EA005367B1 - Substituted pyridones, use thereof, composition and method for inhibiting thrombotic conditions and methods of prophylaxis and treatment - Google Patents

Abstract

The invention relates to substituted polycyclic aryl and heteroaryl pyridone compounds having Formula (I) or a pharmaceutically acceptable salt thereof, wherein B is selected from phenyl, C1-C6 alkyl and C3-C6 cycloalkyl; A is selected from a single covalent bond, -(CH2)n-, wherein n is an integer from 1 to 5, -SO2- and -C(O)-; R<1> and X<0> are hydrogen; R<2> is an optionally substituted phenyl, or R<2> is together with R<1> form quinoline; K is -(CH2)m-, wherein m is an integer from 1 to 3; E<0> is -C(O)NH-, -NH- or -SO2NH-; and Y<0> is benzyl optionally substituted by amidino- or guanidino group, or an optionally substituted C1-C6 alkyl. The compounds of the present invention are useful as inhibitors of serine proteases of the coagulation cascade and can be used for manufacturing corresponding pharmaceutical compositions. The invention also relates to compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

Description

Field of Invention

This invention relates to the field of anticoagulation therapy, and specifically relates to compounds, compositions and methods for the prevention and treatment of thrombotic disease states, such as coronary artery disease and cerebrovascular disease. More specifically, the invention relates to substituted polycyclic aryl and heteroaryl pyridone compounds that inhibit the serine proteases of the coagulation cascade.

BACKGROUND OF THE INVENTION

Physiological systems control the flow of blood in mammals. | Ma) egi5 R.A. e! A1: ApCsoaschbapG T11gotho1ubs apb Apr1a1s1s1 Bgidk. In Nagbtap 1.0. apb YtYgb L.E., editors: Ooobtap &Obtap'k TBe RBagtas1oDsa1 Vaak oG TBegareiBsk. 9 ' ¹ ' ebayup. Iete Wogk. Msogate-NSh Vook So, 1996, pp. 1341-1343]. Blood must remain liquid in the vascular system and must also be able to quickly undergo hemostasis, stopping the loss of blood from a damaged vessel. Hemostasis or coagulation begins when platelets initially stick together with macromolecules in the subendothelium region of wounded and / or damaged vessels. Such platelets aggregate to form a primary hemostatic plaque and stimulate local activation of coagulation factors in blood plasma, leading to the generation of a fibrin clot, which strengthens aggregated platelets.

Coagulation factors for blood plasma include factors II, V, VII, VIII, IX, X, XI and XII; they are also called protease zymogens. These coagulation factors or protease zymogens (proenzymes) are activated by a serine protease, leading to coagulation in the so-called “coagulation cascade” or chain reaction [Napbt KT: Vljebshd apb TBrtoboyk. At AShop 1. e! A1., editors; Natkop'k rppsK p1ez oG [p1egpa1 Mebkshe, 12 ^4b Ebyup, Iete-Wogk, Msogate-NSh Vook So., 1991, p. 350]. Coagulation or coagulation of blood is carried out in two ways in different ways. Own or contact path leads from XII to XIIa to HB1 to Ka and to the conversion of X into Xa. Xa together with factor Va convert prothrombin (II) into thrombin (Na), leading to the conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. The external pathway is initiated by the conversion of coagulation factor VII into UPa using Xa. The presence of tissue factor and UPA accelerates the formation of XA in the presence of calcium ion and phospholipids. The formation of Ha leads to thrombin, fibrin and fibrin clot, as described above. The presence of one or more of these many different coagulation factors and two individual coagulation pathways enables effective selective control and a better understanding of parts of the coagulation or blood coagulation process.

Although blood coagulation as a result of damage to a blood vessel is a crucial physiological process in mammals such as humans, coagulation can also lead to painful conditions. A pathological process called thrombosis occurs when a platelet aggregate and / or fibrin clot blocks (i.e. clogs) a blood vessel. Arterial thrombosis can lead to ischemic necrosis of the tissue supplied by the artery. When thrombosis occurs in the coronary artery, myocardial infarction or heart attack can occur. Thrombosis occurring in a vein can lead to swelling and inflammation of the tissues drained by this vein. Deep vein thrombosis can be complicated by a pulmonary embolism. Prevention or treatment of clots in a blood vessel can be used therapeutically by inhibiting the formation of aggregates of blood platelets, inhibiting the formation of thrombus, inhibiting the formation of a blood clot, inhibiting the formation of embolism and for treating or preventing unstable angina that can not be treated for angina pectoris, short-term attacks of ischemia, atrial fibrillation, atrial fibrillation, , embolic stroke, deep vein thrombosis, diffuse intravascular coagulation, ocular formation Ibrin and repeated blockage or restenosis of recanalized vessels.

There are several reports of non-peptide and peptide pyridone compounds that act as an inhibitor of the coagulation factor present in the coagulation cascade or blood coagulation process. PCT Patent Application AO 98/47876, Vaen Voieske1 et al., Describe peptide 6-alkylpyridones and 2-alkylpyrimidinones as antithrombotic compounds. PCT Patent Application AO 98/16547, Ζΐιιι and 8сагЬогоидБ, describes 3- (I-heterocyclylamino) -4,5,6-substituted pyridonylacetamides and 2,4-substituted 5- (I-heterocyclylamino) pyrimidinonylacetamides containing amide substituents and having activity against factor Xa of mammals. US Pat. No. 5,656,645 to Tatiga et al. Describes 4,5,6-substituted 3-aminopyridonylacetamides, 1,6-substituted 5-aminouracil acetamides and 2,4-substituted 5-aminopyrimidinonylacetamides containing amide substituents having formyl function and having activity against thrombin. US Pat. No. 5,658,930 to Tatiga et al. Again describes 4,5,6-substituted 3-aminopyridonylacetamides, 1,6-substituted 5-aminouracil acetamides and 2,4-substituted 5-aminopyrimidinonylacetamides containing amide substituents having formyl function and having activity against thrombin. PCT Patent Applications 96/18644 and 97/46207, Tatiga et al., Additionally describe 4,5,6-substituted 3-aminopyridonylacetamides, 1,6-substituted 5-aminouracil acetamides and 2,4-substituted 5-aminopyrimidinilacetamides containing amide substituents having formyl function and possessing activity against thrombin. PCT Patent Application AO 98/09949, §c

-1005367 ζιιΙ <ί et al., 2-heterocyclylacetamido derivatives of 1,2-diketones are described and it is reported that they inhibit proteases, especially chymase inhibitors. US Pat. No. 5,668,289 to Zabbegzop et al. Describes 6-alkyl, 6-cycloalkyl and 6-trifluoromethylpyridones unsubstituted at positions 4 and 5 and is said to inhibit thrombin. PCT Patent Application AO 97/01338, Zapbegzop et al., Discloses 6-alkyl, 6-cycloalkyl- and 6-trifluoromethyl-pyridones unsubstituted at positions 4 and 5 and is said to inhibit thrombin. US Pat. No. 5,792,779 to Zabbegzop et al. Describes 4,6-alkyl, 4,6-cycloalkyl and 4,6-trifluoromethyl-pyridones, which are useful as thrombin inhibitors. PCT Patent Application AO 97/30708, Zabbegzop et al., Describes additional substituted 4,6-alkyl, 4,6-cycloalkyl and 4,6-trifluoromethylpyridones, which are useful as thrombin inhibitors. U.S. Pat. No. 5,869,487, CoBigp et al., Describes pyrido [3,4-b] pyrazines containing a condensed 6methylpyridone function and having utility as thrombin inhibitors. PCT Patent Application AO 98/31670, Zapbegzop et al., Describes additional 4-substituted 6-alkyl, 6-cycloalkyl and 6-trifluoromethylpyridones, which are useful as thrombin inhibitors. PCT Patent Application AO 98/17274, Cobig et al., Describes 3,4-diamino-6-methylpyridones having utility as inhibitors of human thrombin. PCT Patent Application AO 98/42342, 1caasz et al. Describe additional 6-alkyl, cycloalkyl and trifluoromethyl substituted pyridones and pyrazinones that are reported to inhibit human thrombin.

Summary of the invention

The aim of the present invention is to provide compounds useful for anticoagulation therapy and having the general structure:

Formula (I)

Another objective of the present invention is to provide methods for the prevention and treatment of thrombotic diseases such as coronary artery disease, cerebrovascular disease and other diseases associated with coagulation. Prevention and treatment of such thrombotic diseases is carried out by introducing an effective amount of the compounds of formula (I) to a patient in need thereof.

Other various objects and advantages of the present invention will be apparent from the following description of the invention.

Description of the invention

The present invention relates to a class of compounds comprising substituted polycyclic aryl and heteroaryl pyridones that are useful for anticoagulation therapy for the treatment and prevention of a variety of thrombotic diseases, including coronary artery disease and cerebrovascular disease, represented by formula (I) in ¹

o or its pharmaceutically acceptable salts, wherein B is selected from the group consisting of phenyl, C1-C6 alkyl, and C ₃ -C ₆ cycloalkyl;

A is selected from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, —CO ₂ - and —C (O) -;

In ¹ and X ⁰ represents hydrogen;

K ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or B ² together with B ¹ forms quinoline;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents —C (O) PN—, —ΝΗ—, or —OZ ₂ PN—; and

Υ ⁰ represents benzyl, optionally substituted by an amidino or guanidino group, or C ₁ -C ₆ alkyl, optionally substituted by one or more substituent (s), which (s) are selected from the group consisting of guanidino, oxo (= O), 5- member heteroaryl containing 1 or 2 heteroatoms selected from Ν, O and Z.

-2005367

In another embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof, B is phenyl;

And choose from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -8O ₂ - and -C (O) -;

In ¹ and X ⁰ represents hydrogen;

B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or B ² together with B ¹ forms quinoline;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents —C (O) OH —, —ΝΗ—, or —8Ο ₂ ΝΗ—; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In yet another embodiment of the compounds of formula I, or a pharmaceutically acceptable salt thereof, B is phenyl;

A is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ ;

In ¹ and X ⁰ represents hydrogen;

B ² represents phenyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents —C (OSH11-, -ΝΗ- or -8Ο ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In a further embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof, B is phenyl or thienyl;

A is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ ; In ¹ and X ⁰ represents hydrogen;

B ² represents phenyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents —C (OSH11-, -ΝΗ- or -8Ο ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In further embodiments, the compounds of the present invention have the formula

and may be in the form of a pharmaceutically acceptable salt thereof. In the indicated formula, B ² represents 3-aminophenyl, B represents phenyl, A represents CH ₂ , Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; or

B ² represents 3-methylphenyl, B represents phenyl, A represents CH2CH2, Υ ⁰ represents 4 amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; or

B ² represents phenyl, B represents phenyl, A represents CH2, Υ ⁰ represents 4 amidinobenzyl, B ¹ represents hydrogen, and X ⁰ represents hydrogen.

In yet another embodiment of the compounds of formula I, or a pharmaceutically acceptable salt thereof, B is selected from C ₁ -C ₆ alkyl;

And choose from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -8O ₂ - and -C (O) -;

In ¹ and X ⁰ represents hydrogen;

B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or B ² together with B ¹ forms quinoline;

K represents - (C11 ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents —C (O) H1—, —ΝΗ—, or —8O ₂ H1—; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In another embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof, B is selected from C ₁ -C ₆ alkyl;

A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ ;

In ¹ and X ⁰ represents hydrogen;

B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen;

-3005367

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents -Ο (Θ) ΝΗ-, -ΝΗ- or -8Ο ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In yet another embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof, B is selected from C ₁ -C ₆ alkyl;

A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ ;

In ¹ and X ⁰ represents hydrogen;

I ² represents phenyl or pyridyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen;

K represents - (CH ₂ ) _t -, where _t represents an integer from 1 to 3;

E ⁰ represents -ί. '(Ϋ) ΝΗ-. -ΝΗ- or -8Θ ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In the following embodiments of the compounds of formula

K ¹

ABOUT

I ² represents 5-amino-2-fluorophenyl, B represents isopropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 2-methyl-2-aminophenyl, B represents isopropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents ethyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents isopropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents 2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents (I) -2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents (8) -2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents 3-pentyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents ethyl, A represents CH2, Υ ⁰ represents 4a-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents 2-methylpropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents 2-propyl, A represents CH ₂ CH ₂ , Υ ⁰ represents

4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents propyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents tert-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-aminophenyl, B represents butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen; or

I ² represents 3-carboxyphenyl, B represents 2-propyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, I ¹ represents hydrogen and X ⁰ represents hydrogen.

In another embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof B is selected from C3-C6 cycloalkyl;

A is selected from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -§O ₂ - and -C (O) -;

I ¹ and X ⁰ represents hydrogen;

I ² is phenyl, pyridyl or thienyl, optionally substituted with one or more substituent (s) which is (s) selected from the group consisting of amino, carboxyl, _C1-C3 alkyl, amidocarbonyl, hydroxy, carboxamido and halo or I ² together with I ¹ forms quinoline;

K represents - (cs ^ -, where m represents an integer from 1 to 3;

-4005367

E ⁰ represents -Ο (Θ) ΝΗ-, -ΝΗ- or -§Θ ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In a further embodiment, in the above compounds or a pharmaceutically acceptable salt thereof, B is selected from C ₃ -C ₆ cycloalkyl;

A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ ;

TO? and X ⁰ represents hydrogen;

K ² is phenyl, pyridyl or thienyl, optionally substituted with one or more substituent (s) which is (s) selected from the group consisting of amino, carboxyl, C ₃ -C _£ alkyl, amidocarbonyl, hydroxy, carboxamido and halo;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents -ί. '(Ϋ) ΝΗ-. -ΝΗ- or -8Θ ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In a further embodiment of the compound or a pharmaceutically acceptable salt thereof B is selected from C3C6 cycloalkyl;

A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ ;

K ¹ and X ⁰ represents hydrogen;

K ² represents phenyl or pyridyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents Α (Θ) ΝΗ-, -ΝΗ- or -8Θ ₂ ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group.

In another embodiment of the compounds of formula I or a pharmaceutically acceptable salt thereof, B is phenyl;

And choose from the group consisting of - (CH ₂ ) _P -, where η represents an integer from 1 to 5 and -8O ₂ -;

X ⁰ represents hydrogen;

K ² together with K ¹ forms quinoline;

K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3;

E ⁰ represents -ί. '(Ό) ΝΗ-; and

Υ ⁰ represents benzyl optionally substituted with an amidino or guanidino group, or C ₆ -C ₆ alkyl optionally substituted with one or more substituent (s), which (s) are selected from the group consisting of guanidino, oxo (= O), 5- a heteroaryl member containing 1 or 2 heteroatoms selected from Ν, O and 8.

In the particular case of the previous embodiment of the compound or its pharmaceutically acceptable salt B is phenyl;

A represents CH ₂ CH ₂ or -8O ₂ -;

X ⁰ represents hydrogen;

K ² together with K ¹ forms quinoline;

K represents CH ₂ ;

E ⁰ represents -ί. '(Ό) ΝΗ-; and

Υ ⁰ is benzyl optionally substituted with an amidino group, or C ₅ alkyl substituted with an oxo group, guanidino group and thiazolyl.

Preferred embodiments of the compounds of the present invention are compounds of the formulas below

-5005367

or

or their pharmaceutically acceptable salts.

The compounds of this invention can be used in anticoagulation therapy for the treatment and prevention of a variety of thrombotic disease conditions, including coronary artery disease and cerebrovascular disease. The compounds of this invention can be used to inhibit the serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI or XII. The compounds of the invention can inhibit the formation of aggregates of blood platelets, inhibit the formation of fibrin, inhibit the formation of a blood clot and inhibit the formation of embolism in mammals in the blood, blood products and organs of mammals. The compounds can also be used to treat or prevent unstable angina pectoris, non-treatable angina pectoris, short-term attacks of ischemia, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular fibrin formation and repeated blockage or mammalian vascularization. The compounds can also be used in the prophylactic treatment of subjects at risk of developing such diseases. Compounds can be used to reduce the risk of atherosclerosis. The compounds of formula (I) may also be useful in the prevention of stroke (ΟνΑ) or stroke.

In addition to being used for human treatment, these compounds can also be used for veterinary treatment of domestic animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

In another embodiment of the present invention, the new compounds are selected from the compounds indicated in examples 1 to 28 and in the table of examples 1.

In this description, for clarity, the use of general terms in the description of compounds is defined.

The standard individual letters of the element symbols are used to represent specific types of atoms, unless otherwise indicated. The symbol "C" represents a carbon atom. The symbol "O" represents an oxygen atom. The symbol "Ν" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "8" represents a sulfur atom. The symbol "H" represents a hydrogen atom. Symbols of two-letter elements are used to identify elements of the periodic table (for example, C1 represents chlorine, 8e represents selenium, etc.).

As used herein, the term “C ₁ -C ₆ alkyl” means an acyclic alkyl radical containing from 1 to 6 carbon atoms, preferably from 3 to 6 carbon atoms. Said alkyl radicals may optionally be substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, nbutyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, isoamyl, hexyl, octyl and the like.

The term “carbon” radical means a carbon atom without any covalent bonds and capable of forming four covalent bonds.

The term “alkylene” radical means linear or branched radicals having from 1 to 5 carbon atoms and having attachments at two or more covalent bonds. Examples of such radicals include methylene, ethylene, methylene and isopropylidene.

The term “halogen” means halogens. Such as fluorine, chlorine, bromine or iodine atoms.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one ring. The term “aryl” embraces aromatic radicals such as phenyl.

The term “heterocyclyl” embraces saturated and partially saturated heteroatom-containing ring structure radicals having 5 ring members selected from carbon, nitrogen, sulfur and oxygen, where at least one ring atom is a heteroatom. Examples of saturated heterocyclyl radicals include pyrrolidinyl, imidazolidinyl, thiazolidinyl, etc. Examples are hour

60060067 naturally saturated heterocyclyl radicals include dihydrothiophene, dihydropiran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxalanyl, 2H-pyranyl, 4H-pyranyl and the like.

The term “heteroaryl” embraces fully unsaturated heteroatom-containing aromatic radicals of a ring structure having 5 ring members selected from carbon, nitrogen, sulfur and oxygen, in which at least one ring atom is a heteroatom. Examples of “heteroaryl” radicals include a heteromonocyclic group containing 1-4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, triazolyl [for example, 4H-1,2,4-triazolyl, 1H-1,2,3triazolyl, 2H- 1,2,3-triazolyl, etc.]; unsaturated heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc .; unsaturated heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; unsaturated heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc.], etc .; unsaturated heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and t .d.] etc. The specified "heterocyclyl" group may have 1-3 substituents, as defined below. Preferred heterocyclic radicals include five-membered non-condensed radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, thiazolyl, imidazolyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazazolyl, 1,2-oxazazolyl triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, 1,3,4-tritianil and the like.

The term "sulfonyl", if used alone or in connection with other terms, such as, for example, alkylsulfonyl, means, respectively, divalent radicals -O ₂ -.

“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, wherein the alkyl is as defined above.

“Alkylsulfonylalkyl” embraces alkylsulfonyl radicals attached to an alkyl radical, wherein the alkyl is as defined above. The term “aminosulfonyl” means an amino radical attached to a sulfonyl radical.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferred aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are used interchangeably.

The term “heteroaralkyl” embraces heteroaryl substituted alkyl radicals, wherein the heteroaralkyl radical may be further substituted with three or more substituents as defined above for aralkyl radicals.

The term “perhaloaralkyl” embraces aryl-substituted alkyl radicals, wherein the aralkyl radical is substituted with three or more halogen radicals, as defined above.

The term “aralkylsulfonyl” embraces aralkyl radicals attached to a sulfonyl radical, wherein the aralkyl is as defined above.

“Aralkylsulfonylalkyl” embraces aralkylsulfonyl radicals attached to an alkyl radical, wherein the alkyl is as defined above.

The term “cycloalkyl” embraces radicals having from three to 6 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. Preferred cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl.

The term "carbonyl" means a carbon radical, two of the four covalent bonds of which are in common use with an oxygen atom. The term “carboxy” embraces a hydroxyl radical, as defined above, attached to one of two non-socialized bonds of the carbonyl group. The term “carboxamide” embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino and dicycloalkylamino radicals attached to one of two non-socialized bonds of the carbonyl group. The term “carboxamidoalkyl” embraces carboxamide radicals, as defined above, attached to an alkyl group.

The term "amino" means a nitrogen atom containing two substituents, such as hydrido, hydroxy or alkyl, and having one covalent bond available for binding to a single atom, such as carbon. Examples of such amino radicals include, for example, -ΝΗ ₂ , -ΝΗί.Ή ₃ . -ΝΗΟΗ and -ΝΗΟΟΗ ₃ .

The term "imino" means a nitrogen atom containing one substituent, such as hydrido, hydroxy or alkyl, and having two covalent bonds available for binding to a single atom, such as carbon. Examples of such imino radicals include, for example, = ΝΗ, = SPF ₃ , = ΝΟΗ and = ΝΟ0ΝΟ ₃ .

-7005367

The term “iminocarbonyl” means a carbon radical having two of the four covalent binding sites in common use with an imino group. Examples of such iminocarbonyl radicals include, for example, Ο '= ΝΗ. Ο = ΝΟΗ ₃ , Ο = ΝΟΗ and Ο = ΝΟΟΗ ₃ .

The term “amidino” embraces a substituted or unsubstituted amino group bonded to one of the two available bonds of the iminocarbonyl radical. Examples of such amidino radicals include, for example, ΝΗ _2- Ο = ΝΗ, ΝΗ _2- Ο =, ₃ , ΝΗ ₂ -0 = ΝΟΟΗ _3, and ΟΗ ₃ ΝΗ-0 = ΝΟΗ.

The term “guanidino” means an amidino group linked to an amino group, as defined above, wherein said amino group may be linked to a third group. Examples of such guanidino radicals include, for example, ΝΗ ₂ -Ο (ΝΗ) -ΝΗ-, ΝΗ ₂ -Ο (ΝΟΗ ₃ ) -ΝΗ-, ΝΗ ₂ -0 (ΝΟΟΗ ₃ ) -ΝΗ and 0Η ₃ ΝΗ-0 (ΝΟΗ) - ΝΗ-.

Some of the groups defined above may optionally have 1 or more nonhydride substituents, such as amino, carboxyl, amidocarbonyl, hydroxy, guanidino, oxo, halogen, etc.

The term “spacer” may include a covalent bond and a linear moiety having a base of

1-5 adjacent atoms.

The compounds of the present invention may exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans geometric isomers, E and геометрическ geometric isomers, B and 8 enantiomers, diastereomers, bisomers, 1 isomers, racemic mixtures thereof and other mixtures thereof, as falling under the scope of the invention. Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included in this invention.

The terms “cis” and “trans” mean the formation of a geometric isomerism, in which of the two carbon atoms bonded by a double bond, each will have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“ trance").

Some of the compounds described contain alkenyl groups, and it is understood that they include both cis and trans, or “E” and “Ζ” geometric forms.

Some of the compounds described contain one or more stereo centers, and it is understood that they include B, 8 and a mixture of B and 8 forms for each stereo center present.

Some of the compounds described may contain one or more ketone or aldehyde carbonyl groups, or combinations thereof per se, or as part of a heterocyclic ring system. Such carbonyl groups can exist partially or mainly in the form of a “ketone” form and partially or mainly in the form of one or more “enol” forms of each of the aldehyde or ketone groups present. The compounds of the present invention having aldehyde or ketone carbonyl groups are intended to include both the “ketone” and “enol” tautomeric forms.

Some of the compounds described may contain one or more amide carbonyl groups or combinations thereof per se, or as part of a heterocyclic ring system. Such carbonyl groups can exist partially or mainly in the form of a “ketone” form and partially or mainly in the form of one or more “enol” forms of each of the amide groups present. The compounds of the present invention having amide carbonyl groups are intended to include both the “ketone” and “enol” tautomeric forms. Such amide carbonyl groups can be both oxo ^ = Ο) and thiono (C = 8) type.

Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist partially or mainly in the "imine" form and partially or mainly in the form of one or more "enamine" forms for each group present. The compounds of the present invention having the indicated imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.

The present invention also includes the treatment and prevention of anticoagulation therapy for the treatment and prevention of a variety of thrombotic disease states, including coronary artery disease and cerebrovascular disease, in a subject, comprising administering to a subject having such a disease a therapeutically effective amount of a compound of formula (I):

to ¹ (I) or a pharmaceutically acceptable salt thereof.

As an additional embodiment of the compounds of the present invention of formula (I) or their pharmaceutically acceptable salts, the invention includes the treatment and prevention of coronary artery disease, cerebrovascular disease and other coagulation cascade diseases in a subject, comprising administering to a subject having such a disease a therapeutically effective amount of the compounds formula (I) of the present invention or a pharmaceutically acceptable salt thereof.

-8005367

The compounds of the present invention of formula (I) or their pharmaceutically acceptable salts can also be used when it is desired to prevent blood coagulation, such as to prevent coagulation of whole blood during storage and to prevent coagulation in other biological samples for testing or storage. Such blood coagulation inhibitors of the present invention can also be added to or brought into contact with stored whole blood and any medium that contains or is suspected to contain coagulating plasma factors, and in which it is desirable to inhibit blood coagulation, for example, by contacting mammalian blood with material selected from the group consisting of vascular grafts, stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulatory systems.

The compounds of formula (I) are able to inhibit the activity of serine proteases related to the coagulation cascade, and thus can be used in the manufacture of a medicament, in a method for the prevention or therapeutic treatment of diseases mediated by serine proteases of the coagulation cascade, such as for inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibition of thrombus formation and inhibition of embolism in a mammal in the blood, in blood products and in Ghanaian mammals. The compounds can also be used to treat or prevent unstable angina pectoris, non-treatable angina pectoris, myocardial infarction, short-term attacks of ischemia, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, diffuse intravascular coagulation, ocular fibrin formation, and re-clotting in a mammal. The compounds can also be used to study the mechanism of action of the serine proteases of the coagulation cascade with the goal of creating the best inhibitors and developing the best analysis methods. The compounds of formula (I) could also be useful in the prevention of stroke or stroke.

Pharmaceutically acceptable salts thereof are also included in the family of compounds of formula (I). The term “pharmaceutically acceptable salt” embraces commonly used alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carbocyclic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, milk, malic, tartaric, citric, citric, , maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, phydroxybenzoic, phenylacetic, almond, emb new (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, tsiklogeksilaminosulfonovaya, algenovaya, galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts derived from Ν, Ν'-dibesilethylenediamine, choline, chlorprocaine, diethanolamine , ethylenediamine, meglumine (Ν-methylglucamine) and procaine. All of these salts can be prepared by conventional methods from the corresponding compound of formula (I) by reacting it, for example, with a suitable acid or base.

The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with at least one pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical composition of the present invention may include active compounds of formula (I) in combination with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or excipients (collectively referred to herein as “carriers”) and, if desired, with other active ingredients. The active compounds of the present invention can be administered in any suitable way, preferably in the form of a pharmaceutical composition adapted for such a route of administration, and in a dose effective for the intended treatment.

Active compounds and compositions may be administered, for example, orally, intravenously, intraperitoneally, subcutaneously, intramuscularly, ophthalmic or topically. For the treatment of ocular fibrin formation, the compounds can be administered intraocularly or topically, as well as orally or parenterally.

The compounds can be administered as a depot injection or as an implanted preparation, which can be formulated in such a way as to enable the sustained release of the active ingredient. The active ingredient may be compressed into pills or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant. Inert materials, such as biodegradable polymers or synthetic silicones, for example, Ξίΐαδίίο, can be used for implants. silicone rubber or other silicon-containing polymers.

-9005367

The compounds can also be administered in the form of a liposome delivery system, such as, for example, in the form of small single-layer vesicles, large single-layer vesicles or multilayer vesicles. Liposomes can be obtained from a number of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds can also be delivered using individual monoclonal antibody carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as drug carriers capable of targeted delivery. Such polymers may include polyvinylpyrrolidone, a pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethyl aspartamid phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds can be combined with a class of biodegradable polymers used to achieve controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydrocyranates, and polyhydrocyranes, amphipathic block copolymers of hydrogels.

For oral administration, the pharmaceutical composition can be obtained in the form of, for example, tablets, capsules (each of which includes sustained or sustained release formulations), pills, powders, granules, elixirs, tinctures, including syrup liquids and emulsions. The pharmaceutical composition is preferably formulated in a unit dosage form containing a specific amount of the active ingredient. Examples of such unit dosage forms are tablets or capsules. The active ingredient can also be administered by injection in the form of a composition, where, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds to be administered and the dosage regimen for treating a disease state with the compounds and / or compositions of this invention depend on a number of factors, including the age, weight, gender and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound used, and therefore, they can vary over a wide range.

The pharmaceutical compositions may contain active ingredients in the range of from about 0.1 to 2000 mg, and preferably in the range of from about 0.5 to 500 mg. A suitable daily dosage may be from about 0.01 to 100 mg / kg body weight, and preferably from about 0.5 to about 20 mg / kg body weight. The daily dose may be administered as one to four doses per day.

The compounds can be used in the composition of an ointment or cream or in the form of a suppository containing the active ingredients in a total amount, for example, from 0.075 to 30% w / w, preferably from 0.2 to 20% w / w. and most preferably from 0.4 to 15% w / w. When they are introduced into the composition of the ointment, the active ingredients can be used together with either a paraffin wax or a water-based ointment base.

Alternatively, the active ingredients can be incorporated into the cream along with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w. a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol and mixtures thereof. A topical composition may, if desired, include a compound that enhances the absorption or penetration of the active ingredient through the skin or other treated area. Examples of such skin permeability enhancers include dimethyl sulfoxide and related analogs. The compounds of this invention can also be administered using a transdermal device. Preferably, topical administration should be carried out using a patch or reservoir and porous membrane type, or a series of solid matrices. In either case, the active ingredient is delivered continuously from the reservoir or microcapsules through the membrane into the adhesive layer permeable to the active ingredient, which contacts the skin or mucous membrane of the recipient. If the active ingredient is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as a membrane.

The oil phase of the emulsions of this invention can be composed of known ingredients in a known manner. Although the phase may include only an emulsifier, it may contain a mixture of at least one emulsifier with fat or oil, or together with both fat and oil. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier (s) in the presence or absence of stabilizer (s) gives the so-called emulsifying wax, and the wax together with oil and fat forms the so-called emulsifying base of the ointment, which forms the oily dispersed phase of the creams. Emulsifiers and emulsion stabilizers suitable for use in the compositions of the present invention include, among others, Tteeei 60, 8Pai 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

-10005367

The selection of suitable oils or fats for the composition is based on the achievement of the required cosmetic properties, since the solubility of the active compound in most oils suitable for use in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-stainable and laundered product with a suitable consistency to prevent leakage from tubes and other containers. You can use linear or branched mono - and dibasic alkyl esters such as diisoadipate, isoacetyl stearate, propylene glycol coconut fatty acid diesters, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or. They can be used alone or in combination, depending on the required properties.

Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

For therapeutic purposes, the active compounds of the present invention are usually combined with one or more excipients suitable for the indicated route of administration. When reg 08 is administered (oral), the compounds can be mixed with lactose, sucrose, starch powder, cellulosic alkanoic esters, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium or calcium phosphoric salts , gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for normal administration. Such capsules or tablets may contain a controlled release formulation, which can be achieved by dispersing the active compound in hydroxypropyl methylcellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more carriers or diluents noted for use in oral formulations. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride or various buffers. Other excipients and methods of administration are well and widely known in the pharmaceutical field.

In the practical implementation of the methods of the present invention for the treatment and prevention of a variety of thrombotic disease conditions, including coronary artery disease and cerebrovascular disease, the compounds and pharmaceutical compositions of the present invention are administered alone or in combination with each other, or in combination with other drugs or ίη νίνο diagnostic agents. The coagulation cascade inhibitors of the present invention can also be administered in conjunction with suitable anti-platelet aggregating agents, including but not limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists (for example, for the treatment or prevention of unstable angina pectoris or for the prevention of re-blockage after angioplasty and resten such as aspirin, warfarin and heparins, thrombolytic agents, such as plasminogen activators or streptokinase, to achieve synergistic effects in the treatment of various pathologies, agents that reduce fat content, including antihypercholesterolemic drugs (for example, NMO CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin, NMO CoA synthase inhibitors, etc.), antidiabetic drugs agents or other cardiovascular agents (spiral diuretics, thiazide-type diuretics, nitrates, aldosterone antagonists (i.e. spironolactone and epoxymexleronone), angiotensin-converting enzyme inhibitors (e.g. ACE), angiotensin II receptor antagonists, beta-blockers, antiarrhythmic, antihypertensive agents and calcium channel blockers for the treatment and prevention of atherosclerosis). For example, patients suffering from coronary artery disease and patients undergoing angioplasty procedures will benefit from the co-administration of the fibrinogen receptor antagonists and the coagulation inhibitors of the present invention. Inhibitors of the coagulation cascade can also enhance the effectiveness of tissue-plasminogen activator-mediated thrombolytic reperfusion.

Typical doses of the coagulation cascade inhibitors of the present invention in conjunction with other suitable antithrombotic agents, anticoagulant agents, cardiovascular therapeutic agents or thrombolytic agents may be the same as doses of coagulation cascade inhibitors administered without the addition of additional antithrombotic agents, anticoagulant agents, cardiovascular therapeutic agents or thrombolytic agents, or may be significantly lower than the doses of inhibitors Hur coagulation cascade administered without additional sovvedeniya antithrombotic agents, anticoagulant agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on the therapeutic need of the patient.

All marked links are included in this description by reference.

Although the present invention has been described with reference to specific embodiments, the details of these specific embodiments should not be construed as limitations. Following

-11005367 examples are presented to illustrate the present invention and are not intended to limit its scope. Without further elaboration, it is believed that one skilled in the art will be able, using the preceding descriptions, to use the present invention in its entirety. Therefore, the following preferred specific embodiments should be construed as illustrative only and not in any way limiting the remainder of the description. Also contemplated are compounds containing many variations of structural modifications, illustrated in the diagrams or in the following examples. It will be readily apparent to those skilled in the art that known changes in the conditions and methods of the following preparative methods can be used to prepare these compounds.

One of skill in the art can use these general methods to obtain the following specific compounds of the examples that were or could be adequately characterized by * H NMR, mass spectrometry, elemental composition, and similar methods. These compounds may also be formed ΐπ νΐνο. The following examples provide detailed descriptions of methods for preparing compounds of formula (I). Such detailed descriptions are included in the scope of the invention and are presented for illustrative purposes only and are not intended to limit the scope of the invention. All parts are presented by weight, and temperature is expressed in degrees Celsius unless otherwise indicated.

The following general synthetic sequences can be used in the practice of the present invention. The abbreviations used in the diagrams and tables include: “AA” represents amino acids, “AeCY” represents acetonitrile, “AcOH” represents acetic acid, “ΒΙΝΑΡ” represents 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl , VpON represents benzyl alcohol, VPSO represents 2-phenylethanal, Vp8O ₂ C1 represents benzylsulfonyl chloride, Boc represents tert-butoxycarbonyl, BOP represents benzotriazole-1-yl-hydroxy-tris- (dimethylamino) , "B" represents butyl, "b" represents dibenzylideneacetone, "BSS" represents 1,3 dicyclic Clohexylcarbodiimide, “DCM” represents dichloromethane or methylene chloride, “ΌΙΒΑΗ” or “Ι) ΙΒΑΤ” represents diisobutylaluminium hydride, “DMF” represents dimethylformamide, “DMSO” represents dimethyl sulfoxide, “ΌΡΡΑ” represents diphenylphosphorylazide, [3BC 1 - (dimethylamino) propyl] 3-ethylcarbodimide, "Note No." represents an "example number", "Yesos" represents 9-fluorenylmethoxycarbonyl, "ΗΟΒΐ" represents hydroxybenzotriazole, "LDA" represents lithium diisopropylamide, "MV" represents molecular weight , “ΝΜΜ” represents Ν-methylmorpholine, “ΡΙ1” represents phenyl or aryl, “РНТН” represents a phthaloyl group, “ρηΖ” represents 4-nitrobenzyloxycarbonyl, “IFC” represents an interphase catalyst, “ru” represents pyridine, “ΡΝΗ ₂ ” represents a primary organic amine, 8EM represents 2 (trimethylsilyl) ethoxymethyl chloride, ρ-ΤδΟΗ represents paratoluene sulfonic acid, TBAE represents tetrabutylammonium fluoride, TBTC represents 2- (1H-benzotriozole-1yl) -1,1,3 tetrafluoroborate, 3-tetramethyluronium, "TEA" represents triethyl min, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TM8" represents trimethylsilyl, "TM8SSH represents trimethylsilyl, and" Cb / »or« Ζ »represents benzyloxycarbonyl.

General synthesis methods and specific examples

The pyridone compounds of the present invention can be obtained, for example, in accordance with the following methods and the following schemes.

Pyridone having a fused aryl or heteroaryl group may be considered as quinolone. A general quinolone similar structure with the basic type of pyridone ring is shown in FIG. 1. X, Υ, and Ζ are optionally selected from CH.

ABOUT

FIG. 1 Quinolone analogues of pyridones.

Ν, SG, CC1, С-ΟΝ, С-СН ₃ , С-СН ₂ СН ₃ , С-НН ₂ , Ο-ΟΗ ₂ ΝΗ ₂ , С-СН ₂ ONSN ₃ , С-ЯНСН ₃ , Ο-Ν ( ΟΗ ₃ ) ₂ , С-СН (ЦН ₂ ) СН ₃ , С-СН ₂ СН ₂ ЫН ₂ , С-ШОСН ₃ , С-ШОСН ₂ СН ₃ , Ο-Ο (ΝΗ) ΝΗ ₂ , ε-Ο (ΝΟΗ ) ΝΗ ₂ , C-OH, C-CH ₂ OH, C-CH ₂ CH ₂ OH, C-CH (OH) CH ₃ , C-OCH ₃₉ C-OCH ₂ CH ₃ , C-CO ₂ H, C- СО ₂ СН ₃ , С-С (О) ХН ₂ , С-С (О) ННСН ₃ , С-С (О) ХН (СН ₃ ) ₂ , С-СН ₂ СО ₂ Н, 0-80 ₂ ΝΗ ₂ , S-8O ₂ ONSN ₃ , S-G4N (O) SSN ₃ and S-RSh (O) SSG ₃ .

Quinolones in which from \ U-X Υ-Ζ is attached to the fourth or fifth position of the pyridone instead of the fifth and sixth positions can be obtained in comparable ways. A general method for producing a wide variety of quinolone-type 2-pyridones is summarized in Scheme 1 and

-12005367 Scheme 2. These methods can enable the introduction of a wide range of substituents in the fused ring or as precursor groups of target groups (for example, nitro groups for subsequent conversion to amino, acetoxymethyl for subsequent hydrolysis to hydroxymethyl or oxidation to aldehyde or carboxylic acid, and the like similar), or using protecting groups. Obtaining specific quinolone analogues of the pyridone of the present invention are presented in examples 1-16.

Scheme 1. General method of synthesis of 1 quinolone

Scheme 2. General method of synthesis of 1 quinolone (completion)

-13005367 (EX 1A) 3-Nitro-1H-quinolin-2-one (2.35 g, 12.37 mmol) in 50 ml of anhydrous DMF was mixed with 60% ΝαΗ in mineral oil (0.59 g, 14.87 g) and the mixture was stirred for five minutes. To this mixture was added dropwise 2-methyl-2-bromoacetate (2.27 g, 14.84 mmol). After stirring the reaction mixture for 2 hours at 20 ° C., the DMF was removed in vacuo using a rotary evaporator to give the residue as a yellow oil. The residue was triturated in water to give a yellow solid, which was washed with water and hexane. The yellow solid was recrystallized from ethyl acetate to give a yellow solid as needle-shaped crystals (1.38 g) as the expected product, methyl (3 nitro-2-oxo-2H-quinolin-1-yl) acetate. Additional product (1.20 g) was obtained from the mother liquor using flash chromatography on silica gel to separate it from the by-product of O-alkylation (0.334 g). The yield of the target product (EX-1A) was 80%, HPLC mass spectrum (from 0 to 95% ΑεΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.48 min, M + H ⁺ = 263.2 for the formula Οι ₂ Ηι ₀ Ν ₂ Θ ₅ .

Ή NMR (400 MHz, SBS1 ₃ ): δ 3.80 (s, 3H), 5.17 (s, 2H), 7.19 (d, 1 = 8.4 Hz, 1H), 7.40 (t , 1 = 7.6 Hz, 1H), 7.76 (t, 1 = 7.6 Hz, 1H), 7.78 (d, 1 = 8.4 Hz, 1H), 8.61 (s, 1H ) ¹³ C NMR (101 MHz, SBS1 ₃ ): δ 44.2, 52.9, 114.2, 117.1, 124.0, 131.7, 134.8, 137.9, 140.6, 154, 0, 167.6.

(EX-1B) Compound EX-1A (2.51 g, 9.58 mmol) was mixed with 10% Pd on activated carbon (0.51 g, 0.48 mmol) in 150 ml of methanol. The mixture was stirred in an atmosphere of H ₂ , which was introduced from a rubber balloon for 2 hours. The reaction mixture was filtered and methanol was removed to give a white crystalline solid (2.06 g, yield = 93%), which was methyl (3-amino 2-oxo-2H-quinolin1-yl) acetate (3). HPLC mass spectrum (from 0 to 95% ΑcCN / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.12 min, M + H ⁺ = 233.1 for formula C1 ₂ H1 ₂ S ₂ O ₃ .

Compound 3 (2.04 g, 8.79 mmol) and pyridine (3.55 ml, 43.95 mmol) were dissolved in 200 ml of acetonitrile. This mixture was cooled to -10 ° C in a bath with a mixture of water-acetone-dry ice. Α-toluenesulfonyl chloride (4.19 g, 21.98 mmol) dissolved in 10 ml of acetonitrile was quickly added dropwise to this mixture. The reaction mixture was stirred for 2.5 hours at a temperature of from -10 to 0 ° C. During the reaction, the product as a white solid precipitated from solution. The pure product, methyl (3benzylsulfonylamido-2-oxo-2H-quinolin-1-yl) acetate (EX-1B) (2.92 g), was obtained by filtration, washing it with acetonitrile. An additional amount of the product (0.34 g) was obtained by treating the filtrate and subjecting it to column chromatography on silica gel Vue! Ade-40 using 25% ethyl acetate in hexane as eluent. HPLC mass spectrum (from 0 to 95% ΑсСN / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° С): retention time 3.52 min, Μ + Να '= 408.9 for the formula ^ ₉ Η ₁₈ Ν ₂ Ο ₅ 8Να.

Ή NMR (400 MHz, SBS1 ₃ ): δ 3.81 (s, 3H), 4.42 (s, 2H), 5.14 (s, 2H), 7.09 (d, 1 = 8.8 Hz , 1H), 7.27 (m, 5H), 7.48 (t, 1 = 7.6 Hz, 2H), 7.61 (d, 1 = 10 Hz, 1H), 8.61 (s, 1H ) ¹³ C NMR (101 MHz, SBS1 ₃ ): δ 44.5, 52.8, 58.5, 113.3, 119.5, 120.4, 123.5, 127.2, 127.8, 128, 7, 128.8, 129.0, 129.2, 130.8, 135.2, 157.3, 167.9.

(EX-1C) Compound EX-1B (3.19 g, 8.26 mmol) was dissolved in 50 ml of THF, 30 ml of MeOH and 50 ml of 1M OH. The mixture was stirred at 20 ° C for one hour. The mixture was concentrated to remove organic solvents. The remaining aqueous solution was acidified to pH = 1 1M HC1, while a solid precipitated from the solution. The solid was purified by filtration, washed with 1M HCl and water and dried in vacuo to give a white solid as a pure product, (3benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetic acid (EX-1C) (2.98 g yield 97%). HPLC mass spectrum (0 to 95% ΑcCN / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.09 min, Μ + Να '= 395.2 for the formula ^ ₈ Η ₁₆ Ν ₂ Ο ₅ 8Να.

Ή NMR (400 MHz, SBS1 ₃ ): δ 4.54 (s, 2H), 5.13 (s, 2H), 7.15 (t, 1 = 87.2 Hz, 1H), 7.23 (m , 3H), 7.33 (m, 3H), 7.50 (t, 1 = 7.6 Hz, 2H), 7.59 (s, 1H).

(EX-1B) Compound EX-1C (0.209 g, 0.56 mmol), EBS (0.140 g, 0.73 mmol) and NEW! (0.112 g, 0.73 mmol) was mixed in 1.5 ml of DMF and the mixture was stirred at 20 ° C for 10 minutes. To this mixture was added a pre-mixed solution of (48) - (9C1) -Y - [[[4-amino-5-hydroxy-5- (2-thiazolyl) pentyl] amino] iminomethyl] -4-methoxy-2 hydrochloride salt, 3,6-trimethylbenzenesulfonamide (0.387 g, 0.73 mmol), diisopropylethylamine (0.65 ml, 3.93 mmol) in 1.5 ml DMF. The combined reaction mixture was stirred for 45 minutes at 20 ° C. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic phase was washed with a saturated aqueous solution of potassium carbonate and ammonium chloride, dried over Na ₂ 8 O ₄ . After removal of ethyl acetate, the residue was subjected to column chromatography on silica gel Vyuade, obtaining a white solid as a product, X- [2 (8) -1 (B, 8) -2- [1-hydroxy-1- (2-thiazolyl)] -5 - [[(4-methoxy-2,3,6-trimethyl) sulfonylamino] iminomethyl] aminopentyl] - (3-benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetamide (EX-1B) (0.347 g, yield = 76%). HPLC mass spectrum (from 0 to 95% ΑοΤ'Ν / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.75 min, M + H ^- = 810.3 for the formula C ₃ -H _{) 3} TO ₈ 8 ₃ . Since the compound is a mixture of two diastereomers, the ¹ H NMR and ¹³ C NMR spectra were complex.

(EX-1E) Compound EX-1B (0.32 g, 0.395 mmol) was mixed with 1,3-dihydro-1-hydroxy-3,3bis (trifluoromethyl) -1-oxide-1,2-benzodioxol (0.238 g, 0.593 mmol) in 5 ml of acetonitrile. Mix re

-14005367 was stirred at 20 ° C for 2 hours. Then it was mixed with 30 ml of a 1M aqueous solution of ΝαΗ8ϋ ₃ . The combined solution was extracted with ethyl acetate and the organic phase was washed with saturated aqueous solution No. ₁ HCO ₃ and dried over Ν α ₂ 8ϋ. ₁ . After removal of ethyl acetate, the remaining residue was subjected to flash column chromatography on silica gel using 30% ethyl acetate in hexane as an eluent, to give a white solid as a product, Y- [2 (§) -2- [1-oxo-1- (2- thiazolyl)] - 5 - [[[(4-methoxy2,3,6-trimethyl) sulfonylamino] iminomethyl] amino] pentyl] - (3-benzylsulfonyl-amino-2-oxo-2Hquinolin-1-yl) acetamide (EX- 1E) (0.296 g, 93%). HPLC mass spectrum (from 0 to 95% ΆοΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 4.07 min, M + H ⁺ = 808.2 for formula C ₃ -H-cNoO ₈ 8 ₃ .

'H NMR (400 MHz, acetone-6 ₆ ): δ 1.71 (br., 4H), 2.07 (s, 3H), 2.59 (s, 3H), 2.64 (s, 3H) , 3.24 (m, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.17 (d, I = -16.4 Hz, 1H), 5.22 (d , I = 16.4Ng, 1H), 5.62 (m, 1H), 6.47 (br., 2H), 6.64 (s, 1H), 7.24 (m, 4H), 7.36 (m, 3H), 7.44 (m, 2H), 7.59 (t, I = 7.2 Hz, 2H), 7.95 (br., 1H), 8.08 (m, 3H). ¹³ C NMR (101 MHz, COC1 ₃ ): δ 12.0, 15.6, 18.6, 24.2, 41.1, 46.6, 55.8, 55.9, 58.5, 66, 1, 112.3, 120.3, 121.2,

123.8, 124.8, 128.5, 129.1, 129.2, 129.3, 129.6, 129.7, 129.9, 123.0, 131.9, 135.8, 136, 7, 137.0, 139.0, 146.1, 157.4, 158.0, 158.8, 165.6, 167.7, 192.0.

Compound EX-1E (0.240 g, 0.296 mmol) was treated with thioanisole (0.220 g, 1.78 mmol) and 8 ml of trifluoroacetic acid for 5 hours. After removal of TFA, the residue was triturated twice with diethyl ether and once with ethyl acetate to give white amorphous solid as a product, trifluoroacetic acid salt No. [[2 (8) -2- [1-oxo-1- (2-thiazolyl)] - 5 - [(amino) iminomethyl] amino] pentyl] - (3benzylsulfonylamino-2- oxo-2H-quinolin-1-yl) acetamide (0.183 g, 87% yield). HPLC mass spectrum (0 to 95% Λοί.'Ν / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.07 min, M + H ⁺ = 596.2 for formulas C ₂₇ H ₂₉ ^ O ₅ 8 ₂ .

'H NMR (400 MHz, DMSO-6 ₆ ): δ 1.58 (br.m, 2H), 1.67 (br.m, 1H), 1.90 (br., 1H), 3.10 ( broad m, 2H), 4.60 (s, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.01 (d, I = -17.2 Hz, 1H) , 5.11 (d, I = -17.2 Hz, 1H), 5.38 (m, 1H), 6.80-7.70 (m, 15H), 8.14 (s, 1H), 8 23 (s, 1H), 8.88 (broad, 1H), 9.99 (d, I = 8.0 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-6 ₆ ): δ 25.3, 28.0, 44.9, 48.6, 54.4, 58.0, 114.2, 119.7, 121.9, 124.8, 126.1, 128.2,

128.3, 128.7, 131.0, 135.9, 137.1, 138.7, 144.7, 145.4, 156.6, 157.4, 164.4, 166.8, 191, 4.

(EX-2A) (3-Benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetic acid was condensed with the benzyl [[(4-aminomethylphenyl) iminomethyl] amino] carbamate hydrochloride salt using EEC, NEW! as condensing reagents in the presence of ΌΙΕΑ in DMF. The procedure for processing the reaction mixture gave a white amorphous solid as product No. [[4 - [(benzylcarbonylamino) iminomethyl] phenyl] methyl] - (3-benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetamide. HPLC mass spectrum (from 0 to 95% ΑcCN / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.38 min, M + H ⁺ = 638.3 for formula C ₃₄ H ₃ ^ ₅ O ₆ 8.

'H NMR (400 MHz, COC1 _; ): δ 4.38 (s, 2H), 4.50 (d, I = 6.0 Hz, 2H), 4.92 (s, 2H), 5.14 ( s, 2H), 7.06 (t, I = 7.2 Hz, 1H), 7.13 (t, I = 7.6 Hz, 2H), 7.15-7.24 (m, 6H), 7.30-7.40 (m, 6H), 7.45 (m, 3H), 7.52 (m, 1H), 7.57 (d, I = 8.4 Hz, 2H), 8.65 (broad., 1H); 9.09 (broad., 1H).

Compound EX-2A (0.118 g, 0.185 mmol), p-toluenesulfonic acid monohydrate (0.035 g, 0.185 mmol) and 10% P6 on activated carbon (0.029 g, 0.018 mmol) were mixed with 5 ml of methanol. The mixture was stirred for 2 hours in a hydrogen atmosphere, which was introduced through a rubber balloon. After filtering off the catalyst and removing methanol, the remaining residue was recrystallized from a solvent containing ether and methanol in a 2: 1 ratio to obtain a white amorphous solid as a product, p-toluenesulfonic acid salt No. [[4 - [(amino) iminomethyl] phenyl] methyl ] - (3benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetamide (0.080 g, yield = 64%). HPLC mass spectrum (0 to 95% ΑcCN / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.81 min, M + H ^- = 504.5 for formula C ₂₆ H ₂₅ ^ O ₄ 8.

'H NMR (400 MHz, UIS): δ 2.36 (s, 3H), 4.52 (s, 2H), 4.57 (s, 2H), 5.15 (s, 2H), 7.18 -7.32 (m, 7H), 7.36 (t, I = 7.2 Hz, 2H), 7.48-7.55 (m, 4H), 7.59 (s, 1H), 7, 70 (d, I = 8.0 Hz, 2H); 7.74 (d, I = 8.4 Hz, 2H).

Example 3

n-MERPO ₃ N ΝΗ

-15005367 (EX-3A) Methyl 2- [3-amino-2-oxo-2H-quinolin-1-yl] acetate (9.1 g, 39.2 mmol) was mixed with Vosanhydride (9.41 g, 43, 1 mmol), triethylamine (6 ml, 43.1 mmol) and ΌΜΑΡ (50 mg, 0.4 mmol) in 200 ml of DCM. The reaction mixture was stirred at 20 ° C for 14 hours. The reaction solution was washed twice with a 1M citric acid solution, three times with a saturated sodium bicarbonate solution, once with a saturated solution of ammonium chloride and dried over anhydrous Mg80 ₄ . After filtering and removing the solvent, the residue was treated with methanol. A white solid precipitated. After filtration and washing with methanol, the pure product, EX-3A, was obtained as a white powder (9.90 g, 87%). HPLC mass spectrum (from 0 to 95% ΆοϋΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.85 min, M + H ⁺ = 291.1 for formula ϋι ₄ Ηι ₅ Ν ₂ 0 ₅ . ¹ H NMR (400 MHz, methanol-f): ά 3.76 (s, 3H), 3.82 (s, 3H), 5.15 (s, 2H), 7.09 (d, D = 8, 4 Hz, 1H), 7.26 (t, D = 7.6 Hz, 1H), 7.43 (t, D = 7.6 Hz, 2H), 7.61 (d, D = 7.6 Hz , 1H), 7.96 (s, 1H), 8.39 (s, 1H). ¹³ C NMR (101 MHz, methanol-04): ά (ppm) 44.4, 52.5, 52.6, 113.1, 118.9, 121.0, 123.3, 127.4 , 128.4, 128.5, 134.5, 153.9, 157.6, 168.1.

(EX-3B) Compound EX-3A (1.09 g, 3.75 mmol) was mixed with KOH (5.2 g, 92.8 mmol) in 30 ml of water and 30 ml of methanol. After refluxing for three hours, the reaction solution was concentrated to 10 ml and acidified with concentrated HCl to pH = 2. After cooling to 0 ° C, the product was filtered off, washed with water and dried in vacuo. Yellow powdery acid was obtained as a pure product (0.733 g, yield = 90%), HPLC mass spectrum (0 to 95% ΆοΆ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): time retention of 1.60 min, M + H ⁺ = 219.1 for the formula C11H11 ^ O3.

(EX-3C) Compound EX-3B (0.296 g, 1.16 mmol) was treated with phenylacetaldehyde (0.21 g, 1.74 mmol) in 15 ml of methanol for 10 minutes. Sodium cyanoborohydride (0.08 g, 1.28 mmol) was added to this mixture. Two hours later, the reaction was completed. Methanol was removed under reduced pressure and the residue was mixed with water. Product-2- [3- (2-phenylethylamino) -2-oxo-2H-quinolin-1-yl] acetic acid (EX3C) was obtained after filtration and washing with water as a white powder (0.225 g, 60%). HPLC mass spectrum (from 0 to 95% ΆοΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.55 min, M + H ⁺ = 323.2 for formula 0ι ₉ Η ₁₉ Ν ₂ 0 ₃ . ¹ H NMR (400 MHz, methanol-f): ά 2.97 (t, D = 7.2 Hz, 2H), 3.45 (t, D = 7.2 Hz, 2H), 5.02 (s , 2H), 6.65 (s, 1H), 7.13-7.29 (m, 8H), 7.46 (d, D = 8.0 Hz, 1H). ¹³ C NMR (101 MHz, methanol-O "): ά (ppm) 35.9, 45.5, 46.6, 105.7, 115.1, 123.9, 124.5, 125, 9, 127.0, 127.4, 129.6, 129.8, 133.9, 137.8,

140.8, 159.9, 173.1.

(ΕΧ-3Ό) Compound ΕΧ-3Ό was obtained in the same manner as described for compound EX-2A. It is a white powder. HPLC mass spectrum (0 to 95% ΆοΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.65 min, M + H ⁺ = 588.6 for formula 0 ₃₅ Η ₃₄ Ν ₅ 0 ₄ .

¹ H NMR (400 MHz, methanol-ά ^: ά 2.95 (t, D = 7.2 Hz, 2H), 3.43 (t, D = 7.2 Hz, 2H), 4.46 (s , 2H), 5.09 (s, 2H), 5.37 (s, 2H), 6.64 (s, 1H), 7.13-7.29 (m, 9H), 7.38-7, 41 (m, 3H), 7.47 (m, 4H), 7.70 (d, D = 8.4 Hz, 2H). ¹³ C NMR (101 MHz, methanol-ά ^: ά (ppm) ) 35.8, 43.7, 45.4, 46.9, 70.6, 105.8, 114.9, 124.2, 124.6, 126.0, 127.2, 127.4, 129 , 1, 129.6, 129.7, 129.8, 129.9, 130.0, 133.8, 137.8, 140.7, 160.2, 170.3.

The product of example 3 was obtained in the same manner as described for the compound of example 2, in the form of a salt of p-toluenesulfonic acid and an amorphous solid. HPLC mass spectrum (from 0 to 95% ΑοϋΝ / 6 min @ 1.0 ml / min @ 254 nm ® 50 ° C): retention time 3.18 min, M + H ⁺ = 454.1 for the formula С27Н28 ^ 02.

¹ H NMR (400 MHz, methanol ^): ά 2.32 (s, 3H), 3.03 (t, D = 7.2 Hz, 2H), 3.56 (t, D = 7.2 Hz, 2H), 4.48 (s, 2H), 5.14 (s, 2H), 7.19 (d, D = 8.0 Hz, 4H), 7.26-7.34 (m, 6H), 7.48 (d, D = 8.0 Hz, 2H), 7.55 (s, 1H), 7.64 (d, D = 7.6 Hz, 1H), 7.69 (t, D = 8 Hz, 4H), 8.72 (s, 2H), 9.18 (s, 2H), ¹³ C NMR (101 MHz, methanol-ά ^ ά (ppm) 21.3,

34.3, 43.7, 46.8, 59.6, 115.4, 122.0, 124.6, 126.9, 127.8, 128.2, 128.3, 129.0, 129.2, 129.5, 129.7, 129.8, 129.9,

130.3, 131.4, 137.4, 138.9, 141.8, 146.7, 159.5, 168.2, 168.3, 169.7.

Example 4 G th gt ° one Ρη N ⁿ Υ ^ΝΗ2 p-MERBO ₃ N II ΝΗ

(EX-4A) 2- [3-amino-2-oxo-2H-quinolin-1-yl] acetic acid (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removal of the pyridine, the residue was recrystallized from acetone to give a white crystalline solid as the product, 2- [3-benzenesulfonylamino-2-oxo-2H-quinolin-1-yl] acetic acid, (EX-4A) (0.117 g, yield = 41 %). HPLC mass spectrum (0 to 95% Α ^ Ν / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.85 min, M + H ⁺ = 359.2 for the formula C17H15 ^ 028. ¹ H NMR (400 MHz, acetone ^ 6): ά 5.12 (s, 2H), 7.28 (t, D = 7.2 Hz, 1H), 7.36 (d, D = 8.8 Hz) , 1H), 7.48-7.63 (m, 4H), 7.75 (dd, D = 8, 1.6 Hz, 1H), 7.74 (s,

-16005367

1H), 8.00-8.03 (m, 2H). ¹³ C NMR (101 MHz, acetone-b ₆ ): b (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129, 4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1.

(EX-4B) Compound EX-4A was prepared in the same manner as described for the compound of Example EX2A, giving a white powder. HPLC mass spectrum (0 to 95% Ά ^ Ν / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.23 min, M + H ⁺ = 624.2 for the formula S331130ZHO6Z. ¹ H NMR (400 MHz, methanol-b4): b 4.45 (s, 2H), 5.06 (s, 2H), 5.38 (s, 2H), 7.24-7.60 (m, 14H), 7.71 (d, I = 8.0 Hz, 2H), 7.84 (s, 1H),

7.94 (d, I = 7.2 Hz, 2H). ¹³ C NMR (101 MHz, methanol-b ₄ ): b (ppm) 43.7, 47.0, 70.7, 115.3, 121.7, 122.5, 124.5,

127.3, 128.4, 129.1, 129.6, 129.7, 129.9, 130.0, 130.1, 130.2, 130.3, 134.4, 135.8, 137.2, 140.8, 147.7, 154.6,

159.3, 167.9, 169.8.

The compound of this example was obtained in the same manner as described for the compound of example 2. It is an amorphous off-white solid in the form of a salt of p-toluenesulfonic acid. HPLC mass spectrum (5 to 95% Ά ^ Ν / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.02 min, M + H ⁺ = 490.1 for the formula С ₂₅ Н ₂₄ ^ О ₄ З.

¹ H NMR (400 MHz, methanol-b ₄ ): b 2.34 (s, 3H), 4.46 (s, 2H), 5.06 (s, 2H), 7.20 (d, I = 8 , 0 Hz, 1H), 7.247.29 (m, 2H), 7.46-7.51 (m, 6H), 7.55 (d, I = 7.2 Hz, 1H), 7.62 (d , I = 8.0 Hz, 1H), 7.71 (m, 4H), 7.86 (s, 1H),

7.95 (d, I = 8.0 Hz, 2H). ¹³ C NMR (101 MHz, methanol-b ₄ ): b (ppm) 21.3, 43.6, 46.9, 115.1, 121.6, 122.4, 124.4,

126.8, 127.9, 128.2, 128.9, 129.0, 129.5, 129.7, 130.1, 130.2, 134.3, 137.0, 140.6, 146, 6, 159.2, 169.5, 184.2,

Example 5

(EX-5A) A solution of 2-aminopyridine (20.42 g, 217.0 mmol) in dichloromethane 500 ml was cooled to 0 ° C and treated with triethylamine (36.29 ml, 260.4 mmol) and pivaloyl chloride (28.06 ml , 227.8 mmol). After 15 minutes, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto ice and the organic layer was washed with saturated No. 11CO ₃ (aq) and dried over No _.: ZO. |. Volatile components were removed and brown oil was isolated. Crystallization in hexanes afforded 31 g of No. (pyrid-2-yl) -2,2-dimethylacetamide (EX-5A) as white crystals in 80% yield. Link: Tigpeg, I.A., b.Ogd.Siet., 1983, 48, 3401.

(EX-5B) A solution of EX-5A (2.00 g, 11.23 mmol) in THF (115 ml) at -78 ° C was treated with p-ViM (14.1 ml, 28.10 mmol of a 2.0 M solution in hexanes). The reaction was allowed to warm to 0 ° C and stirred for 2 hours. The reaction was again cooled to -78 ° C and the mixture was quenched with DMF (2.18 ml, 28.10 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a suspension of ice and 6N HCl and the acidified mixture was stirred for 15 minutes. The organic layer was separated (discarded), and the aqueous layer was neutralized with K2CO3 and extracted with ether (3 x 100 ml). The combined organic layers were washed with water, brine and dried over MgSO ₄ . After filtration and evaporation of the volatile components, a yellow oil was isolated, which solidified upon standing, 1.23 g (53%) of the EX5B product was isolated. Reference: Tigpeg, I. A., Yugd. SEet., 1990, 55, 4744.

(EX-5C) A mixture of EX-5B (0.62 g, 3.01 mmol) and 3N. HCl (30 ml) was heated under reflux overnight. Then the reaction mixture was allowed to cool to room temperature, washed with ether (2 x 50 ml). The organic layer was discarded. The aqueous layer was neutralized with K2CO3 and extracted with ether (4 x 50 ml). The combined ether layers were dried over K2CO3, filtered and concentrated to give 2-aminopyridinecarboxaldehyde (EX-5C) as a yellow oil (0.36

g), which was cured when standing. The crude material was used without further purification. Link: Mogtapp A.E .; Ηеη S. Н .; Υυ Z., Zup. Sottip., 1987, 77, 1695.

(EX-5E) A mixture of hippuric acid (0.54 g, 3.01 mmol) and acetic anhydride was heated to 80 ° C. After 2 hours, the reaction mixture became homogeneous. The hot reaction mixture was treated with a solution of EX-5C (0.37 g, 3.01 mmol) in acetic anhydride. After stirring the reaction mixture for an additional 16 hours, the reaction mixture became homogeneous. Volatile components were removed in vacuo and the precipitate was filtered. The filter cake was washed with ether (3 x 30 ml) and 0.36 g of 3-benzamido-2-oxo-2H-1,8-naphthyridine (EX-5E) was isolated as a brownish-orange powder in 45% yield.

¹ H NMR (300 MHz, b-DMSO) b 12.77 (s, 1H), 9.47 (s, 1H), 8.72 (s, 1H), 8.45 (d, 1 = 3.42 Hz, 1H), 8.218.18 (m, 1H), 7.95 (d, 1 = 7.6 Hz, 2H), 7.66-7.54 (m, 3H), 7.28 (dd, 11 = 4.6 Hz, 12 = 4.8 Hz, 1H). ¹³ C NMR (75 MHz, COC 13) b 165.8, 159.4, 149.2, 146.6, 136.6, 134.3, 133.0, 130.3, 129.61 (2C), 129 58, 127.9, 120.2, 119.8,

-17005367

115.7; NKM8 (high resolution mass spectrometry) (E! (Electron impact)) calculated for С ₁₅ Н _П ^ О ₂ 266.0930, found 266.0939.

(EX-5E) A solution of ΕX-5 ^ (0.072 g, 0.271 mmol) in DMF (5 ml) was cooled to 0 ° C and ΝαΗ (60% dispersion in mineral oil, 0.013 g, 0.325 mmol) was slowly added. After five minutes, methyl bromoacetate was added dropwise with a syringe. The reaction mixture was allowed to warm to room temperature and stirred until, according to TLC, the starting material remained in it. DMF was removed in vacuo to give a yellow residue. The residue was triturated in water and washed with water and hexanes to give 0.062 g of methyl 2- [3-benzamido-2-oxo-2H-1,8-naphthyridin-1-yl] acetate (EX-5E) in 68% yield.

¹ H NMR (400 MHz, SPS13) ά 9.30 (s, 1H), 8.88 (s, 1H), 8.45 (d, 1 = 4.6 Hz, 1H), 7.95-7, 91 (m, 3H), 7.567.46 (m, 3H), 7.23-7.20 (m, 1H), 5.37 (s, 2H), 3.74 (s, 3H). ¹³ C NMR (100 MHz, ATP13) ά 168.8, 166.1, 159.0, 148.0, 145.5, 136.5, 134.0, 132.6, 129.12, 129.11, 129.08, 128.8, 127.4, 119.8, 119.0, 116.7, 52.7, 43.2; NKM8 (S) calculated for C1 ₈ H ^ zO ₄ 338.1156, found 338.1141.

(ΕX-5Ε) A solution of EX-5E (0.053 g, 0.157 mmol) in THF and methanol (3: 2.5 ml) was treated with 1.0 M E1OH (aq). The reaction mixture was stirred overnight. The mixture was concentrated to remove volatile components. The resulting aqueous solution was acidified with 1N. HC1, and a solid precipitated from the solution. After filtration, the filter cake was washed with 1N. HCl and water, getting 0.038 g of 2- (3-benzamido-2-oxo-2H-1,8-naphthyridin-1-yl) acetic acid (ΕX-5Ε) as a white solid with 74% yield.

¹ H NMR (400 MHz, ά-DMSO) ά 13.10 (broad s, 1H), 9.53 (s, 1H), 8.78 (s, 1H), 8.51-8.50 (m , 1H), 8.26 (d, 1 = 7.8 Hz, 1H), 7.93 (d, 1 = 8.1 Hz, 2H), 7.62-7.51 (m, 3H), 7 36-7.32 (m, 1H); 5.14 (s, 2n); ¹³ C NMR (100 MHz, ά-DMSO) ά 169.9, 166.0, 158.7, 148.8, 145.9, 137.5, 134.2, 133.0, 129.5 (2C) , 128.8, 128.0 (2C), 120.4,

120.2, 116.2, 43.5; NKM8 (S) calculated for C ₁₇ H ₁₃ ^ O ₄ 324,1004, found 324,098.

(ΕX-5Ο) A solution of ΕX-5Ε (0.099 g, 0.30 mmol) in 3 ml of DMF was treated with Ν-hydroxybenzotriazole (0.054 g, 0.40 mmol) and 1- [3- (dimethylamino) propyl] hydrochloride] -3- ethyl carbodiimide (0.076 g, 0.40 mmol) and Ν, Ν-diisopropylethylamine (0.37 ml, 2.14 mmol). The resulting mixture was allowed to stir for 15 minutes at room temperature. Then the reaction mixture was treated with 4 - (\ - C'b / amidino) benzylamine (0.127 g, 0.40 mmol) as a solution in DMF (3 ml). The resulting reaction mixture was allowed to stir for 18 hours. The reaction mixture was partitioned between ethyl acetate and a saturated solution of XH ₄ Cl (aq.). The separated organic layer was washed with saturated K ₂ CO ₃ (aq.), Saturated Ν ^ Ο (aq.) And saturated aqueous salt solution. The organic solution was dried (No. ₂ 8 O ₄ ), filtered and concentrated. (EX-5O) was isolated as a white solid and the crude product was used in the next step without further purification. LC mass spectrum (L) calculated for C ₃₃ H ₂ ^ ₆ O ₅ 589.2178, found 589.2199.

A solution of C'b / -amidine (XX-5Ο) (0.090 g, 0.15 mmol) in 6 ml of methanol and 1 ml of 4N. HCl in dioxane was treated with 25 mg of 10% Ρά / C in one portion. The resulting reaction mixture was stirred under an atmosphere of hydrogen gas (25 psi) for 18 hours. After filtering the reaction mixture through a celite pad, the solvent was removed under reduced pressure. Slow addition of 1M HC1 precipitated the pure product of the invention as a white solid.

H NMR (400 MHz, ά-DMSO) ά 9.52 (s, 1H), 9.24 (s, 2H), 8.91-8.83 (m, 2H), 8.77 (s, 1H) 8.53-8.52 (m,

DMSO) ά 167.7, 166.0, 165.9, 159.0, 148.6, 146.4, 146.2, 137.4, 134.2, 133.1, 129.6, 128.9 , 128.8, 127.93 (2C), 127.88 (2C), 127.0, 120.21, 120.16, 116.5, 72.9, 60.9, 44.8, 42.4 ; NKM8 (S) calculated for С ₂₅ Н ₂₂ ЯО ₃

455.1832, found 455.1840.

Additional substituted No. [substituted] - - (3-benzylsulfonylamino-2-oxo-2H-quinolin-1 yl) acetamides can be obtained by a person skilled in the art using methods similar to the above. These acetamides are presented in the table of examples 1.

Table of Examples 1. No. [substituted1e] - (3-benzylsulfonylamino-2-oxo-2H-quinolin-1-yl) acetamide

ABOUT

-18005367

Note No. t ------------------ 6 2- [4-aminophenyl] ethyl 7 4-amine o butyl 8 5-aminopen teal nine 6- (Ν, Ν-Dimethylamino) hexyl 10 4-aminomethylbenzyl eleven Z-aminomethylbenzyl 12 3- [Imidazo-1-yl] propyl thirteen 2- [Imidazo-5-yl] ethyl 14 2- [Pyrid-Z-yl] ethyl fifteen 3- [Y-Methylpiperidin-4-yl] propyl sixteen 4-aminobenzyl

The pyridone analogs of the present invention have the general structure as shown in FIG. 2

K ¹

ABOUT

FIG. 2. The general structure of pyridone analogues

The general synthesis route is illustrated in Scheme 3, where substituents are defined herein. These compounds are illustrated in examples 17-23.

Scheme 3. General method for the synthesis of pyridones

ΝαΒΗ (ΟΑο) ₃

IT

Ason boiling with reverse REFRIGERATOR! 12 hours EPPRA / TEA / Dioxane H 2. В-ViOH boiling under reflux H (refrigerator for 12 hours

Delete

-19005367

Example 17

No. [2 (8) -2- [1-hydroxy-1- (2-thiazolyl)] - 5 - [[[(4-methoxy-2,3,6-trimethyl) sulfonylamino] iminomethyl] amino] pentyl] - 6- (2-phenylethyl) -2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) -pyridineacetamide (0.084 g, 0.098 mmol) was treated with 1,3-dihydro-1-hydroxy-33- bis (trifluoromethyl) -1-oxide-1,2-benzodioxol (0.0588 g, 0.147 mmol) in 1 ml of acetonitrile. Used a similar methodology for processing the reaction mixture as in the preparation of EX-1E, obtaining the oxidation product. The oxidation product was treated with thioanisole (0.073 g, 0.59 mmol) and 3 ml of trifluoroacetic acid for 6 hours. After removal of TFA, the residue was triturated with ether. It was purified using preparative reverse phase C-18 HPLC using a gradient ranging from 5% to 95% acetonitrile in H ₂ O in the presence of 0.1% TFA, for 30 min, obtaining the product, trifluoroacetic acid salt No. [ 2 (8) -2- [1-oxo-1- (2-thiazolyl)] - 5 - [[[(amino) iminomethyl] amino] pentyl] -6- (2-phenylethyl) -2-oxo-3 [ [(phenylmethyl) sulfonyl] amino] -1 (2H) -pyridineacetamide as a white amorphous solid (0.0232 g, yield = 31%). HPLC mass spectrum (0 to 95% LSI / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.43 min, M + H ⁺ = 650.2 for formula C ^ Schz ^ ozz ^

Example 18

This compound, trifluoroacetic acid salt No. [[2 (8) -2- [1-oxo-1- (2-thiazolyl)] - 5 - [(amino) iminomethyl] amino] pentyl] -6-methyl-2-oxo -3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) -pyridineacetamide, synthesized analogously to the method of Example 1. HPLC mass spectrum (from 0 to 95% HPC No 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.69 min, M + H ⁺ = 560.3 for the formula CrShr ^ OzSr.

Example 19

Compound, p-toluenesulfonic acid salt No. [[[4- (amino) iminomethyl] phenyl] methyl] -6- (2phenylethyl) -2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) - pyridineacetamide was synthesized analogously to the method of example 2, using 6- (2-phenylethyl) -2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] 1 (2H) -pyridineacetic acid as the starting material. HPLC mass spectrum (from 0 to 95% HPLC / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.23 min, M + H ⁺ = 558.5 for the formula СзοΗз1N5Ο48.

Ή NMR (400 MHz, SI ₃ OD): δ 2.36 (s, 3Η), 2.92 (broad m, 4H), 4.43 (s, 2H), 4.54 (s, 2H), 4.87 (s, 2H), 6.10 (d, I = 8.0 Hz, 1H), 7.21 (m, 5H), 7.26-7.31 (m, 8H), 7.55 (d, I = 8.4 Hz, 2H), 7.69 (d, I = 8.0 Hz, 2H), 7.71 (d, I = 8.0 Hz, 2H).

Example 20

This compound, a salt of p-toluenesulfonic acid No. [[[4- (amino) iminomethyl] phenyl] methyl] 6-methyl-2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) -pyridine acetamide, synthesized in the same manner as in Example 2 using 6-methyl-2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) pyridinoacetic acid as the starting material. HPLC mass spectrum (0 to 95% HPLC / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.41 min, M + H ⁺ = 468.1 for the formula C23W5 ^ O48.

-20005367 ¹ H NMR (400 MHz, SEZOE): δ 2.34 (s, 3Η), 2.36 (s, 3Η), 4.43 (s, 2H), 4.53 (s, 2H), 4 87 (s, 2H), 6.15 (d, 1 = 7.6 Hz, 1H), 7.21-7.31 (m, 8H), 7.56 (d, 1 =

8.70 (br. 1H); 9.19 (br. 1H).

8.4 Hz, 2H), 7.69 (d, 1 = 8.0 Hz, 2H), 7.72 (d, 1 = 8.0 Hz, 2H),

This compound was synthesized in a manner analogous to the method of Example 2, using 6- (2phenylethyl) -2-oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) pyridinoacetic acid as the starting material and combining it with 4- [1 - (^ No. Bis-Boc-amidino) piperidinyl] methylamine. The reaction product was treated with 4n. HC1 in dioxane to obtain the product. The compound was purified by reverse phase C-18 HPLC to obtain the final pure product. HPLC mass spectrum (from 0 to 95% ΆοΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.10 min, M + H ⁺ = 565.6 for the formula

This compound was synthesized in a manner analogous to the method of Example 2, using 6-methyl-2oxo-3 - [[(phenylmethyl) sulfonyl] amino] -1 (2H) -pyridinoacetic acid as the starting material and combining it with 4- [1- ( C, No. bis-Boc-amidino) piperidinyl] methylamine. The reaction product was treated with 4n. HC1 in dioxane to obtain the product. Compounds were purified by reverse phase C-18 HPLC to obtain final pure products. HPLC mass spectrum (0 to 95% ΆοΟΝ / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 2.42 min, M + H ⁺ = 475.3 for the formula C ^ U ^ Oh ^.

One subclass of pyridone analogs has a heteroaryl group replacing the pyridone ring at position 5 or 6. Scheme 4 illustrates a method for preparing heteroaryl substituted pyridones. The preparation method is illustrated in Example 23, which describes the preparation of a 6-substituted pyridyl group, although it can easily be seen that a large number of substituted pyridines, as well as other 5- and 6-membered heteroaryl groups, can be introduced using the method described below.

Scheme 4. Obtaining heteroarylpyridones

Sun— ΗΝ

ABOUT

(CH ₃ O) ₂ CHM (CH ₃ ) ₂

2-cyanoacetamide

N0

HBg / Ason reflux for 12 hours

Sun— ΗΝ

IN·

1. IAN

2. VgSN ₂ - <

5b

Η 1. ERRA / TEL / Dioxane

2.1-ViOH, refluxing

ΝΗ-cr

-21005367

(EX-23A) One equivalent of commercially available 4-acetylpyridine is treated with three equivalents of Ν, Ν-dimethylformamide in boiling acetonitrile for 12 hours. After removal of the solvent and an excess of Ν, Ν-dimethylformamide dimethyl acetal, the resulting yellow solid was dissolved in DMF. One equivalent of cyanoacetamide and two equivalents of sodium methoxide were added to this solution. The resulting mixture was heated at 100 ° C for 5 hours. After cooling, the reaction mixture was mixed with water and acidified with HCl to pH 5. The resulting yellow precipitate was filtered off, washed with water and dried in vacuo to give the product EX-23A as a yellow solid.

(EX-23B) Compound EX-23A is heated under reflux in one part of 48% aqueous HBg and two parts of acetic acid for 12 hours. After cooling the mixture, mixing with water and adjusting the pH to 5, a light yellow is formed. sediment. The light yellow precipitate is filtered off, washed with 1N. HCl and water, dried in vacuum, obtaining the product EX-23B in the form of an off-white solid.

(EX-23C) Compound EX-23B is treated with 1.1 equivalent ΌΡΡΆ, 1 equivalent of triethylamine in dioxane at reflux temperature for two hours. Five equivalents of tert-butanol are added to the mixture, and then the mixture is refluxed overnight.

After removing the solvent, the obtained residue is treated using a conventional aqueous treatment method. The residue was then purified by silica gel column chromatography to give Compound EX-23C.

(ΕΧ-23Ό) Compound EX-23C is successively mixed with one equivalent of sodium hydride in DMF and one equivalent of methyl bromoacetate. After stirring at ambient temperature for 12 hours, the reaction mixture was worked up in the usual manner. Product ΕΧ-23Ό was purified by silica gel column chromatography.

(EX-23E) Compound ΕΧ-23Ό was treated with 50% TFA in dichloromethane for 1 hour. After removal of the solvent and TFA, the residue was redissolved in THF with one equivalent of triethylamine. One equivalent of phenylacetaldehyde and two equivalents of sodium triacetoborohydride are added to this solution. After stirring for 12 hours, the reaction mixture was quenched by the addition of aqueous ammonium chloride. Conventional water treatment and silica gel column chromatography afforded the desired EX-23E product.

(ΕΧ-23Ρ) Compound EX-23E is treated with 1M MON in a mixture with a 1: 1: 1 ratio of THF, methanol and water for half an hour. After acidification 1n. HC1 organic solvent is removed and a precipitate forms. The precipitate was filtered off, washed with water and dried in vacuo to obtain the desired product ΕΧ-23Ρ. Compound ΕΧ-23Ρ is treated with one equivalent of POC and NEW! in the presence of three equivalents of diisopropylethylamine in DMF for 10 minutes Then, one equivalent of 4-aminomethylbenzamidine is added to the reaction mixture, which is protected by C 1 / at the amidino group. After stirring at ambient temperature for four hours, the reaction mixture was worked up in the usual manner and the product ΕΧ-23Ο was purified by silica gel column chromatography.

Compound ΕΧ-23Ο was dissolved in methanol in the presence of 5 equivalents of HC1 and 5% equivalent of 10% Ρά / C. The mixture was stirred under a hydrogen atmosphere (ambient pressure) for five hours. After filtration and removal of solvent, compound 23 was obtained as a pure product.

In a similar manner, 5-substituted pyridones can be prepared as illustrated in Examples 24 and 25.

-22005367 (EX-24A) 3-Nitro-2-hydroxylpyridine (49.5 g, 0.35 mol) and 10% S / C (4.21 g, 4 mmol) in 500 ml of ethanol was stirred in an atmosphere of hydrogen introduced using a balloon for 24 hours. After filtering through a Celite 545 layer and removing ethanol, a brown solid was obtained as a pure product, 3-aminopyrid-2-one, (38 g, 97%). HPLC mass spectrum (from 0 to 30% AcF / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 0.097 min, M + H ⁺ = 111.1 for formula C ₅ H ₇ S ₂ O.

(EX-24B) Compound EX-24A (27.25 g, 0.248 mol) was treated with Boc anhydride (59.47 g, 0.272 mol), triethylamine (52 ml, 0372 mol) and ΏΜΛΡ (1.5 g, 12, 4 mmol) in 500 ml of DCM for 4 hours. After water treatment and removal of the solvent, the residue was passed through a thin, compressed layer of silica gel using 40% ethyl acetate in hexane as the eluent to obtain a crude (crude) product (28 g, 56% ) The pure product, 3- (Y-Boc-amino) pyrid-2-one, was obtained by recrystallization from acetone as a needle-like white crystalline solid. HPLC mass spectrum (from 0 to 95% VLF / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 239 min, M-Boc + H ⁺ = 111.1 for the formula С5Н7Ы2О. ¹ H NMR (400 MHz, COC13): ά 1.52 (s, 9H), 632 (t, I = 7.2 Hz, 1H), 7.00 (dd, I = 6.4, 1.6 Hz) , 1H), 7.55 (s, 1H), 8.10 (d, I = 6.4 Hz, 1H), 12.86 (br., 1H). ¹³ C NMR (101 MHz, COC1 ₃ ): ά 28.2, 80.8, 107.7, 121.8, 125.2, 129.7, 152.7, 158.8.

(EX-24C) Compound EX-24B (13.58 g, 64.6 mmol) and Y-iodosuccinimide (21.8 g, 97 mmol) in 250 ml of dichloromethane was stirred at room temperature for 18 hours. After filtration to remove the succinimide by-product, the solvent was removed under reduced pressure. The resulting residue was flash chromatographed on silica gel to give a brown solid as the product, 3- (Y-Boc-amino) -5-iodopyrid-2-one, (17.3d, 80%). HPLC mass spectrum (from 0 to 95% AcSY / 6 min @ 1.0 ml / min @ 254 nm ® 50 ° С): retention time 3.22 min, M + Na ⁺ = 359.0 for the formula СшН1 ₃ 1Y2O ₃ Ya.

(ΕΧ-24Ώ) Compound EX-24C (9.62 g, 28.6 mmol) was treated with 60% sodium hydride in mineral oil (1.71 g, 42.9 mmol) in 200 ml of THF for 10 min. Methyl bromoacetate (4.33 ml, 45.8 mmol) was added to this mixture. The resulting mixture was stirred at room temperature for 1 h. After THF was removed, the residue was washed with hexanes to remove mineral oil. It was then partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride three times and dried over anhydrous MgO ₄ . Removal of the solvent gave a yellow amorphous solid as the product, methyl 2- [3- (Y-Boc-amino) -5-iodo-2-oxopyrid-2-yl] acetate, (11.1 g, 95%).

(EX-24E) 3-Pyridylboronic acid (2.0 g, 4.93 mmol) was suspended in 80 ml of toluene and the mixture was degassed, sparging nitrogen into it for 10 minutes. In a pre-degassed mixture of 20 ml of toluene and 50 ml of methanol, tetrakis (triphenyl) phosphine palladium (0.54 g, 0.46 mmol) was dissolved. The catalyst solution was added to a solution of boronic acid in a nitrogen atmosphere. Compound ΕΧ-24Ώ (3.80 g, 9.31 mmol) in 25 ml of methanol was added to the resulting mixture, followed by 22 ml of a 2M solution of Na2CO3. The reaction solution was heated under reflux for 2.5 hours. Then it was cooled to room temperature, mixed with 10 ml of 2.5N. NaOH and stirred for half an hour. Then the solvent was completely removed, the obtained residue was redissolved in methanol, and the pH of the solution was adjusted to 6 1 N. HC1. After complete removal of the solvent, the residue was absorbed on silica gel and flash chromatographed on silica gel using 5% methanol in DCM as eluent. The pure product, methyl 2- [3- (Y-Boc-amino) -5- (pyrid-3-yl) -2-oxopyrid-2-yl] acetate (EX24E), was obtained as a white amorphous solid (1, 01 g, 57%). HPLC mass spectrum (5 to 95% AcF / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 1.89 min, M + H ⁺ = 346.0 for formula C ₁₇ H ₁₉ S ₃ O ₅ .

¹ H NMR (400 MHz, COC13): ά 1.53 (s, 9H), 4.82 (s, 2H), 7.62 (d, I = 2.4 Hz, 1H), 7.87 (t , I = 6.0.1 H), 8.36 (s, 1 H), 8.47 (d, I = 8.4 Hz, 1 H), 8.68 (d, I = 4.4 Hz, 1 H) 9.05 (s, 1H). ¹³ C NMR (101 MHz, ATP13): ά 28.0, 50.9, 81.6, 113.8, 117.3, 126.5, 128.9, 130.4, 136.4, 139.8 , 140.4, 140.6, 152.7, 156.6, 169.0.

Starting with intermediate EX-24E, the final inhibitory compound is prepared in a similar manner as described in other examples using the methods described above.

Example 25

(EX-25A) 3-Nitrobenzeneboronic acid (1.41 g, 8.43 mmol) was suspended in 50 ml of dioxane and the mixture was degassed with nitrogen. Tetrakis (triphenyl) phosphine palladium (0.406 g, 0.35 mmol) dissolved in

-23005367 ml of dioxane was added to a solution of boronic acid in a nitrogen atmosphere. Compound соединение-24 2 (2.87 g, 7.03 mmol) and 7 ml of 2M potassium phosphate solution were added to this mixture. The reaction mixture was heated under reflux for 3 hours. After removal of dioxane, the resulting residue was partitioned between ethyl acetate and aqueous saturated ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride and dried over sodium sulfate. The pure product was isolated by flash chromatography on silica gel to give a yellow crystalline solid (1.13 g, 40%). The product, methyl 2- [3- (X-Boc-amino) -5- (3-nitrophenyl) -2-oxopyrid-2-yl] acetate, showed one peak in the LC mass spectrum. However, based on ¹ H NMR and ¹³ C NMR data, it is a mixture of two isomers in a ratio of 2.8 to 1. One isomer has a nitro group on the same side of the Vosaminogroup, the other in the opposite direction. The NMR data for the main isomer is shown here. HPLC mass spectrum (5 to 95% HPLC / 6 min @ 1.0 ml / min @ 254 nm @ 50 ° C): retention time 3.74 min, Μ + Να '= 426.3 for the formula ^ 9Η21Ν3Ο7Νη . ¹ H NMR (400 MHz, COC13): b 1.50 (s, 9H), 3.82 (s, 3Η), 4.80 (s, 2H), 7.20 (d, I = 2.4 Hz , 1H), 7.56 (t, I = 8.0, 1H), 7.66 (s, 1H), 7.81 (d, I = 8.0 Hz, 1H), 8.15 (d, I = 8.0 Hz, 1H), 8.28 (d, I = 2.4 Hz, 1H), 8.36 (s, 1H).

Starting from intermediate EX-25A, the final inhibitory compound is prepared analogously to the methods described in other examples, by the methods described above.

The preparation of sulfonyl analogues of the pyridones of the present invention, in which the sulfonyl replaces the carbonyl group of the β-1 acetamide side chain, can be carried out using the general method in Scheme 3. Example 26, which is a specific example of the sulfonamide of the present invention, is obtained in accordance with the general method shown in Scheme 5.

Scheme 5. Obtaining pyridonylalkylsulfonamides.

ΝΟ

(0Η ₃ Ο) ₂ 0ΗΝ (0Η ₃ ) 2 “h 2-cyanoacetamide

HBg / Ason reflux 12 hours noos

1. ORRATEA / Dioxane

2.1-ViOH, refluxing

Example 26

-24005367

Compound EX-26C can be obtained using the same methods as described in example 23 for compounds EX-23A, EX-23B and EX-23C.

(ΕΧ-26Ό) Compound EX-26C was treated with 1.1 equivalents of ΝαΗ and 1.5 equivalents of sodium bromomethanesulfonate in DMF overnight. The reaction is quenched by dilution with water and adding 1N. HC1 to bring the reaction solution to pH 3 to precipitate the product. The crude product is obtained by filtration and washing with water and ether. Pure product ΕΧ-26Ό is further purified by recrystallization from ethanol.

(EX-26E) Compound ΕΧ-26Ό was treated with 50% TFA in dichloromethane for 1 hour. After removal of the solvent and TFA, the residue was redissolved in a mixture of THF / methanol with one equivalent of triethylamine. One equivalent of phenylacetaldehyde and two equivalents of sodium triacetoxyborohydride are added to this solution. After stirring for 12 hours, the reaction mixture was quenched by the addition of an aqueous solution of ammonium chloride. Standard aqueous work-up and column chromatography on silica gel gave the desired product EX-26E.

(ΕΧ-26Ε) Compound EX-26E was treated with one equivalent of PC1 ₅ in toluene for half an hour. Then, one equivalent of 4-aminomethylbenzamidine protected by Cx at the amidino group is added to the reaction mixture after five equivalents of pyridine are added. The mixture was allowed to stir for 12 hours. The reaction mixture was worked up in the usual manner and the product ΕΧ-26Ε was purified by silica gel column chromatography.

Compound 26 was prepared from ΕΧ-26Ε using the method for compound 23 in Example 23.

Obtaining methylene analogues of the pyridones of the present invention, in which methylene replaces the carbonyl group of Ν-1 acetamide side chain, can be carried out using the essential features of the General method of scheme 3. Example 27, a specific example of ethyleneamine of the present invention, can be synthesized, as shown specifically in the scheme 6.

Scheme 6. Obtaining ethylenepyridone analogues (CH ₃ O) ₂ SNI (CH ₃ ) ₂

---------- ►

2-cyanoacetamide

-XX

HBg / Ason reflux for 12 hours

About _K .A

H 1. ORRA / TEA / Dioxane

2. ί-ΒχιΟΗ, refluxing.

to ²

K ²

-25005367 (EX-27A) To a solution of pyridinyl ether of acetic acid ester with a added BA group, diisobutylaluminium hydride (5 eq.) Is added at -78 ° C. After 30 minutes stirring, methanol was added to quench the reaction mixture. The resulting mixture was poured into a saturated aqueous Rochelle salt solution (KosKe11e). The layers were separated and the aqueous layer was extracted with diethyl ether. The combined extract was dried over MgSO ₄ and the solvent was evaporated to dryness. The resulting residue was subjected to silica gel column chromatography to obtain a pure aldehyde product (EX-27A).

(EX-27B) Compound EX-27A is mixed with one equivalent of CX-protected 4amidinobenzylamine and two equivalents of sodium triacetoxyborohydride in THF. The reaction mixture is treated in accordance with a standard procedure. Product EX-27B was purified by silica gel column chromatography.

Compound EX-27B was initially treated with 4n. HCl in dioxane for 4 hours. After removal of dioxane, the residue was redissolved in methanol in the presence of 5 equivalents of HCl and 5% equivalent of 10% S / C. The mixture was stirred under a hydrogen atmosphere (ambient pressure) for five hours. After filtration and removal of solvent, the compound was obtained as a pure product.

Another subclass of pyridone analogues has the general structure shown in FIG. 3. The substituents have the definitions disclosed in this description. Ζ ⁰ may be heteroatoms such as 8, O, N, and others. The preparation of this subclass of pyridone analogues is illustrated by the synthesis example of Example 28, as briefly presented in Scheme 7.

FIG. 3

-26005367

(EX-28A) A commercially available compound, 2-amino-3-nitro-6-chloropyridine, is reacted with one equivalent of phenylthiol in the presence of sodium carbonate in DMF at 80 ° C. After completion of the reaction, the reaction mixture is mixed with water. Filtration gives the crude product EX-28A, which can be purified by recrystallization from methanol.

(EX-28B) Compound EX-28A was dissolved in 12n. Both ₂ 8O ₄ and the solution are treated with an aqueous solution of NaO3 (3 equiv.) Initially at 0 ° C, then at 100 ° C. When diluted with water, the product precipitates. Filtration and washing with water and ether give the crude product EX-23B, which can be further purified by recrystallization from ethanol.

(EX-28C) Compound EX-28B is successively mixed with one equivalent of sodium hydride in DMF and one equivalent of methyl bromoacetate. After stirring at ambient temperature for 12 hours, the reaction mixture was treated in accordance with a conventional method. The EX-28C product was purified by silica gel column chromatography.

(ΕΧ-28Ό) Compound EX-28C was dissolved in methanol in the presence of 5% equivalent of 10% Pb / C. The mixture is stirred in an atmosphere of hydrogen (ambient pressure) for half an hour. After filtering and removing the solvent, compound ΕΧ-28Ό was obtained as a pure product.

The compound of example 28 can be obtained from ΕΧ-28Ό in the same manner as described in the preparation of compounds EX-23E, ΕΧ-23Ρ, ΕΧ-236 and 23.

The compounds of formula (I) of the present invention having hydroxyl, thiol and amine functional groups can be converted into a large number of derivatives. Alternatively, the converted compounds of formula (I) can be prepared by initially converting one or more intermediates in the preparation processes before converting the converted intermediates into compounds of formula (I). The alcohol or phenolic hydroxyl group can easily be converted into esters of carboxylic, sulfonic, carbamic, phosphonic and phosphoric acids. The acylation with carboxylic acid ester formation is easily carried out using a suitable acylating reagent such as aliphatic acid anhydride or acid chloride. The corresponding anhydrides and acid chlorides of aryl and heteroaryl acids can also be used. Such reactions are usually carried out using an amine catalyst, such as pyridine, in an inert solvent. Similarly, carbamic acid esters (urethanes) can be prepared by reacting a hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate and phosphate esters can be prepared using the appropriate acid chloride and similar reagents. Compounds of formula (I) that have at least one thiol group present can be converted to the corresponding thioester derivatives, similar to derivatives of alcohols and phenols, using the same reagents and comparable reaction conditions. Compounds of formula (I) having at least one primary or secondary amino group can be converted to the corresponding amide derivatives. Carboxylic acid amides can be prepared using a suitable acid chloride or acid hydride under reaction conditions similar to those used with alcohols and phenols. The ureas of the corresponding primary or secondary amine can be prepared using isocyanates and carbamoyl chlorides directly in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of an aqueous solution of sodium hydroxide or a tertiary amine. Suitable methods and methods for obtaining these derivatives can be found in Yoike'k Mobegpp 8Up (Hs11s Keasyopu A.L. Wei) at1p, ys., 811ppsg, Rivop, and Site at Tys 8y51etais [Nep (1Psa (1op o £ Ogdats Sotroipbk, 5 ' ¹ ' BISHOP, 1O1t Ayu & 8op§ and Rkeg apb Rkeg in Keadepiy og Ogdats 8up! E518, Uo1ite 1, 1oyp Abeu & 8opv A large number of reagents that can be used to convert hydroxyls, thiols and amines in the compounds of formula (I) available from commercial sources or from the references cited above, which are incorporated herein by reference.

The compounds of formula (I) of the present invention having hydroxyl, thiol and amine functional groups can be alkylated to produce a large number of derivatives. Alternatively, alkylated compounds of formula (I) can be prepared by first alkylating one or more intermediates in a preparation process before converting the alkyl derivative to compounds of formula (I). Hydroxyl

The 27005367 group of compounds of formula (I) can easily be converted to ethers. Alkylation with the formation of ether is easily carried out using a suitable alkylating reagent, such as alkyl bromide, alkyl iodide or alkyl sulfonate. Suitable aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl and heteroaralkyloxyalkyl bromides, iodides and sulfonates may also be used. Such reactions are usually carried out using an alkoxide-forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide and n-butyl lithium, using an inert polar solvent such as DMF, DMSO, THF, and suitable comparable solvents, an amine catalyst, such as pyridine, in an inert solvent.

Compounds of formula (I) that have at least one thiol group can be converted to the corresponding thioether derivatives, similar to derivatives of alcohols and phenols, using the same reagents and comparable reaction conditions. Compounds of formula (I) having at least one primary, secondary or tertiary amino group can be converted to the corresponding secondary, tertiary or quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using suitable bromides, iodides and sulfonates, similar to those used in reactions with alcohols and phenols. Conditions include the interaction of an amine when it is heated with an alkylating reagent taken in stoichiometric amounts relative to the amine (i.e., one equivalent with a tertiary amine, two with a secondary and three with a primary). With primary and secondary amines, two and one equivalent, respectively, of an acid acceptor are used simultaneously. Secondary and tertiary amines can be obtained from the corresponding primary or secondary amines. The primary amine can be double-alkylated by reductive amination using an aldehyde such as formaldehyde and sodium cyanoborohydride in the presence of glacial acetic acid. Primary amino can be monoalkylated by initially protecting the amine with an easily cleavable protecting group such as trifluoroacetyl. An alkylating agent such as dimethyl sulfate in the presence of a non-nucleophilic base such as Barton's base (2-tert-butyl-1,1,3,3-tetramethylguanidine) gives a monomethylated protected amine. Removal of the protecting group using aqueous potassium hydroxide affords the desired monoalkylated amine. Additional suitable methods and methods for the preparation of such derivatives can be found in Noike'k Mobegpp 8up1BeBs KeasBopk, A.A. Veshchatsh, Bchs., 8Bppeg, Rivop, and Siegip in TBe 8u5! ^4b Ebayup, 1oBp Ayeu & 8op§ and Rieg apb Rieg in Redep Gog Ogdashs 8up1Be515, published by 1oBp Ayeu & 8op§. Perfluoroalkyl derivatives can be prepared as described in BekMapeai, 1.Cbet.8os. Cbet. Sottip, 2241 (1998). A large number of reagents that can be used to convert hydroxyls, thiols, and amines in the compounds of formula (I) are available from commercial sources or from the references cited above, which are incorporated herein by reference.

Biological Activity Assays

TR-MPa analysis

In this assay, 100 nM recombinant soluble tissue factor and 2 nM recombinant human UPA factor are added to a 96-well assay plate containing 0.4 mM substrate, Y-methylsulfonyl-O-rBe-d1y-agd-p-nitroaniline, and either an inhibitor, or buffer (5 mM CaCl ₂ , 50 mM TG18-HC1, pH 8.0, 100 mM BaCl, 0.1%> BSA). Measure the reaction mixture immediately in a final volume of 100 μl at 405 nm to determine background absorption. The plate is incubated at room temperature for 60 minutes, at this stage, the rate of substrate hydrolysis is measured by monitoring the reaction of p-nitroaniline release at 405 nm. The percentage inhibition of TP-UPa activity is calculated from the OD value of _405nm for the experimental and control samples.

Ha analysis

0.3 nM human factor Xa and 0.15 mM β-α-benzyloxycarbonyl-E-argenyl-L-glycyl-L-arginine-p-nitroaniline dihydrochloride were added to a 96-well assay plate containing either an inhibitor or a buffer (50 mM Thu- HC1, pH 8.0, 100 mM No. C1, 0, 1%> BSA). The reaction in a final volume of 100 μl was measured immediately at 405 nm to determine the background absorption. The plate is incubated at room temperature for 60 minutes, at this stage, the rate of substrate hydrolysis is measured by monitoring the reaction of p-nitroaniline release at 405 nm. The percent inhibition of Xa activity is calculated from an OD value of _405nm for the experimental and control samples.

Thrombin analysis

0.28 nM human thrombin and 0.06 mM N-Phenylalanyl-P-pipecolyl-L-arginine-nitroaniline dihydrochloride was added to a 96-well assay plate containing either an inhibitor or a buffer (50 mM TG18-HCl, pH 8.0, 100 mM No. C1, 0.1% BSA). The reaction in a final volume of 100 μl was measured immediately at 405 nm to determine the background absorption. The plate is incubated at room temperature for 60 minutes, at this stage, the rate of substrate hydrolysis is measured by monitoring the reaction of p-nitroaniline release at 405 nm. The percent inhibition of thrombin activity is calculated from the OD405nm value for the experimental and control samples.

-28005367

Trypsin analysis of μg / ml trypsin type IX from pork pancreas and 0.375 mM Ν-α-benzoyl-L-arginine-nitroaniline (L-ΒΑΡΝΑ) was added to a 96-well assay plate containing either an inhibitor or a buffer (50 mM TP5-HC1, pH 8.0, 100 mM No. C1, 0.1% BSA). The reaction in a final volume of 100 μl was measured immediately at 405 nm to determine the background absorption. The plate is incubated at room temperature for 60 minutes, at this stage, the rate of substrate hydrolysis is measured by monitoring the reaction of p-nitroaniline release at 405 nm. The percent inhibition of thrombin activity is calculated from an OD value of _405nm for the experimental and control samples.

Recombinant soluble TB, consisting of amino acids 1-219 of the mature protein sequence, was expressed in E. coB and purified using liquid rapid chromatography of proteins on mono-0 8 spacer. Recombinant human UPA was purchased at Lshepsap O | adpo511sa. Sgheetuyu N ST and No. methylsulfonyl-E-rye-d1u-agd-p-nitroaniline were obtained in Lshepsap Rorbbe Sotrapu, 1 ps., 8ppuaua, CA. Factor Xa was obtained from Ephute VekeaggsBaogaUpeh, 8op1b Vepb ΙΝ, thrombin from Ca1Bosbet, ba 1o11a, CA and trypsin, and b ΒΑΡΝΑ from 81dta, 81. Bosh5 MO. Chromogenic substrates 8-2765 and 82238 were purchased from Sygotodesh, 8 \ ye6ep.

The biological activity of the compounds of examples 1-22, determined by bioanalysis methods, is summarized in table. one.

Table 1. The inhibitory activity of pyridones against factor XA, TB-UPa, thrombin II and trypsin II. ____________________________________________________________

Example Number ΤΓ-νΐΙΑ 1С50 (μM) Thrombin II 1C50 (μM) Factor ha 1C50 (μM) Trypsin II 1C50 (μM) one 4, 6 0.7 0.07 0.21 2 46 5.5 7.7 0.5 3 26.1 11.0 > 30 0.86 4 > 30 22, 7 23.1 0.48 5 40% 40% 27% - 6 > 30 > 30 > 30 > 30 7 > 30 > 30 > 30 > 30 8 > 30 > 30 > 30 > 30 nine > 30 > 30 > 30 > 30 10 > 30 > 30 > 30 > 30 eleven > 30 > 30 > 30 > 30 12 > 30 > 30 > 30 > 30 thirteen > 30 > 30 > 30 > 30 14 > 30 > 30 > 30 > 30 fifteen > 30 > 30 > 30 > 30 sixteen > 30 > 30 > 30 > 30 17 eleven 0.2 oh 1 0.3 eighteen 0, 8 <0.04 <4.0 0.2 nineteen 18, 0 0.4 4.1 <0.1 twenty 23.0 0.3 5.7 0.5 21 > 30 0.5 17 0, 6 22 > 30 <0.04 > 0 11.1

CLAIM

Claims (28)

CLAIM 1. The compound having the formula to ¹ about or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl; A is selected from the group consisting of a single covalent bond, - (CH2) p-, where n is an integer from 1 to 5, -8O2- and -C (O) -; In ¹ and X ⁰ represent hydrogen; -29005367 K ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or K ² together with K ¹ forms quinoline; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents —C (O) OH —, —ΝΗ—, or —8Ο ₂ ΝΗ - and Υ ⁰ represents benzyl, optionally substituted by an amidino or guanidino group, or C ₁ -C ₆ alkyl, optionally substituted by one or more substituent (s), which (s) are selected from the group consisting of guanidino, oxo (= O), 5- a heteroaryl member containing 1 or 2 heteroatoms selected from Ν, O and 8. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is phenyl; And choose from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -8O ₂ - and -C (O) -; K ¹ and X ⁰ represent hydrogen; K ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or K ² together with K ¹ forms quinoline; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents —C (O) OH —, —KH—, or —8O ₂ OH — and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein B is phenyl; A is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2; K ¹ and X ⁰ represent hydrogen; K ² represents phenyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents —C (O) OH —— —I— or —8O ₂ KH— and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is phenyl; A is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2; K ¹ and X ⁰ represent hydrogen; K ² represents phenyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents —C (O) LH—, —Ν4— or —8O ₂ KH— and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 5. The compound according to claim 1 K ¹ where K ² represents 3-aminophenyl, B represents phenyl, A represents CH ₂ , Υ ⁰ represents 4 amidinobenzyl, K ¹ represents hydrogen and X ⁰ represents hydrogen; K ² represents 3-methylphenyl, B represents phenyl, A represents CH ₂ CH ₂ , Υ ⁰ represents 4 amidinobenzyl, K ¹ represents hydrogen and X ⁰ represents hydrogen; K ² represents phenyl, B represents phenyl, A represents CH 2, Υ ⁰ represents 4 amidinobenzyl, K ¹ represents hydrogen and X ⁰ represents hydrogen. 6. The compound according to claim 1 or its pharmaceutically acceptable salt, where B is selected from C ₁ -C ₆ alkyl; And choose from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -8O ₂ - and -C (O) -; K ¹ and X ⁰ represent hydrogen; K ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or K ² together with K ¹ forms quinoline; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; -30005367 E ⁰ represents -C ((')) \ 11-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from C ₁ -C ₆ alkyl; A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ ; In ¹ and X ⁰ represent hydrogen; B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents -C ((')) \ 11-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from C ₁ -C ₆ alkyl; A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ ; In ¹ and X ⁰ represent hydrogen; B ² represents phenyl or pyridyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents <(Ο) ΝΗ-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 9. The compound according to claim 1 of the formula K ¹ About where B ² is 5-amino-2-fluorophenyl, B is isopropyl, A is a single covalent bond, Υ ⁰ is 4-amidinobenzyl, B ¹ is hydrogen, and X ⁰ is hydrogen ^; ₂ B ² represents 2-methyl-2-aminophenyl, B represents isopropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents ethyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents isopropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents 2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents (B) -2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents (8) -2-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents 3-pentyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents ethyl, A represents CH ₂ , Υ ⁰ represents 4 amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents 2-methylpropyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents 2-propyl, A represents CH ₂ CH ₂ , Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents propyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents tert-butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-aminophenyl, B represents butyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen; B ² represents 3-carboxyphenyl, B represents 2-propyl, A represents a single covalent bond, Υ ⁰ represents 4-amidinobenzyl, B ¹ represents hydrogen and X ⁰ represents hydrogen. 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from C3-C6 cycloalkyl; -31005367 And choose from the group consisting of a single covalent bond, - (CH ₂ ) _P -, where η represents an integer from 1 to 5, -8Ο ₂ - and -C (O) -; In ¹ and X ⁰ represent hydrogen; B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen, or B ² together with B ¹ forms quinoline; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents -Ο (Ο) ΝΗ-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein B is selected from C3-C6 cycloalkyl; A is selected from the group consisting of a single covalent bond, CH2, CH2CH2, CH2CH2CH2; In ¹ and X ⁰ represent hydrogen; B ² represents phenyl, pyridyl or thienyl optionally substituted with one or more substituent (s) which is selected from the group consisting of amino, carboxyl, C ₁ -C ₃ alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents -Ο (Ο) ΝΗ-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein B is selected from C3-C6 cycloalkyl; A is selected from the group consisting of a single covalent bond, CH2, CH2CH2, CH2CH2CH2; In ¹ and X ⁰ represent hydrogen; B ² represents phenyl or pyridyl optionally substituted with one or more substituent (s), which is selected from the group consisting of amino, carboxyl, C1-C3 alkyl, amidocarbonyl, hydroxy, carboxamido and halogen; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents -Ο (Ο) ΝΗ-, -ΝΗ- or -8Ο ₂ ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino or guanidino group. 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B is phenyl; A is selected from the group consisting of - (CH ₂ ) _P -, where η represents an integer from 1 to 5, and -8Ο ₂ -; X ⁰ represents hydrogen; In ² together with B ¹ forms quinoline; K represents - (CH ₂ ) _t -, where t represents an integer from 1 to 3; E ⁰ represents -Ο (Ο) ΝΗ- and Υ ⁰ represents benzyl optionally substituted with an amidino or guanidino group, or C ₆ -C ₆ alkyl optionally substituted with one or more substituent (s), which (s) are selected from the group consisting of guanidino, oxo (= Ο), 5- member heteroaryl containing 1 or 2 heteroatoms selected from Ν, Ο and 8. 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein B is phenyl; A represents CH ₂ CH ₂ or -8Ο ₂ -; X ⁰ represents hydrogen; In ² together with B ¹ forms quinoline; K represents CH2; E ⁰ represents -Ο (Ο) ΝΗ- and Υ ⁰ is benzyl optionally substituted with an amidino group, or C ₅ alkyl substituted with an oxo group, guanidino group and thiazolyl. 15. The compound according to 14 of one of the formulas n Ν ΝΗ ₂ ΝΗ -32005367 ΝΗ ΝΗ OR or a pharmaceutically acceptable salt thereof. 16. A composition that inhibits thrombotic blood diseases, comprising a compound according to any one of claims 6 to 8 and a pharmaceutically acceptable carrier. 17. A thrombotic blood disease inhibitory composition comprising a compound according to any one of claims 13-15 and a pharmaceutically acceptable carrier. 18. A method of inhibiting a thrombotic blood disease, comprising adding to the blood a therapeutically effective amount of a composition according to any one of claims 16 and 17. 19. A method of inhibiting the formation of aggregates of blood platelets, comprising adding to the blood a therapeutically effective amount of a composition according to any one of claims 16 and 17. 20. A method of inhibiting the formation of a blood clot in the blood, comprising adding to the blood a therapeutically effective amount of a composition according to any one of claims 16 and 17. 21. A method for the treatment or prevention of venous thromboembolism and pulmonary embolism in a mammal, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of claims 16 and 17. 22. A method of treating or preventing deep vein thrombosis in a mammal, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of claims 16 and 17. 23. A method of treating or preventing cardiogenic thromboembolism in a mammal, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of paragraphs 16 and 17. 24. A method of treating or preventing thromboembolic stroke in humans and other mammals, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of paragraphs 16 and 17. 25. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy for humans and other mammals, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of claims 16 and 17. 26. A method of treating or preventing unstable angina in humans and other mammals, comprising administering to the mammal a therapeutically effective amount of a composition according to any one of paragraphs 16 and 17. 27. A method of inhibiting the formation of a blood clot in the blood, comprising adding to the blood a therapeutically effective amount of a compound according to any one of claims 1 to 15, together with a therapeutically effective amount of a fibrinogen receptor antagonist. 28. The use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing thrombus formation, treating thrombus formation or preventing thrombus formation in a mammal.