RU2638155C1 - Benzo[d]isoxazole derivatives and their application - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to a compound of the formula

(I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the linker L₁ is selected independently and represents -CH₂-, -NH-, -O- or -S-; R₁ is selected independently and is hydrogen, halogen, -C_1-3-alkyl, partially or fully halogenated -C_1-3-alkyl, -CN, -OH, -O-C_1-3-alkyl, -NH₂, -NHC_1-3-alkyl, -N (C_1-3-alkyl) C_1-3-alkyl, -C₁-₃-alkyl-NH₂, -C_1-3-alkyl-NH-C_1-3-alkyl, -C_1-3-alkyl-N(C_1-3-alkyl)C_1-3-alkyl or a 5-membered heteroaryl ring containing 1 to 4 N atoms and 0 to 1 S atom; R₁ group contains 0-2 R₄ substituents; R₂ is selected independently and is halogen, partially or fully halogenated -CH₃ or -OCH₃; R₃ is selected independently and is hydrogen or halogen; R₄ is selected independently and is halogen or C_1-3-alkyl; A cycle is selected independently and represents phenyl, a 5-6 membered heteroaryl ring containing 1 to 2 N atoms; A cycle contains 0-1 R₅ substituent and 0-2 R₆substituent; R₅ is selected independently and is phenyl; 5-9 membered heteroaryl containing 1 to 2 N atoms and 0 to 1 S or O atom, 5-6 membered cycloalkyl or 5-6 membered heterocycle containing 1 to 2 N atoms, 0 to 1 S or O atoms; R₅ contains 0-2 R'₆substituents; R₆ and R'₆ are selected independently and represent -OH, -C_1-3-alkyl, -C(O)OH, -C(O)NH₂, -NHC(O)H, -NHC(O)C_1-3-alkyl, -C_1-3-alkyl-NHC(O)H, -C_1-3-alkyl-NHC(O)C_1-3-alkyl, -NHC(O)OH, -C_1-3-alkyl-NHC(O)OH, -NH₂, -NHC_1-3-alkyl, -N(C_1-3-alkyl)C_1-3-alkyl, -C_1-3-alkyl-NH₂, -C_1-3-alkyl-NHC_1-3-alkyl, -C_1-3-alkyl-N(C_1-3-alkyl)C_1-3-alkyl, -CN, halogen, -S(O)₂NH₂, a 5-6 membered saturated, unsaturated or partially saturated heterocycle containing 1 to 4 N atoms, 0 to 1 atom S; R₆ and R'₆ contain 0-2 R₇ substituents; R₇ is selected independently and is = O, -C_1-3-alkyl, -NH₂, -NHC_1-3-alkyl, -N (C_1-3-alkyl) C_1-3-alkyl, -C_1-3-alkyl-NH₂, -C_1-3-alkyl-NHC_1-3-alkyl, -C_1-3-alkyl-N(C_1-3-alkyl)C_1-3-alkyl, -OH, -OC_1-3-alkyl, -C_1-3-alkyl-OH, -C_1-3-alkyl-O-C_1-3-alkyl or halogen. The compounds of the invention are intended to be used as inhibitors of the coagulation factor XIa in blood or plasma, as well as for preparation of a pharmaceutical composition for treatment and/or prevention of a condition of a mammal characterized by undesirable thrombosis. A pharmaceutical composition for treatment and/or prevention of a condition of a mammal characterized by undesired thrombosis comprises an effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.

EFFECT: increased efficiency of derivatives.

9 cl, 5 ex

Description

FIELD OF TECHNOLOGY

This invention relates to the chemistry of organic compounds, pharmacology and medicine, and relates to the prevention and treatment of diseases whose etiology or pathogenesis is associated with undesirable thrombosis, in particular thrombosis and thromboembolism, using a new class of chemical compounds that are highly effective in inhibiting therapeutically significant proteases, coagulation factor XIa, as well as increased selectivity and bioavailability.

BACKGROUND

Thromboembolic diseases are one of the leading causes of death in developed countries. By thrombosis is understood the formation of a thrombus (clot) in the lumen of a blood vessel. A blood clot can form both in the veins and in the arteries; most often, blood clots are localized in the veins, especially in the veins of the lower extremities. Coronary artery thrombosis results in insufficient blood supply to one of the heart segments, which can cause the development of acute myocardial infarction. In some cases, a blood clot comes off and moves freely along the bloodstream, which can lead to acute blockage of a blood vessel by a thrombus (thromboembolism) with subsequent violation of local blood supply. Thromboembolism of large branches of the pulmonary artery is especially dangerous - a common cause of sudden death. Cerebral vascular blockage is the cause of ischemic strokes. According to statistics from the World Health Organization, 17 million people die every year from diseases of the cardiovascular system.

Blood coagulation is a complex biological process of formation of fibrin protein filaments in the blood, forming clots. In a healthy person, damage to blood vessels causes the activation of the so-called external coagulation pathway. This pathway is launched using a special protein - a tissue factor that enters the bloodstream during an injury. Tissue factor causes a cascade of enzymatic reactions, starting with the activation of a special enzyme, factor VII, which in turn activates another enzyme, factor X. The active form of factor X (factor Xa) catalyzes the conversion of prothrombin to thrombin, which performs the main work of converting free fibrinogen into fibrin. Individual fibrin fibers are crosslinked using factor XIIIa, which is activated by thrombin.

In addition to the tissue pathway of blood coagulation, there is also a contact activation pathway, which, unlike the external pathway, is quite non-specific. The activation of the contact path occurs when blood plasma comes into contact with almost any foreign surface. The contact cascade is triggered by coagulation factor XII (Hageman factor), which activates factor XIa. In turn, activated factor XIa causes activation of factor IX, then factor X, and further coagulation proceeds similarly to the tissue pathway.

The anticoagulants currently used in the clinic act on both the contact and tissue coagulation pathways. Traditional direct and indirect anticoagulants (warfarin, heparin, etc.) either disrupt the production of most coagulation factors, or use the extensive coagulation inhibition system existing in the body. New generation anticoagulants (dabigatran, rivaroxaban, apixaban, etc.) suppress coagulation factors common to the contact and external coagulation pathways - thrombin and factor Xa. Therefore, the antithrombotic efficacy of the anticoagulants used in the clinic is associated with an increased risk of bleeding: at the same time, blood coagulation mechanisms are blocked due to structural damage to the vessels (external activation pathway) and spontaneous thrombosis in the vessels.

Thus, the problem arises of the search for new effective anticoagulants, the use of which is not associated with a high risk of bleeding and which have a wider therapeutic window compared to existing drugs.

Active research into detailed coagulation and thrombosis mechanisms, triggered by the search for new strategies to prevent thrombosis without increasing bleeding, has renewed interest in the contact pathway of activation. Factor XI deficiency is known to cause hemophilia C, which, in contrast to hemophilia A and B, is characterized by the absence or weak severity of hemorrhage. Clinical studies have shown that patients with factor XI deficiency have less frequent ischemic strokes (Salomon O. et al. Blood 2008; 111: 4113) and the risk of deep vein thrombosis (Salomon O. et al. Thromb Haemost 2011; 105: 269) is reduced. An increase in factor XI leads to the opposite effect: a significant increase in the risk of thromboembolism (Meijers J.C. et al. N Engl J. Med 2000; 342: 696) and myocardial infarction (Doggen CJ et al. Blood 2006; 108: 4045-51 ) In addition, the role of coagulation factor XI is confirmed by numerous animal studies. A study in baboons showed the antithrombotic effect of antibodies against factor XIa, while administration of antibodies did not increase bleeding time (Gruber A., Hanson S.R. Blood 2003; 102: 953). Another study showed the effectiveness of a selective irreversible factor XIa inhibitor in a rat venous thrombosis model and demonstrated that inhibition of factor XIa does not affect the duration of bleeding (Schumacher W.A. et al. Eur J Pharmacol 2007; 570: 167).

Thus, coagulation factor XIa is an extremely promising target for antithrombotic therapy: its inhibition will suppress thrombosis, absolutely without affecting hemostasis.

SUMMARY OF THE INVENTION

The objective of the present invention is to develop and create new effective inhibitors of coagulation factor XIa, promising for use in clinical practice.

The technical result of the invention is the development and production of new chemical compounds that are highly effective in inhibiting coagulation factor XIa and are promising for use in the treatment of diseases whose etiology or pathogenesis is associated with undesirable thrombosis, in particular thrombosis, thromboembolism and other diseases associated with thrombosis.

The specified technical result is achieved through the development and creation of compounds of General formula (I)

,

,

as well as their tautomers, stereoisomers or enantiomers, pharmaceutically acceptable salts, solvates or hydrates, where

the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O— or —S—;

R ₁ is independently selected and represents hydrogen, halogen, —C _1-3 alkyl, partially or fully halogenated —C _1-3 alkyl, —CN, —OH, —OC _1-3 alkyl, —NH ₂ , - NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl or 5-membered heteroaryl ring containing 1-4 N atoms and 0-1 O or S atom; R ₁ contains 0-2 substituents of R ₄ ;

R ₂ is independently selected and is halogen, partially or fully halogenated —CH ₃ or —OCH ₃ ;

R ₃ is independently selected and is hydrogen or halogen;

R ₄ is independently selected and is halogen or —C _1-3 alkyl;

cycle A is independently selected and represents a phenyl or 5-6 membered heteroaryl ring containing 1-2 N atoms; cycle A contains 0-1 substituent R ₅ and 0-2 substituent R ₆ ;

R ₅ is independently selected and represents phenyl, a 5-9 membered heteroaryl containing 1-2 N atoms and 0-1 an S or O atom, a 5-6 membered cycloalkyl or a 5-6 membered heterocycle containing 1-2 N atoms , 0-1 atom S or O; R ₅ contains 0-2 substituents R '₆;

R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, —NHC (O) C _1-3 -alkyl, -C _1-3 -alkyl-NHC (O) H, -C _1-3 -alkyl-NHC (O) C _1-3 -alkyl, -NHC (O) OH, -C _{1- 3-} alkyl-NHC (O) OH, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NNS _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -CN, halogen, -S (O) ₂ NH ₂ , 5-6 membered saturated, unsaturated or partially saturated heterocycle containing 1-4 N atoms, 0-1 S or O atom, 5-6 membered heteroaryl containing 1-4 N atoms, 0-1 atom S or O; R ₆ and R ′ ₆ contain 0-2 substituents of R ₇ ;

R ₇ is independently selected and represents = O, -C _1-3 -alkyl, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _{1 -3-} alkyl-NH ₂ , -C _1-3 -alkyl-NHS _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -OH, -OC _1-3 -alkyl, -C _1-3 -alkyl-OH, -C _1-3 -alkyl-O-C _1-3 -alkyl or halogen.

Preferred Embodiments

A separate subclass of compounds of interest includes compounds of formula (I) in which:

the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O— or —S—;

R ₁ is independently selected and is hydrogen, halogen, partially or fully halogenated —C _1-3 alkyl, —CN, —NHC _1-3 alkyl or a 5 membered heteroaryl ring containing 1-4 N atoms; R ₁ contains 0-2 substituents of R ₄ ;

R ₂ is independently selected and is halogen or —OCH ₃ ;

R ₃ is independently selected and is hydrogen or halogen;

R ₄ is independently selected and is halogen or —C _1-3 alkyl;

cycle A is independently selected and represents a phenyl or 5-6 membered heteroaryl ring containing 1-2 N atoms; cycle A contains 0-1 of R ₅ and 0-2 of R ₆ ;

R ₅ is independently selected and represents phenyl, a 5-9 membered heteroaryl containing 1-2 N atoms and 0-1 an S or O atom, a 5-6 membered cycloalkyl or a 5-6 membered heterocycle containing 1-2 N atoms , 0-1 atom S or O; R ₅ contains 0-2 substituents R '₆;

R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, —C _1-3 - alkyl-NHC (O) H, -NHC (O) OH, -C _1-3 -alkyl-NHC (O) OH, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl ) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl ) C _1-3 -alkyl, -CN or -S (O) ₂ NH ₂ ; R ₆ and R ′ ₆ contain 0-1 substituents of R ₇ ;

R ₇ is independently selected and is = O or C _1-3 alkyl;

Another subclass of compounds of interest includes compounds of formula (I) in which:

the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O— or —S—;

R ₁ is independently selected and represents hydrogen, halogen, —CF ₃ , —NH ₂ , —NHC _1-3 -alkyl or a 5-membered heteroaryl ring containing 4 N atoms;

R ₂ represents halogen;

R ₃ is independently selected and is hydrogen or halogen;

cycle A is independently selected and represents a phenyl or 5-membered heteroaryl ring containing 2 N atoms; cycle A contains 0-1 substituent R ₅ and 0-2 substituent R ₆ .

R ₅ represents phenyl; R ₅ contains 0-1 substituent R '₆;

R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, or —NHC (O) OH ; R ₆ and R ′ ₆ contain 0-1 substituent R ₇ ;

R ₇ is —C _1-3 alkyl.

A separate subclass of compounds of interest includes compounds of formula (I) wherein ring A is phenyl.

Of particular interest are compounds of formula (I) wherein ring A is phenyl substituted with one substituent R ₅ and one substituent R ₆ .

Of additional interest are compounds of formula (I) wherein ring A is phenyl substituted with one R ₅ and one R ₆ , where R ₆ is —C (O) OH. Illustrative examples of this class are the following compounds:

A particular class of compounds of interest includes compounds of formula (I) wherein R ₃ is hydrogen, R ₂ is halogen, and R ₁ is either a 5 membered heteroaryl ring containing 4 N atoms, or R ₁ is is —CF ₃ , or R ₁ is —NHC _1-3 -alkyl.

Another class of compounds of interest includes compounds of formula (I) in which R ₁ is hydrogen, R ₂ and R ₃ are halogen.

Of particular interest are compounds of formula (I) in which cycle A is phenyl substituted with one R ₅ and one R ₆ , where R ₅ is phenyl or 5-9 membered heteroaryl containing 1-2 N atoms, 0 -1 S or O atom, substituted with 0-2 substituents R ' ₆ , which are independently selected.

Of particular interest are compounds of formula (I) in which cycle A is phenyl substituted with one R ₅ and one R ₆ , where R ₅ is phenyl substituted with 0-2 R ′ ₆ which are independently selected. Illustrative examples of this class are the following compounds:

Another class of compounds of interest includes compounds of formula (I) wherein ring A is phenyl substituted with one R ₅ and one R ₆ , where R ₅ is a 9 membered heteroaryl containing 1 to 2 N atoms and 1 S atom, substituted with 0-2 substituents R ' ₆ , which are independently selected. Illustrative examples of cycle A with the substituent R _{5 are} presented below:

A particular class of compounds of interest includes compounds of formula (I) wherein ring A is substituted with one R ₅ group which is substituted with one R ′ ₆ group selected from —COOH, —C (O) NH ₂ , —NHC (O) OH or —C _1-3 -alkyl-NHC (O) OH, wherein R ′ _{6 is} substituted with 0-1 substituent R ₇ representing —C _1-3 -alkyl. Illustrative examples of R ₆ with 0-1 substituent R _{7 are} presented below:

In certain particular embodiments of the invention, the compounds of interest may be selected from the following compounds of general formula (I):

5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid;

5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yloxy) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid;

4- (6- (5-chloro-2-cyanophenyl) benzo [d] isoxazol-3-ylamino) -2- (2-methylbenzo [d] thiazol-5-yl) benzoic acid;

ethyl 2- (2-carbamoyl-5- (6- (5-chloro-2- (ethylamino) phenyl) benzo [d] isoxazol-3-ylamino) phenyl) thiazole-5-carboxylate;

4- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -2-morpholinobenzoic acid;

3 ', 5'-dichloro-5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) biphenyl-2-carboxylic acid;

5 '- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -2' - (1H-tetrazol-1-yl) biphenyl-4-sulfonamide;

5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (1H-imidazol-1-yl) biphenyl-2-carboxylic acid;

5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (2-oxopiperidin-1-yl) biphenyl-2-carboxylic acid;

5- (6- (5-chloro-2- (trifluoromethyl) phenyl) benzo [d] isoxazol-3-ylthio) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid;

2- (3-amino-1H-indazol-6-yl) -4- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) benzoic acid;

5 - ((6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yl) methyl) -4'-methoxybiphenyl-2-carboxylic acid.

The invention also relates to the use of the subject compounds as inhibitors of coagulation factor XIa in blood or plasma.

The present invention also relates to the use of the subject compounds for the preparation of a pharmaceutical composition for the treatment and / or prevention of a condition of a mammal characterized by undesirable thrombosis.

The invention also relates to a method for treating and / or preventing a condition of a mammal characterized by undesirable thrombosis.

Mammalian conditions characterized by unwanted thrombosis are well known, in particular they are thrombophilia, acute coronary syndrome, myocardial infarction, unstable angina pectoris, refractory angina pectoris, transient ischemic attack, thrombosis caused by post-thrombolytic therapy, and coronary artery syndrome stroke, thrombotic stroke, transient ischemic attacks, peripheral arterial occlusion, venous thrombosis, t romboz deep vein thrombosis, thrombophlebitis, arterial thromboembolism, thrombosis, coronary artery thrombosis, cerebral artery, renal thromboembolism, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with geparinoindutsirovannoy thrombocytopenia, thrombus in atrial fibrillation, thrombogenesis with atherosclerosis, thrombotic complications associated with cardiopulmonary bypass, thrombotic complications, ligament data with prosthetic devices.

Thrombotic complications associated with cardiopulmonary bypass and with prosthetic devices include, in particular, thrombosis resulting from: a) prosthetic heart valves and other implanted devices, b) permanently installed catheters, c) stents, d) cardiopulmonary bypass devices, e ) hemodialysis, e) other procedures in which blood comes into contact with an artificial surface that promotes thrombosis.

In addition, conditions for the treatment and / or prophylaxis of which the compounds of the invention can be used include thrombotic complications, including malignant neoplasms, obstetric pathologies and pregnancy pathologies, severe injuries, medications, sepsis, and systemic inflammatory syndrome reactions.

In addition, the invention provides pharmaceutical compositions for treating and / or preventing the condition of a mammal characterized by undesirable thrombosis, comprising an effective amount of at least one compound of the present invention and at least one pharmaceutically acceptable excipient. In particular, the excipient may be a carrier, adjuvant and / or solvent.

Another aspect of the invention is a method of inhibiting coagulation of biological samples (in vitro), comprising the step of introducing into the sample at least one compound of formula (I). In particular, an aspect of the invention is a method for inhibiting coagulation of factor XIa in blood or plasma, comprising the step of introducing into the sample at least one compound of formula (I).

Compounds of the present invention of particular interest have one or more of the following characteristics:

- a molecular weight of less than 1000 g / mol, preferably less than 750 g / mol and most preferably less than 650 g / mol (not including the mass of any solvating or co-crystallizing substances, as well as counterions in the case of salt); and / or

- inhibitory activity against coagulation factor XIa with an IC ₅₀ value of 5 μM or less (obtained using any scientifically based experiment to determine protease inhibition), preferably with an IC _{50 of} 500 nM or lower and optimally with an IC _{50 of} 250 nM or lower; and / or

- inhibitory activity with respect to coagulation factor XIa with IC ₅₀ is at least 100 times less than the corresponding IC ₅₀ values for other proteases (in particular, for other coagulation factors, serine proteases of the complement system and others) of interest; and / or

- are able to provide an increase in blood coagulation time in a relevant experiment by more than 20% compared with the control when the compound is exposed to a concentration of 1 μM.

The compounds of this invention, in addition to being highly effective in inhibiting coagulation factor XIa, also have enhanced bioavailability and selectivity.

The present invention also relates to a method for the treatment and / or prophylaxis of diseases whose etiology or pathogenesis is associated with undesired thrombosis, in particular thrombosis and thromboembolism, comprising administering (as monotherapy or in combination with one or more agents) a therapeutically effective amount of a compound of the subject inventions into a human or animal organism in need of treatment and / or prevention of such diseases. "Administration" of a compound of the present invention to an organism includes the delivery to a recipient of a compound described in the present invention of a prodrug or other pharmacologically acceptable derivative of such a compound using any acceptable preparation or route of administration to the body that is well known to those skilled in the art. Typically, the compound is administered to the patient once or several times a week, for example, daily, every other day, 5 days a week, etc. Oral administration is of particular interest.

The invention also includes the preparation of compounds of general formula (I).

The compounds of the present invention can also be used as standards and reagents for characterizing various serine proteases, in particular, but not limited to, coagulation factor XIa, as well as for studying the role of such proteases in biological and pathological phenomena.

Definitions (terms)

The following definitions apply throughout this document unless otherwise indicated. In addition, unless otherwise indicated, all occurrences of functional groups are independently selected, as indicated by the use of a slash to determine that two occurrences can be the same or different (for example, R, R ', etc.).

The term "alkyl" in this document means both unbranched and branched. In addition, “alkyl” may be either substituted or unsubstituted.

The term “alkyl” as used herein refers to groups typically having one to three carbon atoms. For example, the term “C _1-3 alkyl” means methyl, ethyl, isopropyl, n-propyl.

The term "partially or fully halogenated alkyl" includes branched and linear saturated hydrocarbon chains in which one or more hydrogen atoms are replaced by halogen. Examples of haloalkyl groups include, but are not limited to, the following groups: trifluoromethyl, trichloromethyl, pentafluoroethyl, —C (CF ₃ ) ₂ CH _3, and the like.

The term “cycloalkyl” as used herein refers to groups having five to six carbon atoms in a monocyclic structure. By way of illustration, cycloalkyls include, but are not limited to, the following radicals: cyclopentyl, cyclohexyl, which, as with other aliphatic or heteroaliphatic or heterocyclic substituents, may be substituted. The terms “cycloalkyl” and “carbocycle” are equivalent.

The term “heteroaliphatic” as used herein means aliphatic substituents that contain an oxygen, sulfur, nitrogen, phosphorus or silicon atom in place of one or more carbon atoms. Heteroaliphatic substituents can be unbranched, branched or cyclic, and also include acyclic moieties such as CH ₃ OCH ₂ CH ₂ O-, as well as heterocycles such as morpholino, pyrrolidinyl, etc.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” means non-aromatic ring systems (saturated or partially unsaturated) having five to six atoms containing N, O or S hetero atoms in this document. Examples of heterocyclic rings include, but are not limited to, the following: tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, morpholin-2-yl, thiomorpholin-4-yl, piperazin-1-yl, piperazin-2-yl, etc. Heterocycles may also be substituted.

The term “aryl” as used herein means groups containing an aromatic ring having six carbon atoms. An example of aryl ring groups is phenyl.

The term “heteroaryl,” “heteroaryl ring,” as used herein, means a stable heterocyclic and polyheterocyclic aromatic moiety having 5-9 atoms in the ring. A heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include, but are not limited to, any of the previously mentioned substituents. Examples of typical heteroaryl rings are five- and six-membered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl and the like; as well as polycyclic heterocyclic groups such as benzo [b] thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, and the like. (see A.R. Katritzky, Handbook of Heterocyclic Chemistry). The term “heteroaryl” may be used equivalently with the terms “heteroaryl ring” or “heteroaromatic”.

An aryl group or heteroaryl group (including the heteroaryl part of heteroarylalkyl or heteroaralkoxy moieties and the like) may contain one or more substituents. Examples of a suitable substituent on an unsaturated carbon atom of an aryl or heteroaryl group include, but are not limited to, halogen (F, Cl, Br or I), C _1-3 alkyl, —CN, —OH, —C _1-3 alkyl, - C (O) OH, -C (O) NH ₂ , -NHC (O) H, -NHC (O) C _1-3 -alkyl, -C _1-3 -alkyl-NHC (O) H, -C _{1 -3-} alkyl-NHC (O) C _1-3 -alkyl, -NHC (O) OH, -NHC (O) OC _1-3 -alkyl, -C _1-3 -alkyl-NHC (O) OH, - NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _{1- 3-} alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -S (O) ₂ NH ₂ , optionally substituted with 1-2 substituents R.

The substituents R are independently selected and include, but are not limited to, hydrogen, = O, —C _1-3 alkyl, —NH ₂ , —NHC _1-3 alkyl, —N (C _1-3 alkyl) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -OH, -OC- _1-3 -alkyl, -C _1-3 -alkyl-OH, -C _1-3 -alkyl-O-C _1-3 -alkyl or halogen.

This invention contains only those combinations of substituents and derivatives that form a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions, for at least one week.

Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.

Unless otherwise indicated, the structures depicted here also imply all stereoisomers, i.e., R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (> 90%, and preferably> 95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with optically pure acid in an activated form or optically pure isocyanate. The resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

The optically active compounds of this invention can be prepared using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester or salt.

The compounds of the invention may exist in a radioisotope-labeled form, i.e. these compounds may contain one or more atoms, whose atomic mass or mass number differs from the atomic mass or mass number of the most common natural isotopes. The radioisotopes of hydrogen, carbon, phosphorus, chlorine include ³ H, ¹⁴ C, ³² P, ³⁵ S, and ³⁶ Cl, respectively. Compounds of the present invention that contain such radioisotopes and / or other radioisotopes of other atoms are within the scope of the present invention. Tritium, i.e. ³ N, and carbon, i.e. ^14C , radioisotopes are particularly preferred due to the ease of preparation and detection.

The compounds of the present invention labeled with radioactive isotopes can be prepared using methods well known to those skilled in the art. Labeled compounds can be prepared using the procedures described herein by simply replacing unlabelled reagents with the corresponding labeled reagents.

The term "protective group" in this document means a functional group that introduces into the molecule of a chemical compound to ensure chemoselectivity of the necessary chemical reaction. Protective groups play an important role in organic synthesis. Some reagents used in organic synthesis can interact immediately with many functional groups of the transformed molecule. In the event that it is necessary to carry out a reaction with only one type of functional groups, without affecting the others, the latter are modified (“protected”) by means of protective groups. An example of a protecting group is a tert-butoxycarbonyl group (Boc).

The term "patient" covers all types of mammals, preferably humans.

The terms “treatment”, “therapy” cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.

The term "prevention", "prevention", "preventive therapy" covers the elimination of risk factors, as well as the prophylactic treatment of subclinical stages of the disease in mammals, preferably humans, aimed at reducing the likelihood of clinical stages of the disease. Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increase in the risk of clinical stages of the disease compared with the general population. Preventive therapy includes a) primary prevention and b) secondary prevention. Primary prophylaxis is defined as prophylactic treatment in patients whose clinical stage of the disease has not yet occurred. Secondary prophylaxis is the prevention of the repeated onset of the same or similar clinical condition of the disease.

The term "risk reduction" covers therapy that reduces the incidence of the clinical stage of the disease. Examples of reducing the risk of disease are primary and secondary disease prevention.

The term "thrombosis" means the formation or presence of a thrombus; intravascular coagulation, which can cause ischemia or heart attack of tissues supplied with the vessel.

The term "embolism" means the sudden blockage of a blood or lymph vessel by a clot or other foreign particle that has been brought to the site of blockage by blood flow (lymph). The term "thromboembolism" means a blockage of a blood vessel by thrombotic material brought from the place of origin to another blood vessel.

Under the condition of a mammal characterized by undesirable thrombosis, this document refers to diseases whose etiology or pathogenesis is associated with thrombosis, such as, for example, thrombosis and thromboembolism.

DETAILED DESCRIPTION OF THE INVENTION

The implementation of the invention

Overview of the methods for producing compounds of the invention

The compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

Intermediates for the preparation of certain compounds of the invention (compounds T1 and I1) can be prepared by the procedures described below.

Intermediate T1: methyl 5-amino-4 '- (methoxycarbonylamino) biphenyl-2-carboxylate:

1) Intermediate T1-A: methyl 4-bromophenylcarbamate.

To a solution of 4-bromoaniline (25 g, 172 mmol) in DCM (dichloromethane) (1 L) was added NaHCO ₃ (13.4 g, 159 mmol) at 0 ° C, then methyl chloroformate (20.6 g, 217.5 mmol), the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with ice water, extracted with DCM, washed with water and saturated NaCl solution. The organic layer is dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (60-120 mm) and a gradient of 20-25% ethyl acetate in petroleum ether to give the T1-A intermediate as an off-white powder. Yield: 30 g, 90%.

2) Intermediate T1-B: methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate.

To a solution of T1-A intermediate (30 g, 131 mmol) in 1,4-dioxane (600 ml), potassium acetate (38.57 g, 393 mmol) and bis (pinacolato) dibor (33.26 g, 131 mmol) are added at room temperature. The reaction mixture was degassed for 15 minutes and bis (triphenylphosphine) palladium (II) dichloride (4.6 g, 6.55 mmol) was added at room temperature, after which the mixture was degassed again for 10 minutes. The reaction mixture is heated at 100 ° C for 6 hours. Upon completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (60-120 mm) and 30-40% ethyl acetate in petroleum ether. The T1-B intermediate is obtained in the form of an off-white powder. Yield: 33 g, 91%.

3) Intermediate T1-C: methyl 4 '- (methoxycarbonylamino) -5-nitrobiphenyl-2-carboxylate.

To a solution of T1-B intermediate (17.6 g, 63.4 mmol) in methanol (300 ml) was added potassium acetate (16.96 g, 172.8 mmol), methyl-2-bromo-4-nitrobenzoic acid (15 g, 57.6 mmol) at room temperature and degassed at room temperature for 15 minutes. Bis (triphenylphosphine) palladium (II) dichloride (2 g, 2.88 mmol) was added to the reaction mixture at room temperature and degassed again for 10 minutes. The reaction mixture was maintained at a temperature of 100 ° C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product is purified by chromatography using silica gel (230-400 mm) and 50-60% ethyl acetate in petroleum ether. The T1-C intermediate is obtained in the form of a yellow powder. Yield: 12 g, 63%.

4) Intermediate T1: methyl 5-amino-4 '- (methoxycarbnylamino) biphenyl-2-carboxylate.

To a solution of T1-C intermediate (12 g, 36.36 mmol) in methanol (240 ml), Pd / C (10%) (2.4 g) was added with stirring. The reaction mixture was stirred at room temperature in an atmosphere of H ₂ (pressure 1 ATM) for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite, washed with a mixture of methanol and DCM, and concentrated to give T1 as a white powder. Yield: 10 g, 92%.

Intermediate I1: tert-butyl 5-chloro-3'-fluoro-4 '- ((hydroxyimino) methyl) biphenyl-2-ylcarbamate.

1) Intermediate I1-A: 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde.

To a solution of 4-bromo-2-fluoro-benzaldehyde (8 g, 39.4 mmol) in 1,4-dioxane (160 ml) are added potassium acetate (11.6 g, 118.22 mmol) and bis (pinacolato) dibor (10 g, 39.4 mmol) at room temperature. The reaction mixture was degassed for 30 minutes and bis (triphenylphosphine) palladium (II) dichloride (1.4 g, 1.97 mmol) was added at room temperature, after which the mixture was degassed again for 10 minutes. The reaction mixture was stirred for 6 hours at 100 ° C. Upon completion of the reaction, the mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer is dried over Na ₂ SO ₄ , concentrated under reduced pressure to obtain intermediate I1-A as an off-white powder. Yield: 8 g, 81%.

2) Intermediate I1-B: tert-butyl 5-chloro-3'-fluoro-4'-formylbiphenyl-2-ylcarbamate. To a solution of intermediate I1-A (6.53 g, 26.14 mmol) in methanol (300 ml) was added potassium acetate (7.7 g, 78.43 mmol) and tert-butyl 2-bromo-4-chlorophenylcarbamate (8 g, 26.14 mmol) at room temperature . The reaction mixture was degassed for 10 minutes and bis (triphenylphosphine) palladium (II) dichloride (1.84 g, 2.614 mmol) was added at room temperature, after which the mixture was degassed again for 10 minutes. The reaction mixture was kept at 100 ° C for 16 hours. Upon completion of the reaction, the mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer is dried over Na ₂ SO ₄ , concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (230-400 mm) and 10-15% ethyl acetate in petroleum ether. Intermediate I1-B is obtained in the form of a white powder. Yield: 5 g, 55%.

3) Intermediate I1: tert-butyl 5-chloro-3'-fluoro-4 '- ((hydroxyimino) methyl) biphenyl-2-ylcarbamate. To a solution of intermediate I1-B (5 g, 14.32 mmol) in ethanol (100 ml) at 0 ° C was added triethylamine (4 ml, 28.64 mmol), then hydroxylamine hydrochloride (1.99 g, 28.64 mmol) and stirred at room temperature in within 2 hours. The solvent was removed, the concentrated reaction mixture was diluted with ethyl acetate and washed with water and a saturated NaCl solution. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (230-400 mm) and 8-10% ethyl acetate in petroleum ether. Intermediate I1 is obtained in the form of a white powder. Yield: 3.6 g, 69%.

Example 1: 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid.

1) Intermediate 1-A: methyl 5- (2 '- (tert-butoxycarbonylamino) -5'-chloro-3-fluoro-N'-hydroxybiphenyl-4-ylcarboximidamido) -4' - (methoxycarbonylamino) biphenyl-2-carboxylate .

To a solution of intermediate I1 (2 g, 5.48 mmol) in DMF (N, N-dimethylformamide) (24 ml) was added N-chlorosuccinimide (0.95 g, 7.12 mmol) and stirred at room temperature for 45 minutes. To the resulting chlorine-containing intermediate was added intermediate T1 and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate, washed with water, saturated NaCl. The organic layer was separated and concentrated after drying over sodium sulfate. The product is purified by chromatography using 0.5-1% methanol in DCM. Intermediate 1-A is obtained in the form of a white powder. Yield: 1.4 g, 39%.

2) Intermediate 1-B: methyl 5- (6- (2- (tert-butoxycarbonylamino) -5-chlorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylate.

To a suspension of NaH (0.1 g, 2.74 mmol) in DMF (14 ml) at 0 ° C was added intermediate 1-A (1.4 g, 2.11 mmol) and heated at 70 ° C for 1 hour. The reaction mixture was cooled to 0 ° C, quenched with ice and ethyl acetate was added. The organic layer was washed with saturated NaCl and concentrated after drying over sodium sulfate. The dirty product is purified by chromatography using 25-30% ethyl acetate in petroleum ether. Intermediate 1-B is obtained in the form of a white powder. Yield: 0.6 g, 45%.

3) Intermediate 1-C: 5- (6- (2-amino-5-chlorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid methyl ester.

To a solution of intermediate 1B (0.6 g) in DCM (4.8 ml) at 0 ° C. was added TFA (1.2 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was completely concentrated, diluted with ethyl acetate, washed with water, 10% NaHCO ₃ , saturated NaCl. The organic layer was separated, dried over sodium sulfate and concentrated completely. Intermediate 1-C is obtained in the form of a white powder. Yield: 0.45 g, 90%.

4) Intermediate 1-D: 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl methyl ester -2-carboxylic acid.

To a solution of 1C intermediate (0.45 g, 0.82 mmol) in glacial acetic acid (9 ml) was added triethylorthoformate (1.37 ml, 8.28 mmol), then trimethylsilyl azide (0.28 g, 2.48 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, saturated NaCl. The organic layer was separated and concentrated completely after drying over sodium sulfate. The dirty product is purified by chromatography using 40-50% ethyl acetate in petroleum ether. Intermediate 1D is obtained in the form of a white powder. Yield: 0.35 g, 71%.

5) Intermediate 1-E: 5 '- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -2' - (hydroxymethyl) methyl ester biphenyl-4-ylcarboxylic acid.

To a solution of 1D intermediate (0.35 g, 0.58 mmol) in THF (tetrahydrofuran) (14 ml) at -78 ° C, DIBAL-H (diisobutyl aluminum hydride) (5.8 ml, 5.8 mmol) was added and stirred for 2 hours. The reaction mixture was quenched with potassium tartrate and stirred at room temperature for 15 minutes. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was washed with saturated NaCl and concentrated completely after drying over sodium sulfate. The dirty product is purified by chromatography using 2% MeOH in DCM. Intermediate 1-E is obtained in the form of a white powder. Yield: 0.2 g, 61%.

6) Intermediate 1-F: 5 ′ - (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -2′-formyl biphenyl methyl ester 4-yl carboxylic acid.

To a solution of intermediate 1-E (0.2 g, 0.35 mmol) in DCM (8 ml), DMSO (dimethyl sulfoxide) (1 ml), Dess-Martin periodate (0.19 g, 0.45 mmol) was added at 0 ° C and stirred at room temperature in within 2 hours. The reaction mixture was cooled to 0 ° C, quenched with sodium thiosulfate dissolved in NaHCO ₃ solution and extracted with DCM. The organic layer was washed with water, saturated NaCl, dried over sodium sulfate and concentrated completely to give 1-F intermediate as a white powder. Yield: 0.16 g, 80%. 7).

Getting the final product.

To a solution of 1-F intermediate (0.16 g, 0.28 mmol) in acetone (6.4 ml) and water (1.6 ml), sulfamic acid (0.06 g, 0.62 mmol) was added and cooled to 0 ° C. Then, sodium chlorite (0.03 g, 0.33 mmol) is added portionwise to the mixture and stirred for 5 hours. The reaction mixture was diluted with water, the resulting solid powder was filtered off and dried. The dirty product is purified by chromatography using 5% MeOH in DCM. The final product is obtained in the form of an off-white powder. Yield: 0.12 g, 73%.

¹ H-NMR (400 MHz, D ₆ -DMSO): 3.53 (s, 3H, COOMe), 7.01 (d, 1H, J = 7.1 Hz, H (Ar)), 7.27 (d, 1H, J = 7.0 Hz , H (Ar)), 7.46-7.53 (m, 4H, H (Ar)), 7.54 (s, 1H, H (Ar)), 7.62-7.83 (m, 5H, H (Ar)), 7.85 (d , 1H, J = 7.3 Hz, H (Ar)), 9.57 (s, 1H, H (Ar)), 9.75 (s, 1H, NH), 9.96 (br.s, 1H, NH), 12.38 (br. s, 1H, COOH).

Intermediates for the preparation of certain compounds of the invention (compounds C2, I2, H2, I3, T3, I4 and T4) can be prepared using the procedures described below.

Intermediate C2: 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid methyl ester.

1) Intermediate C2-A: 4-bromo-2-fluorobenzoic acid methyl ester.

21.9 g (0.1 mol) of 2-fluoro-4-bromobenzoic acid is dissolved in 200 ml of methanol, carefully, 10 ml of thionyl chloride are added dropwise with vigorous stirring and the reaction mixture is left for 2 days at room temperature. The solvent was removed in vacuo, 300 ml of dichloromethane was added to the residue, and the resulting solution was washed with water (2 × 100 ml), saturated sodium hydrogen carbonate solution, and then again with water until neutral. The solution was dried over sodium sulfate, after which the solvent was removed in vacuo. Receive: 22.8 g (97%) of intermediate C2-A.

2) Intermediate C2: 2-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid methyl ester.

To a solution of 2.30 g (0.01 mol) of methyl 2-fluoro-4-bromobenzoate (C2-A intermediate) in 1,4-dioxane (10 ml) was added 0.02 mol of potassium acetate and 0.015 mol of bis at room temperature (pinacolato) diborane. The reaction mixture was degassed for 15 minutes and 0.0015 mol of dichloridebis (triphenylphosphine) palladium (II) was added at room temperature, after which the mixture was degassed again, heated to 100 ° C and kept at this temperature with vigorous stirring for 6 hours. The solvent was removed in vacuo and diluted with ethyl acetate, 100 ml of a saturated sodium hydrogen carbonate solution were added, the organic layer was separated, washed with water and a saturated NaCl solution. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was separated chromatographically using mixtures of petroleum ether: ethyl acetate of increasing polarity. 2.13 g (76%) of intermediate C2 are obtained.

Intermediate H2: 1- (4-chloro-2-iodophenyl) -1H-tetrazole.

1) Intermediate H2-A: 2-iodine-4-chloroaniline.

To a finely divided suspension of 4-chloroaniline, 12.7 g (0.1 mol) in 300 ml of a saturated sodium hydrogen carbonate solution is added in small portions of 25.4 g (0.1 mol) of finely divided iodine. The reaction mixture was stirred for 4 hours at room temperature and 200 ml of a saturated solution of sodium hydrogen carbonate and 300 ml of dichloromethane were added. The organic phase is separated, washed with 5% sodium thiosulfate solution (2 × 200 ml), water (4 × 300 ml), and then dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue was separated by chromatography using a dichloromethane: propanol system of increasing polarity. Receive: 17.0 g (69%) of the product.

2) Intermediate H2: 1- (4-chloro-2-iodophenyl) -1H-tetrazole.

2.53 g (0.01 mol) of 2-iodo-4-chloroaniline H2-A is dissolved in 100 ml of trimethylorthoformate, 3.25 g (0.05 mol) of sodium azide and 5 ml of glacial acetic acid are added. The resulting mixture is boiled for 8 hours, cooled, 10 ml of water are added, the solvents are removed in vacuo, the residue is triturated with 20 ml of isopropanol, the precipitate is filtered off and recrystallized from isopropanol. Receive: 1.16 g (38%) of intermediate H2.

Intermediate T2: 5-hydroxy-4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid methyl ester.

1) Intermediate T2-A: methyl 4-bromophenylcarbamate.

To a solution of 4-bromoaniline (25 g, 172 mmol) in DCM (1 L) at 0 ° C was added NaHCO ₃ (13.4 g, 159 mmol), then methyl chloroformate (20.6 g, 217.5 mmol), the reaction mixture was stirred at room temperature in within 16 hours. After completion of the reaction, the reaction mixture was quenched with ice water, extracted with DCM, washed with water and saturated NaCl solution. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (60-120 mm) and a gradient of 20-25% EtOAc in petroleum ether to give the T2-A intermediate as an off-white powder (yield: 30 g, 90%).

2) Intermediate T2-B: methyl 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenylcarbamate.

To a solution of T2-A intermediate (30 g, 131 mmol) in 1,4-dioxane (600 ml), potassium acetate (38.57 g, 393 mmol) and bis (pinacolato) dibor (33.26 g, 131 mmol) are added at room temperature. The reaction mixture was degassed for 15 minutes and dichloride bis (triphenylphosphine) palladium (II) (4.6 g, 6.55 mmol) was added at room temperature, after which the mixture was degassed again for 10 minutes. The reaction mixture is heated at 100 ° C for 6 hours. Upon completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography using silica gel (60-120 mm) and 30-40% EtOAc in petroleum ether. The T2-B intermediate is obtained in the form of an off-white powder. Yield: 33 g, 91%.

3) Intermediate T2: 5-hydroxy-4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid methyl ester.

To a solution of 13.8 g (0.05 mol) of pinacol ether in 100 ml of methanol, 0.12 mol of potassium acetate, 0.05 mol of methyl 2-bromo-4-hydroxybenzoate are added at room temperature and degassed at room temperature for 15 minutes. 0.0015 mol of dichloridobis (triphenylphosphine) palladium (II) is added to the reaction mixture at room temperature and degassed again for 10 minutes. The reaction mixture was maintained at a temperature of 100 ° C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product is purified by chromatography using silica gel (230-400 mm) and 50-60% EtOAc in petroleum ether. Intermediate T2 is obtained in the form of a yellow powder. Yield: 12 g, 63%.

Intermediate 12: 6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yl trifluoromethanesulfonate.

1) Intermediate I2-A: methyl 5'-chloro-3-fluoro-2 '- (1H-tetrazol-1-yl) biphenyl-4-carboxylate.

0.02 mol of potassium acetate and 3.06 g (0.01 mol) of intermediate H2 are added to a solution of 2.80 (0.01 mol) of C2 intermediate, degassed at room temperature for 15 minutes. 0.001 mol of bis (triphenylphosphine) palladium (II) dichloride was added to the reaction mixture, degassed repeatedly for 10 minutes, after which it was heated and kept at a temperature of 50 ° C for 20 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was separated chromatographically using mixtures of petroleum ether: ethyl acetate of increasing polarity. Yield 2.96 g (89%) of intermediate I2-A.

2) Intermediate I2-B: 6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3 (2H) -one.

To a solution of 3.32 g (0.01 mol) of the I2-A intermediate in 30 ml of warm ethanol was added 5 ml of a 50% aqueous hydroxylamine solution and the reaction mixture was stirred at 45 ° C for 6 hours until the starting compound disappeared (HPLC control). The solvents were removed in vacuo, the residue was dried to constant weight, dissolved in 20 ml of anhydrous DMAA (dimethylacetamide) and 0.02 mol of sodium hydride was added as a 60% suspension in mineral oil. The reaction mixture was stirred under argon and 100 ° C for 4 hours, cooled, 2 ml of 2M hydrochloric acid was added, the solvent was removed, and the residue was separated chromatographically using petroleum ether: ethyl acetate of increasing polarity. Yield 2.29 g (73%) of intermediate I2-B.

3) Intermediate I2: 6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yl trifluoromethanesulfonate.

To a solution of 3.13 g (0.01 mol) of I2-B intermediate in 100 ml of anhydrous dichloromethane, 2 ml of triethylamine and 4.00 g (0.012 mol) of N-phenyl bis (trifluoromethanesulfonimide) are added, the reaction mixture is boiled for 6 hours, cooled 200 ml of dichloromethane are added and washed with saturated sodium hydrogen carbonate solution (2x50 ml) and then with saturated NaCl solution. The solution was dried over sodium sulfate, the solvent was removed, and the residue was used in further transformations without further purification. Yield 4.36 g (98%) of intermediate 12.

Example 2. 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yloxy) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid.

1) Intermediate 2-A: 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yloxy) -4 '- (methoxycarbonylamino) biphenyl methyl ester -2-carboxylic acid.

To a solution of 445 mg (0.001 mol) of intermediate 12 in 5 ml of anhydrous DMF was added 0.0001 mol of BINAP, 0.0001 mol of tris (dibenzylideneacetone) dipalladium (0) and 0.001 mol of intermediate T2. The reaction mixture was stirred at 80 ° C for 12 hours, cooled, the solvent was removed in vacuo, the residue was separated by chromatography using a hexane: ethyl acetate system of increasing polarity. Yield 167 mg (28%) of intermediate 2-A.

2). Getting the final product.

0.001 mol of intermediate 2-A is dissolved in 50 ml of a 0.3 M solution of lithium hydroxide in THF and stirred for 2 hours. The solvent is removed, 5 ml of water is added to the residue and acidified to pH ~ 4. The precipitate was filtered off, washed, dried and chromatographed. Yield 413.8 mg (71%).

¹ H-NMR (400 MHz, D ₆ -DMSO): 3.32 (s, 3H, COOMe), 7.04 (d, 1H, J = 7.0 Hz, H (Ar)), 7.37 (d, 1H, J = 7.0 Hz , Н (Ar)), 7.41 (d, 2Н, J = 7.2 Hz, Н (Ar)), 7.43-7.62 (m, 4Н, Н (Ar)), 7.66-7.97 (m, 3Н, Н (Ar) ), 8.02 (s, 1H, H (Ar)), 8.32 (d, 1H, J = 6.9 Hz, H (Ar)), 9.62 (s, 1H, H (Ar)), 9.92 (br.s, 1H , NH), 12.36 (br s, 1H, COOH).

Intermediate I3: 6- (5-chloro-2-fluorophenyl) benzo [d] isoxazol-3-yl trifluoromethanesulfonate.

Intermediate I3 is prepared analogously to intermediate I2 using intermediate C2 and 2-iodo-1-fluoro-4-chlorobenzene as starting reagents.

Intermediate T3: N- (3'-hydroxybiphenyl-4-yl) acetamide.

Intermediate T3 is prepared analogously to intermediate T2, using acetyl chloride in the first step instead of methyl chloroformate, and 3-bromophenol instead of 2-bromo-4-hydroxybenzoic acid methyl ester.

Example 3: N- (3 '- (6- (2-fluoro-5-chlorophenyl) benzo [d] isoxazol-3-yloxy) biphenyl-4-yl) acetamide

To a solution of 0.001 mol of intermediate 13 in 5 ml of anhydrous DMF was added 0.0001 mol of BINAP, 0.0001 mol of tris (dimenzylideneacetone) dipalladium (0) and 0.001 mol of intermediate T3. The reaction mixture was stirred at 80 ° C for 12 hours, cooled, the solvent was removed in vacuo, the residue was separated by chromatography using a hexane: ethyl acetate mixture of increasing polarity. Yield 98 mg (20%).

¹ H-NMR (400 MHz, D ₆ -DMSO): 2.02 (s, 3H, CH ₃ CO), 7.01-7.07 (m, 3H, H (Ar)), 7.12 (s, 1H, H (Ar)) , 7.28-7.34 (m, 2H, H (Ar)), 7.48-7.51 (m, 1H, H (Ar)), 7.61-7.74 (m, 5H, H (Ar)), 7.82 (d, 2H, J = 7.4 Hz, N (Ar)), 9.83 (br s, 1H, NH).

Intermediate I4: 6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-yl trifluoromethanesulfonate.

Intermediate I4 is prepared analogously to intermediate I2 using intermediate C2 and 3-iodo-2-fluoro-1-chlorobenzene as starting reagents.

Intermediate T4: methyl 5-amino-4 '- (2-oxopiperidin-1-yl) biphenyl-2-carboxylate.

1) Intermediate T4-A: 1- (4-bromophenyl) piperidin-2-one.

To a solution of 0.01 mol of 1-bromo-4-iodobenzene in 50 ml of toluene, 0.01 mol of piperidin-2-one, 0.015 mol of K ₃ PO ₄ and 0.001 mol of Cul are added. The mixture was degassed three times at room temperature, then N, N'-dimethylethylenediamine (0.001 mol) was added and heated to boiling. After 48 hours, the precipitate was filtered off and the mixture was washed with 200 ml of toluene. The organic layer was washed with sodium thiosulfite solution, then with saturated NaCl solution, dried over Na ₂ SO ₄ . The solvent was removed in vacuo, the residue was crystallized from AcOEt, T4-A intermediate was isolated as a white powder. Yield 1.7 g (67%).

2) T4-B Intermediate: methyl 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaboran-2-yl) phenylcarbamate.

To a solution of T1-A intermediate (0.01 mol) in 1,4-dioxane (50 ml), potassium acetate (0.01 mmol) and bis (pinacolato) dibor (0.01 mol) are added at room temperature. The reaction mixture was degassed for 15 minutes and bis (triphenylphosphine) palladium (II) dichloride (0.001 mmol) was added at room temperature, after which the mixture was degassed again for 10 minutes. The reaction mixture is heated at 100 ° C for 6 hours. Upon completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The dirty product is purified by chromatography. The T4-B intermediate is obtained in the form of an off-white powder. Yield 2.9 g (95%).

3) Intermediate T4: methyl 5-amino-4 '- (2-oxopiperidin-1-yl) biphenyl-2-carboxylate.

To a solution of 0.05 mol of T4-B intermediate in 100 ml of methanol, 0.12 mol of potassium acetate and 0.05 mol of methyl 2-bromo-4-hydroxybenzoate are added at room temperature and degassed at room temperature for 15 minutes. 0.0015 mol of dichloridobis (triphenylphosphine) palladium (II) is added to the reaction mixture at room temperature and degassed again for 10 minutes. The reaction mixture was maintained at a temperature of 100 ° C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate, washed with water and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product is purified by chromatography using silica gel (230-400 mm) and 50-60% EtOAc in petroleum ether. Yield 11.5 g (71%) of T4 intermediate.

Example 4: 5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (2-oxopiperidin-1-yl) biphenyl-2-carboxylic acid.

1) Intermediate 4-A: methyl ester - (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (2-oxopiperidin-1-yl) biphenyl-2-carbon acids.

To a solution of 0.001 mol of intermediate 14 in 5 ml of anhydrous DMF was added 0.0001 mol of BINAP, 0.0001 mol of Tris (dibenzylideneacetone) dipalladium (0) and 0.001 mol of intermediate 14. The reaction mixture was stirred at 80 ° C for 12 hours, cooled, the solvent was removed in vacuo , the residue was separated by chromatography using a hexane: ethyl acetate system of increasing polarity. Yield 176 mg (31%) of 4-A intermediate.

2) Obtaining the final product.

0.001 mol of intermediate 4-A is dissolved in 50 ml of a 0.3 M solution of lithium hydroxide in THF and stirred for 2 hours. The solvent is removed, 5 ml of water is added to the residue and acidified to pH ~ 4. The precipitate was filtered off, washed, dried and chromatographed. Yield 528 mg (95%).

¹ H-NMR (400 MHz, D ₆ -DMSO): 1.78-1.94 (m, 4H), 2.40 (t, 2H, J = 12.6 Hz, (CH ₂ CO)), 4.06 (t, 2H, J = 12.8 Hz, NCH2)), 7.06 (d, 1H, J = 7.3 Hz, N (Ar)), 7.25 (t, 1H, J = 7.1 Hz, N (Ar)), 7.41-7.53 (m, 5H, H (Ar)), 7.59-7.70 (m, 4H, H (Ar)), 7.84 (d, 1H, J = 7.4 Hz, H (Ar)), 8.22 (d, 1H, J = 7.4 Hz, N ( Ar)), 8.91 (br s, 1H, NH), 12.21 (br s, 1H, COOH).

The use of chemical compounds of the invention

The use of compounds for medical reasons

The compounds described in this invention can be used to treat and / or prevent diseases, the etiology or pathogenesis of which is associated with thrombosis, in particular thrombosis and thromboembolism.

Method for the therapeutic use of compounds

The subject of this invention also includes the administration to a subject in need of appropriate treatment of a therapeutically effective amount of a compound of general formula (I).

The term “therapeutically effective amount” refers to an amount of a compound which, when administered as mono- or combination therapy, causes an inhibition of coagulation factor XIa sufficient to prevent and / or treat a condition of a mammal characterized by undesired thrombosis. When using the compounds of the invention in combination therapy, the term “therapeutically effective amount” refers to a combination of amounts of active ingredients, the administration of which leads to a preventive or therapeutic effect in consecutive or simultaneous administration. The exact amount required can vary from subject to subject depending on the type of mammal, age and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

The compound or pharmaceutical composition containing the compound may be administered to the patient in any amount and by any route of administration effective for the treatment and / or prophylaxis of thrombosis, thromboembolism or other diseases whose etiology or pathogenesis is associated with undesired thrombosis.

Single doses of the compounds of the invention are preferably formulated in a form convenient for administration to a patient. The expression "single dose" in terms of the present invention means a portion of a compound of the invention suitable for the treatment and / or prophylaxis of a condition characterized by undesirable thrombosis. According to existing practice, the total daily dose of the compounds and compositions described in the present invention is prescribed by the attending physician based on a medical opinion. The specific therapeutically effective dosage level for each patient depends on a number of factors, including the type of disorder, the severity of the disease, the activity of the particular drug used, the characteristics of the pharmaceutical composition, age, body weight, general health, gender and diet of the patient, method and schedule of administration, speed metabolism and / or excretion of the compound, duration of treatment, drugs used in combination or in conjunction with the administration of the compounds of the invention, and other tori are well known in medicine.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier in the desired dosage, the compositions constituting the essence of the invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (using skin patches, powders, ointments or drops), sublingually, buccally, in the form of a spray for mouth or nose, etc.

An effective systemic dosage of the compound, administered in a single dose or in the form of several separate doses, usually lies in the range from 0.01 to 500 mg of the compound per kg of patient body weight, preferably from 0.1 to 125 mg / kg. Typically, the compound is administered to a patient in need of such treatment in a daily dosage of from about 50 to 2000 mg per patient. The introduction can be carried out both once and several times a day, week (or any other time interval), or from time to time. For example, the compound may be administered to the patient once or several times a day on a weekly basis (for example, every Monday) for an indefinite time or for several weeks (for example, 4-10 weeks).

The amount of compound that will be effective in treating or preventing a particular disorder or condition depends, in particular, on well-known factors that influence the effective dosage of drugs. In addition, in vitro or in vivo measurements can optionally be used to determine the optimal dose range. A rough way to determine the effective dose is to extrapolate the dose-response curves, which will depend on the in vitro or animal testing model. The exact dosage level determined by the attending physician depends on well-known factors, including the method of administration of the drug, as well as the age, body weight, gender and general health of the patient; the nature, severity and clinical condition of the disease; use (or non-use) of concomitant therapy. To determine the dose level, standard blood coagulation tests can be used, including tests of activated partial thromboplastin time, prothrombin time, as well as tests for determining coagulation in space (thrombodynamics).

When administered orally for the treatment or suppression of a particular condition of a disease or disorder, the effective dosage of a compound of this invention may vary depending on the particular compound used, the route of administration of the drug to the body, the conditions and severity of such administration; the state of the disease, as well as a different number of physical factors associated with the patient undergoing treatment. In most cases, a satisfactory result can be achieved by administering to the patient a compound in a daily dosage of from about 0.01 mg / kg to 500 mg / kg, usually between 0.1 and 125 mg / kg. The estimated daily dosage is expected to vary depending on the method of administration to the patient. Thus, the dosage level for parenteral administration often ranges from 10 to 20% of the oral dosage level.

In the case where the compound of the present invention is used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period. The compounds that make up the combination therapy can be administered into the patient’s body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components; in addition, the combination compounds may be administered to the patient at different times during the treatment period, or one of them may be administered as a preliminary therapy for the other.

Pharmaceutically Acceptable Derivatives of Compounds

The compounds of this invention may exist in free form during processing or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. A detailed description of the properties of such salts is given by Berge S. M., et al., In "Pharmaceutical Salts" J. Pharmaceutical Science, 66: 1-19 (1977), incorporated herein by reference. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or the resulting other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glucose gluconate, formate glucose phosphate heptane, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane, valerate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The term "pharmaceutically acceptable prodrug form", in the context of this invention, means such prodrugs from among the compounds that make up the essence of this invention, which are suitable for use by humans and animals without undue toxicity, irritation, allergic reactions, etc., and correspond to a reasonable ratio benefit and risk. The term "prodrugs" means compounds that are transformed in vivo to form the parent compound of the above formula, for example, by hydrolysis in the blood.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions that contain at least one of the compounds described herein (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, solvents and / or excipients. These compositions may also contain one or more additional therapeutic agents. On the other hand, the compound of this invention can be administered to a patient in need of appropriate therapy in combination with one or more other therapeutic regimens, for example, in combination with antiplatelet agents, anti-inflammatory drugs, drugs for the treatment of concomitant diseases (including antitumor drugs), and t .d. For example, one or more antitumor agents may be additional therapeutic agents for co-administration or incorporation into a pharmaceutical composition with the compounds of this invention.

The pharmaceutical compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form. Remington's pharmaceutical sciences (15th edition, E.W. Martin, Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in the development of pharmaceutical compositions and known methods for their preparation. Except in such cases where the medium of conventional carriers is incompatible with the compound of the invention, for example, upon the appearance of any undesirable biological effects and other undesirable interactions with any other component (s) of the pharmaceutical composition, the use of such compositions is within the scope of this invention. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; malt, gelatin; talcum powder; excipients such as: cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

Dosage Forms

The subject of this invention are also dosage forms — a class of pharmaceutical compositions whose composition is optimized for a particular route of administration into the body at a therapeutically effective dose. The medicinal compositions of this invention can be administered orally, topically, rectally, intraocularly, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally, intraperitoneally, subcutaneously, intramuscularly, intrasternally, as well as by infusion, in the recommended dosages.

The dosage form of the present invention may contain a compound of the formula described here or a pharmaceutically acceptable salt thereof and an additional preparation, for example, selected from the following: antiplatelet agent, cardioprotective agent, neuroprotective agent, antitumor drug, antiviral drug, anti-inflammatory drug, antifungal drug and any pharmaceutically acceptable carrier, adjuvant or solvent. The term "pharmaceutically acceptable carrier or adjuvant" means a carrier or adjuvant that can be introduced into the patient’s body together with the compound constituting the essence of the present invention, and which does not destroy the pharmacological activity of this compound, and is non-toxic when administered in doses sufficient to deliver therapeutic the amount of compound.

Dosage forms of the present invention may contain formulations prepared using liposome or microencapsulation methods, methods for preparing nanoforms of the preparation, and other examples known in the pharmaceutical art.

The use of compounds in combination therapy

Although the compounds of this invention can be administered as an individual active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention and / or one or more other agents. When administered orally, the therapeutic agents can be different dosage forms that are administered simultaneously or sequentially at different times, or the therapeutic agents can be combined into a single dosage form.

The phrase "combination therapy" in relation to the compounds of this invention in combination with other pharmaceutical agents means the simultaneous or sequential administration of all agents, which, one way or another, will provide a beneficial effect of the combination of drugs. Co-administration involves, in particular, co-delivery, for example, in one tablet, capsule, injection, or in another form having a fixed ratio of active substances, as well as simultaneous delivery in several separate dosage forms for each compound, respectively.

Thus, the introduction of the compounds of this invention can be carried out in combination with additional methods of treatment known to specialists in the field of prevention and / or treatment of thrombosis, thromboembolism and / or diseases that are the cause or result of thrombosis.

Characterization of the biological activity of the compounds

Inhibition of coagulation factor XIa

For the compounds of the present invention, the ability to inhibit coagulation factor XIa, which is of interest for the treatment and / or prophylaxis of conditions characterized by undesirable thrombosis, has been studied.

The activity and inhibition of factor XIa was determined in accordance with known protocols.

The cleavage reaction of the chromogenic substrate S-2366 is carried out in buffer D: 50 mm Tris-HCl, pH 8.0; 150 mM NaCl; 0.1 mg / ml BSA. A solution of the enzyme — activated factor XIa — is prepared in buffer D at a concentration of 2 × 0.2 nM. For the studied compounds, stock solutions in 10 mM DMSO are prepared, which are diluted 4 times in buffer D, after which 10-fold solutions of the studied compounds are prepared by successive dilutions in a mixture of 25% DMSO: 75% buffer D. The chromogenic substrate S-2366 is dissolved in buffer D to a concentration of 10 × 0.25 mm.

During the experiment, 60 μl of buffer D, 100 μl of a 2x enzyme solution are added to the wells of the plate, then 20 μl of a 10-fold solution of the test compound. After that, the contents of the wells are thoroughly mixed by pipetting until the DMSO is dissolved in the buffer. The plate was incubated for 5 minutes at 37 ° C, and 20 μl of the substrate solution was added to the wells with stirring. Immediately after adding the substrate, the tablet is placed in a reader to measure absorbance at a wavelength of 405 nm and 37 ° C for 15-45 minutes.

From the curves of absorption versus time, the initial reaction rate of the substrate cleavage is determined, the dependence of the initial rate on the concentration of the studied compounds is built, and the concentration of the compound is determined, which causes a 50% decrease in the initial rate compared to control values in the absence of an inhibitor (IC ₅₀ ).

The following are examples of compounds that inhibit coagulation factor XIa with an IC ₅₀ value of less than 10 μM:

Examples of pharmaceutical compositions

The substances described in this invention can be used for the prevention and / or treatment of human diseases, for example, in the form of the following compositions ("substance" means the active ingredient, the compound according to formula (I)).

These formulations may be prepared in accordance with standard pharmaceutical procedures.

Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications are possible without departing from the gist of the present invention.

Claims (49)

1. The compound of formula (I)

or its stereoisomer, or a pharmaceutically acceptable salt, where the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O—, or —S—; R ₁ is independently selected and is hydrogen, halogen, —C _1-3 alkyl, partially or fully halogenated —C _1-3 alkyl, —CN, —OH, —O — C _1-3 alkyl, —NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C ₁ - ₃ -alkyl-NH ₂ , -C _1-3 -alkyl-NH-С _{1- 3-} alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl or 5-membered heteroaryl ring containing 1-4 N atoms and 0-1 S atom; the group R ₁ contains 0-2 substituents R ₄ ; R ₂ is independently selected and is halogen, partially or fully halogenated —CH ₃ or —OCH ₃ ; R ₃ is independently selected and is hydrogen or halogen; R ₄ is independently selected and is halogen or C _1-3 alkyl; cycle A is independently selected and is phenyl, a 5-6 membered heteroaryl ring containing 1-2 N atoms; cycle A contains 0-1 of R ₅ and 0-2 of R ₆ ; R ₅ is independently selected and is phenyl; 5-9 membered heteroaryl containing 1-2 N atoms and 0-1 S or O atom, 5-6 membered cycloalkyl or 5-6 membered heterocycle containing 1-2 N atoms, 0-1 atom S or O; R ₅ contains 0-2 substituents R '₆; R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, —NHC (O) C _1-3 -alkyl, -C _1-3 -alkyl-NHC (O) H, -C _1-3 -alkyl-NHC (O) С _1-3 -alkyl, -NHC (O) OH, -С _{1- 3-} alkyl-NHC (O) OH, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -CN, halogen, -S (O) ₂ NH ₂ , 5-6 membered saturated, unsaturated or partially saturated heterocycle containing 1-4 N atoms, 0-1 S atom; R ₆ and R ′ ₆ contain 0-2 substituents of R ₇ ; R ₇ is independently selected and is = O, -C _1-3 -alkyl, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl) C _1-3 -alkyl, -C _{1 -3-} alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl) C _1-3 -alkyl, -OH, -OC _1-3 -alkyl, -C _1-3 -alkyl-OH, -C _1-3 -alkyl-O-C _1-3 -alkyl or halogen. 2. The compound according to claim 1, in which: the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O— or —S—; R ₁ is independently selected and is hydrogen, halogen, partially or fully halogenated —C _1-3 alkyl, —CN, —NHC _1-3 alkyl or a 5 membered heteroaryl ring containing 1-4 N atoms; R ₁ contains 0-2 substituents of R ₄ ; R ₂ is independently selected and is halogen or —OCH ₃ ; R ₃ is independently selected and is hydrogen or halogen; R ₄ is independently selected and is halogen or —C _1-3 alkyl; cycle A is independently selected and represents a phenyl or 5-6 membered heteroaryl ring containing 1-2 N atoms; cycle A contains 0-1 substituent R ₅ and 0-2 substituent R ₆ ; R ₅ is independently selected and is phenyl, a 5-9 membered heteroaryl containing 1-2 N atoms and 0-1 S or O atom; 5-6 membered cycloalkyl or 5-6 membered heterocycle containing 1-2 N atoms, 0-1 S or O atom; R ₅ contains 0-2 substituents R '₆; R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, —C _1-3 - alkyl-NHC (O) H, -NHC (O) OH, -C _1-3 -alkyl-NHC (O) OH, -NH ₂ , -NHC _1-3 -alkyl, -N (C _1-3 -alkyl ) C _1-3 -alkyl, -C _1-3 -alkyl-NH ₂ , -C _1-3 -alkyl-NHC _1-3 -alkyl, -C _1-3 -alkyl-N (C _1-3 -alkyl ) C _1-3 -alkyl, -CN or -S (O) ₂ NH ₂ ; R ₆ and R ′ ₆ contain 0-1 substituent R ₇ ; R ₇ is independently selected and is = O, —C _1-3 -alkyl. 3. The compound according to claim 1, in which: the linker L ₁ is independently selected and is —CH ₂ -, —NH—, —O— or —S—; R ₁ is independently selected and is hydrogen, halogen, —CF ₃ ; -NH ₂ , NHC _1-3 -alkyl or 5-membered heteroaryl ring containing 4 N atoms; R ₂ represents halogen; R ₃ is independently selected and is hydrogen or halogen; cycle A is independently selected and represents a phenyl or 5-membered heteroaryl ring containing 2 N atoms; cycle A contains 0-1 substituent R ₅ and 0-2 substituent R ₆ ; R ₅ represents phenyl; R ₅ contains 0-1 substituent R '₆; R ₆ and R ′ ₆ are independently selected and are —OH, —C _1-3 -alkyl, —C (O) OH, —C (O) NH ₂ , —NHC (O) H, —NHC (O) OH ; R ₆ and R ′ ₆ contain 0-1 substituent R ₇ ; R ₇ is —C _1-3 alkyl. 4. The compound according to claim 1, selected from the group: 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-ylamino) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid; 5- (6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yloxy) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid; 4- (6- (5-chloro-2-cyanophenyl) benzo [d] isoxazol-3-ylamino) -2- (2-methylbenzo [d] thiazol-5-yl) benzoic acid; ethyl 2- (2-carbamoyl-5- (6- (5-chloro-2- (ethylamino) phenyl) benzo [d] isoxazol-3-ylamino) phenyl) thiazole-5-carboxylate; 4- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -2-morpholinobenzoic acid; 3 ', 5'-dichloro-5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) biphenyl-2-carboxylic acid; 5 '- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -2' - (1H-tetrazol-1-yl) biphenyl-4-sulfonamide; 5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (1H-imidazol-1-yl) biphenyl-2-carboxylic acid; 5- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) -4 '- (2-oxopiperidin-1-yl) biphenyl-2-carboxylic acid; 5- (6- (5-chloro-2- (trifluoromethyl) phenyl) benzo [d] isoxazol-3-ylthio) -4 '- (methoxycarbonylamino) biphenyl-2-carboxylic acid; 2- (3-amino-1H-indazol-6-yl) -4- (6- (3-chloro-2-fluorophenyl) benzo [d] isoxazol-3-ylamino) benzoic acid; 5 - ((6- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) benzo [d] isoxazol-3-yl) methyl) -4'-methoxybiphenyl-2-carboxylic acid. 5. The use of compounds according to any one of paragraphs. 1-4 as inhibitors of coagulation factor XIa in blood or plasma. 6. The use of compounds according to any one of paragraphs. 1-4 to obtain a pharmaceutical composition for treating and / or preventing the condition of a mammal characterized by undesirable thrombosis. 7. The use according to claim 6, in which the condition of the mammal, characterized by unwanted thrombosis, is thrombophilia, acute coronary syndrome, myocardial infarction, unstable angina, refractory angina pectoris, transient ischemic attack, thrombosis caused by post-thrombolytic therapy and coronary cerebral angiopsy syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, peripheral arterial occlusion, venous thrombosis, deep thrombosis x veins, thrombophlebitis, arterial thromboembolism, thrombosis, coronary artery thrombosis, cerebral artery, renal thromboembolism, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with geparinoindutsirovannoy thrombocytopenia, thrombus in atrial fibrillation, thrombogenesis with atherosclerosis, thrombotic complications associated with cardiopulmonary bypass, thrombotic complications associated with prosthesis E devices. 8. A pharmaceutical composition for treating and / or preventing a condition of a mammal characterized by undesirable thrombosis, comprising an effective amount of a compound according to any one of claims. 1-4 and at least one pharmaceutically acceptable excipient. 9. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutically acceptable excipient is a carrier, adjuvant and / or solvent.