine, and Y represents a nitrogen atom. 2. The compound according to claim 1, selected from:
{1- (2-hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -azetidin-3-yl} -acetonitrile ( 1.1);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2-fluoro-ethanesulfonyl) -azetidin-3-yl} -acetonitrile ( 1.2);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2,2-difluoro-ethanesulfonyl) -azetidin-3-yl} - acetonitrile (1.3);
[3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (2,2,2-trifluoro-ethanesulfonyl) -azetidin-3-yl ] -difluoroethanesulfonyl (1.4);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} acetic acid methyl ester (1.5);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} acetic acid (1.6);
2- {3- [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-yl} ethanesulfonic acid (1.7);
amide of 2- {3 [4 (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-yl} ethanesulfonic acid (1.8);
{1- (2-methanesulfonyl-ethyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -azetidin-3-yl} -acetonitrile (1.9 );
{3- [3- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -1-ethanesulfonyl-azetidin-3-yl} -acetonitrile (1.10);
{1- (2-hydroxy-ethanesulfonyl) -3- [3- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -azetidin-3-yl} -acetonitrile (1.11 );
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - [1,2,3] triazol-2-yl] -1-ethanesulfonyl-azetidin-3-yl} -acetonitrile (1.12);
{1- (2-hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl) - [1,2,3] triazol-2 -yl] -azetidin-3-yl} -acetonitrile (1.13);
{1- (3-hydroxy-propan-1-sulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl)] azetidin-3-yl } -acetonitrile (1.14);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] -3-cyanomethyl-azetidin-1-sulfonyl} propionic acid methyl ester (1.15);
{3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -1- (3-fluoropropanesulfonyl) -azetidin-3-yl} -acetonitrile (1.16) ;
{1- (3-hydroxypropyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidin-3-yl} acetonitrile trifluoroacetate ( 1.17)
or their pharmaceutically acceptable salts. 3. A pharmaceutical composition having the properties of a Janus kinase inhibitor (JAK), comprising, as an active component, a compound of general formula 1 according to claims. 1, 2 and / or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. 4. The pharmaceutical composition according to claim 3 for use in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package. 5. A method of treating JAK-related diseases or disorders, comprising administering to a specified patient a therapeutically effective amount of a compound of claim 1 or 2 or a pharmaceutically acceptable salt or pharmaceutical composition of claim 3 or 4. 6. The method of claim 5, wherein the JAK-related disease or disorder is an autoimmune disease. 7. The method of claim 6, wherein said autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, or juvenile arthritis. 8. A method for producing a compound of general formula 1 according to claim 1, comprising removing the protective group R ^{2 of} the compound of formula 1a:

or its pharmaceutically acceptable salt, where:
R ¹ represents SO ₂ (CH ₂ ) _n CH ₂ OH, SO ₂ (CH ₂ ) _n CH ₂ F, SO ₂ (CH ₂ ) _n CHF ₂ , SO ₂ (CH ₂ ) _n CF ₃ , SO ₂ (CH ₂ ) _n CO ₂ R ^la , SO ₂ (CH ₂ ) _n CO ₂ H, CH ₂ CH ₂ SO ₂ CH ₃ , CH ₂ CH ₂ SO ₃ H, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH ₂ SO ₂ NH ₂ ; n is 1 or 2;
R ^1a represents C ₁ -C ₃ alkyl;
X and Y represent a nitrogen atom, or X represents a nitrogen atom, a Y represents a methine group, or X represents a methine group, a Y represents a nitrogen atom,
or R ¹ represents SO ₂ CH ₂ CH ₃ , and X and Y represent a nitrogen atom or X represents a methine group, and Y represents a nitrogen atom?
R ² represents a protective group. 9. The method of claim 8, wherein R ² is 2- (trimethylsilyl) ethoxymethyl, hydroxymethyl. 10. The method according to p. 8, in which the removal of the protective group R ^{2 is} carried out by the action of lithium tetrafluoroborate or boron trifluoride diethyl etherate on the compound, followed by treatment with ammonium hydroxide. 11. The method according to p. 8, further comprising reacting a compound of formula 1b with a compound of formula 1c

where R ² has the meanings specified in paragraph 8, R ^1b means a protective group, followed by optionally removing the protective group to obtain compound 1d. 12. The method of claim 11, wherein R ^1b is tert-butoxycarbonyl, R ² is 2- (trimethylsilyl) ethoxymethyl, hydroxymethyl. 13. The method according to p. 11, in which the interaction of the compounds of formula 1b and formula 1c is carried out in the presence of a Michael catalyst. 14. The method of claim 13, wherein the Michael catalyst is tetramethylguanidine, 1,8-diazabicyclo (5.4.0) undec-7-ene, 1,5-diazabicyclo (4.3.0) non-5-ene, 1, 4-diazabicyclo (2.2.2) octane, ammonium tert-butyl hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, hydrogen phosphate potassium, triphenylphosphine, triethylphosphine, potassium acetate, or potassium acrylate. 15. The method according to any one of paragraphs. 8-13, further comprising reacting a compound of formula 1d with a compound of formula R ¹ -R ′; in which R ′ represents a leaving group

R ¹ and R ² have the meanings specified in paragraph 8, followed by optionally converting the compound where the R ² group means a SO ₂ (CH ₂ ) _n CO ₂ R ^1a group to a compound where R ² means a SO ₂ (CH ₂ ) _n CO ₂ H and / or to the compound, where R ² means a group SO ₂ (CH ₂ ) _n CH ₂ OH and / or SO ₂ (CH ₂ ) _n CH ₂ F. 16. The method according to p. 14, in which R ′ represents a halogen. 17. The method according to any one of paragraphs. 8-15, in which the reaction of a compound of formula 1d with a compound of formula R ¹ -R ′ is carried out in the presence of a base.